Rhythm is essential: Unraveling the relation between the circadian clock and cancer

Abstract

Physiological processes such as the sleep-wake cycle, metabolism, hormone secretion, neurotransmitter release, sensory capabilities, and a variety of behaviors, including sleep, are controlled by a circadian rhythm adapted to 24-hour day-night periodicity. Disruption of circadian rhythm may lead to the risks of numerous diseases, including cancers. Several epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer. On the contrary, oncogenic processes may suppress the homeostatic balance imposed by the circadian clock. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, and the pharmacological modulation of core clock genes is a new approach in cancer therapy. This review highlights the role of the circadian clock in tumorigenesis, how clock disruption alters the tumor microenvironment, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.

1. Introduction

Circadian rhythms (CR) are ~24-hour biological rhythms controlled by an endogenous clock intended to align biological processes with daily environmental cycles (e.g., light) and metabolism (e.g., food intake) (Lee et al., 2021). A supervisory clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus receives light input to entrain the clock to the 24-hour day, and through a combination of autonomic, behavioral, and metabolic cues, synchronizes peripheral clocks, present in virtually every tissue across the body to the right time of the day (Albrecht, 2012). The circadian clock keeps time through a molecular oscillator composed of core clock genes and proteins that form a transcription-translation feedback loop (TTFL) (Koronowski and Sassone-Corsi, 2021). Temporal circuits govern various physiological processes within the body, including sleep/wake cycles, energy utilization, endocrine and immunological responses, and cell proliferation.

Understanding circadian dysfunction and its health impacts requires defining key concepts: Entrainment, the alignment of the circadian clock with environmental cues (e.g., light-dark cycles), ensures synchronization of physiological processes with external rhythms (Duffy and Czeisler, 2009; Duffy and Wright, 2005). Free-running describes the endogenous circadian rhythm in the absence of external cues, often revealing a natural period slightly deviating from 24 hours. Zeitgebers (e.g., light, food, temperature) are external stimuli that reset and synchronize the circadian clock. These concepts are fundamental to understanding the maintenance, disruption, and misalignment of circadian rhythms and their links to health and disease (Kondratova and Kondratov, 2012).

Thus, it is not surprising that defects in the circadian clock that disrupt the timing of these processes are associated with various diseases, including diabetes and cancer (Zimmet et al. 2019). In addition, disruption of circadian clock components alters the expression and activity of tumor suppressors and oncogenes that can lead to an immunosuppressive state that promotes the growth and spread of cancers (Aiello et al. 2020; Zhou et al. 2018; Jiang et al. 2020; Xiang et al. 2018). A growing body of evidence supports targeting the circadian clock in cancer mitigation and treatment (Zhu et al., 2024) by improving rhythms and optimizing the timing of medication (also known as “chronotherapy”) according to the tumor or host circadian rhythms. Chronotherapy aims to maximize efficacy against tumor cells while minimizing adverse effects on normal cells. The molecular mechanisms connecting core oscillator proteins and cancer are still being studied (Qu, 2023); however, several questions remain unanswered. It is not entirely clear, for instance, whether clock proteins work independently to give cancer cells an advantage or a disadvantage, or whether they have mutually reinforced effects on components that promote or inhibit the growth of tumors.

Three main strategies—sleep, diet, and drug timing (chronotherapy)—have emerged from scientific inquiries connecting circadian rhythms with preventing and managing diseases, including cancer. Exercise has also been identified as a critical intervention for improving sleep quality and circadian rhythm regulation in cancer survivors. Meta-analytic findings indicate significant improvements in outcomes such as the Pittsburgh Sleep Quality Index (PSQI), wake after sleep onset (WASO), and salivary cortisol levels with exercise interventions, though these effects are most evident for specific exercise modalities and select outcomes. Given the established benefits of physical activity across multiple domains of cancer survivorship—encompassing enhanced mood, reduced fatigue, improved physical function, and optimized immune regulation—regular engagement in exercise remains an essential component of survivorship care. Encouraging cancer survivors to incorporate preferred forms of exercise into their weekly routines may facilitate adherence and yield broad physiological and psychological benefits, including the mitigation of sleep and circadian disturbances (Gururaj et al. 2024).

From the perspective of circadian rhythms, regular sleeping and eating involve aligning behaviors with the body’s internal clock, primarily governed by the SCN. Light is the master synchronizer, while secondary cues like meal timing and sleep patterns (zeitgebers) entrain peripheral clocks. Misalignments, such as late or nighttime eating, disrupt metabolic processes, including energy expenditure, hormone regulation (ghrelin, leptin), and substrate utilization. This desynchronization may lead to adverse effects like obesity, type 2 diabetes, and metabolic syndrome (Boege et al., 2021). In addition, D’cunha et al. (2023) illustrated in a systematic review how disruption in sleep patterns and eating behaviors impacted metabolic (glucose, insulin) and inflammatory (C-reactive protein) markers that, in turn, have implications in breast cancer progression (D’Cunha et al. 2023). In contrast, maintaining a healthy circadian rhythm through regular eating and sleeping habits may considerably lower the risk of developing cancer (Boege et al., 2021; D’Cunha et al. 2023). Three main strategies for circadian medicine proposed by Sulli et al. (2019) include: (a) training the clock, (b) drugging the clock, and (c) clocking the drug (Sulli et al., 2019). In this review, we discuss these interactions and their ability to influence the growth and metastasis of tumor cells in the context of chronotherapy.

2. Mechanisms of circadian clock dysregulation in cancer

In mammals, the TTFL cycle begins with the production and activation during the day of the transcriptional activator heterodimer made up of the proteins Brain and muscle Arnt-like protein-1 (BMAL1) and Circadian locomotor output cycle kaput (CLOCK). BMAL1/CLOCK heterodimers bind to E-boxes in the promoters of cryptochrome (CRY1 and 2) and period (PER1, 2, and 3) to activate their expression (Dan et al., 2020). PER/CRY repressor complexes accumulate in the cytoplasm to be translocated into the nucleus to hinder their transcription by creating a negative feedback loop. The post-transcriptional modification regulates stability by binding to SCF (Skp1-Cullin-F-box protein) E3 ubiquitin ligase complexes. PER and CRY are phosphorylated by casein kinase 1ε/δ (CK1ε/δ) and AMP kinase (AMPK), respectively leading to poly-ubiquitination by the associated E3 ubiquitin ligase complexes, which tag the proteins for eventual destruction by 26S proteasome complexes (Fagiani et al. 2022). Once in the nucleus, PER/CRY complexes bind to and inhibit BMAL1/CLOCK(Cao et al. 2021). Additionally, BMAL1 is controlled through an auxiliary feedback loop involving two of its transcriptional targets, REV-ERBα/β (negative feedback loop/repressor) and RORα (positive feedback loop/activator) (Guillaumond et al. 2005). REV-ERBα/β inhibits, while RORα activates BMAL1 expression. These intertwined autoregulatory feedback loops trigger robust molecular oscillations in the level and activity of BMAL1 over the 24-hour day (Fig. 1). BMAL1 knockout in mice results in a complete loss of rhythmicity, altered activity patterns, impaired gluconeogenesis, premature aging, reduced lifespan, and lower body weight (Bunger et al., 2000; Kondratov et al. 2006; Rudic et al. 2004). Interestingly, re-expression of Bmal1 in the brain of Bmal1-null mice restores behavioral circadian rhythms but not activity levels or body weight, while re-expression in skeletal muscle normalizes activity levels and body weight but fails to restore rhythmic behavior (McDearmon et al. 2006). These findings highlight the distinct tissue-specific roles of BMAL1 in regulating circadian and physiological functions. In addition to the core regulatory loops, the molecular oscillator is controlled by numerous epigenetic, post-transcriptional, and post-translational regulators involving kinases and phosphatases, ubiquitin–protease pathway components, nuclear-cytoplasmic transporters, non-coding RNAs, and chromatin remodelers (Chaix et al., 2016). The same set of clock genes is responsible for the central and peripheral clocks coordinating the rhythmic expression of nearly half of the mammalian genome (Takahashi et al., 2008; Yoo et al., 2004).

Fig. 1.

Circadian rhythm and the mechanisms behind the clock system. A. Central and peripheral clocks can be triggered by activity and a feeding regimen. Circadian rhythms regulate hormone regulation, thermogenesis, immunity, metabolism, reproduction, fat storage, and stem cell formation. (Construct influenced by Pérez-Villa et al. (2023) B. The mammalian circadian clock is formed by interlocked TTFLs. The BMAL1/CLOCK heterodimer binds to E-box promoters, to enhance expression of CCGs, their negative regulators, CRY1/2, PER1/2, and REV-ERBα/β, and positive regulators, RORα/β/γ. The heterodimers of PER/CRY are translocated to the nucleus to give negative feedback by blocking BMAL1/CLOCK mediated transcription.

Previous studies offer an ambiguous picture of possible links between the circadian clock system, the early stages of development, and cancer (Weger et al. 2017; Sun et al. 2018; Aiello and Stanger, 2016). Volt et al. (2016) shed light on the impact of a circadian rhythm-related gene CLOCK on embryonic development. The differentiation patterns of wild-type or CLOCK-deleted embryonic stem cells (ESCs) in vitro were similar (Volt et al. 2016). However, CLOCK-null ESCs failed to induce rhythmicity in peripheral tissues and instead showed faster spontaneous differentiation, reduced growth with a delayed cell cycle, and increased cell death rate (Volt et al. 2016). Furthermore, other links were discovered between additional genes associated with clocks, including CRY1 and PER3, and the processes of differentiation and stemness. These connections were mediated through the WNT/β-Catenin signaling pathway (Sun et al. 2018; Li et al. 2021). Taken together, this suggests that CLOCK is necessary to maintain stemness, cell division, apoptosis, and activity of stem cells. Links between the circadian clock and cancer are widespread. (i) The circadian clock directly or indirectly controls the expression of thousands of genes in diverse cell types, which drives rhythms in fundamental cellular processes, including metabolism, redox regulation, cellular secretion, DNA damage repair, autophagy, and protein localization. When rhythms in these cellular processes are altered, tissue homeostasis is lost, and tumorigenesis is induced through metabolic reprogramming, redox imbalance, and chronic inflammation (Lee et al. 2019; Van Dycke et al. 2015; Aiello et al. 2020). (ii) Clock proteins, upon dysregulation of the circadian clock, may protect against or promote cancer when they physically interact with the hallmarks of cancer (Li, 2019). (iii) The interactions between clock components and their target proteins depend on microenvironmental alterations (Sulli, Lam, and Panda, 2019). Alterations in the redox state of the cellular microenvironment adversely interfere with BMAL1/CLOCK binding to DNA (Rutter et al. 2001) and alter the activities of the NAD+-dependent histone deacetylase (HDAC) SIRT1 (Volt et al. 2016). SIRT1 deacetylates and destabilizes PER2 thus, loss-of-SIRT1-mediated circadian control results in the accumulation of PER2 and locking of the TTFL in the repressive state (Asher et al. 2008). Among the other sirtuins, SIRT6 is especially linked with metabolic regulation (Xiao et al. 2010); it constitutively localizes to chromatin and interacts with BMAL1 to modulate the expression of clock-controlled genes (CCGs) by local chromatin remodeling (Sun et al. 2019). The loss of SIRT6 also causes the accumulation of PER2, dysregulating the CR (Sun et al. 2019). (iv) Entrainment of peripheral clocks with the master clock in the SCN requires paracrine and endocrine functions (Li et al. 2023). Circadian clocks in peripheral organs may be disrupted by tumors that release excessive levels of cytokines or other hormones crucial to circadian clocks. To decipher the specific roles of the clock components, gene modification has been used extensively in the last decade.

Global knockout models of circadian clock components have significantly advanced our understanding of their role in physiology but face limitations in cancer research. These models obscure tissue-specific functions of clock genes, as their uniform deletion affects all tissues and disrupts distinct local regulatory mechanisms (Koronowski and Sassone-Corsi, 2021). Additionally, developmental compensations and systemic effects, such as early aging and reduced lifespan, complicate the interpretation of their direct involvement in cancer-related pathways (Yang et al. 2016). The complete loss of rhythmicity also eliminates the baseline necessary for studying subtle circadian misalignments relevant to tumorigenesis (Sahar and Sassone-Corsi, 2009). To address these challenges, tissue-specific and inducible knockouts offer a more refined approach, allowing precise investigation of clock components in cancer development and progression (Zhang et al. 2014).

Tissue-specific knockout studies of BMAL1 reveal its critical roles in regulating local metabolic functions. For example, pancreatic β cell-specific deletion impairs glucose tolerance and insulin secretion, which are critical metabolic dysfunctions potentially linked to cancer progression, without affecting systemic circadian rhythms. Liver-specific knockout increases lipid accumulation, adipocyte-specific deletion leads to obesity through reduced energy expenditure, and cardiomyocyte-specific deletion causes dilated cardiomyopathy and early mortality (Marcheva et al. 2010; Pan, Bradfield, and Hussain, 2016; Jacobi et al. 2015; Paschos et al. 2012; Durgan et al. 2011; Young et al. 2014). Additionally, skeletal muscle-specific knockout disrupts glucose metabolism, while macrophage-specific knockout impairs mitochondrial function and increases reactive oxygen species production, underscoring the dual role of BMAL1 in maintaining circadian rhythms and tissue-specific metabolic homeostasis (Harfmann et al. 2016; Dyar et al. 2014; Alexander et al. 2020). Not much research has been done to conclude the results of tissue-specific deletions of other clock genes. However, we have discussed in this review a few of the impacts observed following the knocking out or -down of BMAL1/-CLOCK/CRY1 in both in vivo and ex-vivo systems in a context-dependent manner.

3. The role of clock proteins in cancer

3.1. Disrupting the circadian clock: Gene-specific effects

Disruption of core clock genes in mice may promote tumorigenesis by impairing circadian rhythm (Sulli, Lam, and Panda, 2019). However, the effect of abnormal clock gene expression on tumor growth or inhibition is not consistently predicted.

For example, circadian clock genes can serve as prognostic bio-markers for certain cancers, such as gliomas where low PER expression has been associated with negative prognosis and enrichment of immune signaling pathways (De La Cruz Minyety et al., 2021) and colorectal cancer, where elevated expression of CRY1 is associated with lymph-node metastasis and poor overall survival (Yu et al. 2013). Alternatively, CRY2 inhibits breast cancer development; however, acetylation of CRY2 by P300 (a histone acetyltransferase; HAT) can negate this effect (Xia et al. 2023). The loss of core clock gene expression has been associated with a poorer prognosis in breast cancer, as shown in a study analyzing clock component expression in node-negative patients who received no neoadjuvant or adjuvant therapy (Cadenas et al. 2014). Clock gene expression alterations are often linked to oncogenic pathways, survival outcomes, tumor stage, and subtypes (Li, 2019; Ye et al. 2015; Tan et al. 2015).

High-level expression of CLOCK serves as an indicator of lung and ovarian cancer in cisplatin-resistant cells (Xu et al. 2018). In CD133⁺ lung cancer cells, where CLOCK protein levels are high, treatment with epigallocatechin-3-gallate (EGCG) has been reported to impair CLOCK expression. Consequently, this impedes the self-renewal ability of stem-like cells (Jiang et al. 2020). Furthermore, it was reported that BMAL1 overexpression allows for colorectal cancer sensitivity to oxaliplatin, and the downregulation or genetic deletion of BMAL1 drives tumor development (Ye et al. 2018), augments MYC-dependent glycolytic metabolism accelerating colorectal cancer (CRC) progression (Ye et al. 2018) and impacts response to anticancer drugs (Zeng et al. 2010).

3.2. BMAL1 and CLOCK: The positive arm of the core molecular clock

BMAL1 and CLOCK belong to the bHLH-PAS structural domain transcription factor family. BMAL1/CLOCK heterodimers bind to E-boxes in the promoters of genes, including the promoters of the core clock-negative elements PER and CRY, to control circadian rhythmicity (Marri et al. 2023). Deletion of Bmal1 is the only genetic alteration that results in the complete loss of rhythmicity in mice, primarily because its paralog Bmal2 is expressed at shallow levels across tissues (Yu and Weaver, 2011). BMAL1 suppresses tumorigenesis by regulating intestinal pathways, including Hippo signaling (Stokes et al. 2021) or through inhibition of invasion that is independent of p53 (Jung et al. 2013) or by competing with MYC for E-box binding sites in the genome (Altman et al. 2015). Silencing of BMAL1 expression by DNA hypermethylation of the promoter in hematologic cancer inhibits the binding of BMAL1/CLOCK proteins to target genes. This exacerbates disrupted circadian rhythms in cancer (Taniguchi et al. 2009).

Several studies showed that BMAL1 overexpression inhibits colorectal cancer (CRC) proliferation (Stokes et al. 2021) and forced expression of BMAL1 in HCC prevents Hepatocyte nuclear factor 4α (HNF4α)-positive tumor growth (Fekry et al. 2018). Patients with CRC, or Tongue Squamous Cell Carcinoma, exhibiting high levels of BMAL1, have better survival rates and improved treatment efficacy (Zeng et al. 2014). An examination of breast cancer datasets (Ramos et al. 2020) revealed that reduced BMAL1 expression in patients with triple-negative breast cancer (TNBC) was correlated with a poor prognosis. BMAL1 and CLOCK silencing have been linked to increased apoptosis in hepatocellular carcinoma (Qu et al. 2023), glioblastoma (Dong et al. 2019), and acute myeloid leukemia (AML) (Puram et al. 2016). In summary, while BMAL1/CLOCK is widely known as a tumor suppressor complex, its role in regulating cancer is dynamic, depending on the cancer type and the downstream targets influenced by their transcriptional activity in different cell types (Zhang et al. 2024; Lee, 2021; Li, 2019).

3.3. PER and CRY: The negative arm of the core molecular clock

Clock genes exhibit varying roles across different tumor environments, but negative circadian regulators function as tumor suppressors more frequently than those in the positive limb (Ye et al. 2018). It has been reported that the induction of apoptosis by PER1 in hepatocellular carcinoma causes differences in the expression of apoptosis-related molecules (Sato et al. 2009). A recent large-scale analysis of 32 human cancer types revealed that PERs and CRYs were downregulated in multiple cancers (Ye et al. 2018). Downregulation of Per1, Per2, and Cry1 in mouse models promotes tumor incidence and clonogenic ability of malignant cells in multiple cancers (Lee et al. 2010), including mammary carcinoma (Hua et al. 2006), acute myeloid leukemia (Gery et al. 2005), gastric cancer (Li et al. 2017), and lung cancer (Papagiannakopoulos et al. 2016). Overexpression of PER2, a tumor suppressor, has been observed in several cancer types, including Lewis lung carcinoma, where it induces apoptosis by upregulating the pro-apoptotic molecule BAX (Hua et al. 2006). Taken together, PER genes exhibit an overall tumor-suppressive role in these cases. In contrast, in a study of mouse strains with a p53 mutation (Ozturk et al. 2009), p53^−/− Cry1^−/− Cry2^−/− mice delayed the onset of cancer and extended the median lifespan of the p53 mutant mice by 1.5-fold, highlighting differing roles for the negative elements in cancer.

3.4. Disruption of circadian rhythms: Physiological factors

Disturbances in circadian rhythms are caused also by a range of physiological factors. These include aging (Hood and Amir, 2017; Chen et al. 2016), and environmental factors, such as shift work (Rajaratnam et al., 2013; Erren et al. 2019), and jet lag (Sack, 2010), all associated with cancer development (Fekry and Eckel-Mahan, 2022). However, the molecular mechanisms underlying the establishment of cancer hallmarks following circadian perturbations remain poorly understood.

Studies have demonstrated that mice with SCN ablation displayed an elevated incidence of tumor formation following subsequent exposure to tumor cells (Filipski and Lévi, 2009; Filipski et al. 2002). Environmental clock disruptions by constant light or jet lag exposure cause an increase in tumor growth (Papagiannakopoulos et al. 2016). In a study by Filipski et al. (2004), mouse strains with low levels of circulating melatonin exhibiting desynchronized chronic jet lag (CJL) showed accelerated tumor growth and shorter survival time than LD12:12 mice (Light/Dark; 12 hours of light followed by 12 hours of darkness) (Filipski et al. 2004). Therefore, mounting evidence from animal experiments, including the manipulation of LD cycles and the induction of genetic mutations that affect the length of circadian cycles, has provided important insights into the causal relationships between circadian desynchronization and malignancy.

4. Molecular mechanisms of clock-mediated oncogenes

Circadian clocks regulate daily rhythms in mRNA accumulation for at least 50 % of the mammalian genome (Li, 2019). These genes called clock-controlled genes (CCGs), are involved in diverse cellular and molecular processes (Liu et al. 2020). C-MYC (an oncogene); WEE1 (Ser/Thr family of protein kinases); p53 (a well-known tumor suppressor); and Cyclin D1 (a cell-cycle regulator), are just a few of the CCGs involved in cell-cycle regulation, DNA damage repair, cell proliferation, and apoptosis (Fig. 2) (Li, 2019). Alterations in the rhythmic expression of these CCGs provide a clear link between the circadian system and cancer (Qu et al. 2023).

Fig. 2.

Cell Cycle and the Circadian Clock. Clock-controlled genes with either ROR or E-box elements in their promoters bridge the biological clock to the cell cycle. This diagram demonstrates where clock-controlled genes and proteins may potentially interact with the cell cycle without going into depth about post-transcriptional outcomes and downstream cascades.

4.1. Circadian clock and cell cycle: The intersected biological circuit

The cell cycle and the circadian clock are tightly regulated processes that maintain cellular and physiological homeostasis (Masri et al., 2013). Cell-cycle progression involving G1, S, G2, and mitosis is controlled to ensure proper cell division and proliferation (Fig. 2). The circadian clock modulates cell-cycle regulators, as exemplified by the direct influence of the BMAL1/CLOCK heterodimer on the crucial cell-cycle gene Wee1 (Qu, 2023). Matsuo et al. (2003) reported that during the process of liver regeneration, there were significant differences in the expression of Wee1 and Cyclin-D in wild-type mice compared to Cry-deficient mice. While the latter showed decreased expression, Wee1 showed enhanced expression following partial hepatectomy between 32 – 72 hours (Matsuo et al. 2003). This study also reported that an increased transcript level of Per1 is observed when Wee1 expression increases, which is implicated in the G2-M transition (Matsuo et al. 2003). Similarly, another study showed the circadian effect on cell-cycle regulation following partial hepatectomy. They observed that the rhythmic oscillations of certain cell cycle regulators such as cyclin A2, cyclin B1, and p-Cdc2 were dampened following Bmal1 specific knockout in hepatocytes of regenerating livers (Jiang et al. 2021). Qu et al. (2023) showed that following Bmal1/Clock knockdown, there are increased levels of apoptosis and G2-M cell cycle arrest linked to Wee1 downregulation and p21 upregulation, respectively (Qu et al. 2023). The negative elements PER and CRY of the circadian clock are known to repress the activity of BMAL1/CLOCK, and alterations in PER protein expression perturb the circadian clock. In a study by Gery and colleagues (2006), they demonstrated that Per1 overexpression sensitizes colon cancer cells to DNA damage-induced apoptosis through interactions with the checkpoint proteins ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) (Gery et al. 2006).

p21 is a key regulator of the cell cycle, and its expression has been reported to be regulated by the circadian system through the inhibitory effect of ROR and REV-ERB. A study showed that the overexpression of p21 in Bmal^−/− primary hepatocytes decreases proliferation, highlighting the role of the circadian clock in G1 progression during liver cell proliferation (Grechez-Cassiau et al. 2008). Aiello et al. (2020) also reported that the cell cycle inhibitor p21 lost its rhythmic expression following circadian clock disruption in tumor-bearing mice, while CcnA2 expression was increased in these mice (Aiello et al. 2020). Furthermore, Kang and Leem (2014) demonstrated that Cry1 mediates clock-controlled ATR activation through temporal interactions with Timeless (Tim) , emphasizing the connection between circadian clock components and cell-cycle regulation (Kang and Leem, 2014). A study by Wang et al. (2021), showed that TIM, which has an important role in modulating clock-control genes affects the cell cycle. Specifically, they reported that by silencing TIM, glioma cells were arrested in the G0 phase, consequently inhibiting cell proliferation (Wang et al. 2021).

Cell cycle genes have also been reported to regulate the circadian clock (Gaucher et al., 2018). An example is the p53 gene which has been reported to bind to the Per2 promoter and causes the inhibition of BMAL1-CLOCK transcription (Gaucher et al., 2018). REV-ERB, which is a BMAL1 repressor has also been shown to be regulated by CDK1-mediated phosphorylation (Gaucher et al., 2018). Furthermore, another study reported that CDK1 was repressed in endothelial cells following BMAL1 knockout, this plays an important role in angiogenesis (Astone et al. 2023). Finally, the cell cycle and circadian clock overlap with common kinases such as CK1δ, GSK3β, and AMPK (Gaucher et al., 2018). An additional approach to understanding the overlap between the circadian clock and cell cycle was reported by a study where the authors determined that bidirectional coupling between both processes could allow for their co-existence, promoting coordination between these two complex processes (Yan and Goldbeter, 2019). The commonality between these two regulated processes could provide an avenue for the development of novel therapies for treating cancer.

4.2. Circadian clock and WNT/β-catenin pathway

The Wnt signaling pathway regulates cell proliferation, migration, differentiation, stem cell renewal, and genetic stability by controlling genes such as c-MYC, cyclin D1, and pyruvate dehydrogenase, which, when perturbed, could lead to cancer development and progression (Pai et al. 2017). This pathway regulates core clock proteins like BMAL1, CLOCK, and PER1/2, as downregulating β-catenin suppressed BMAL1, and its silencing disturbed the protein levels of CLOCK and PER1/2 in colon cancer (Eum et al. 2023). Another study showed that inactivating the Per2 gene increases β-catenin and cyclin D, leading to enhanced cell growth and polyp formation in the intestines and colon of mice. Reducing both β-catenin and PER2 prevents this increase in cell growth. In mice with the Per2 mutation, higher levels of beta-catenin and cyclin D are linked to the development of colon polyps (Wood et al. 2008).

Li et al. (2021) discovered a link between PER3 expression and reduced clonogenicity and tumorigenicity via the Wnt/β-catenin pathway. The study found that reduced PER3 expression led to enhanced BMAL1 expression and phosphorylation of β-catenin, activating the Wnt/β-catenin pathway (Li et al. 2021). Sun et al. (2018) shed light on the association of CRY1 and adipogenic differentiation. While normal CRY1 expression did not interfere with the differentiation process, knockdown of CRY1 hindered GSK3β expression thus upregulating the β-catenin pathway and inhibiting adipogenicity differentiation (Sun et al. 2018). Guo et al. (2012) first demonstrated that this adipogenesis pathway, governed by the downregulation of the β-catenin pathway, is regulated by BMAL1 (Guo et al. 2012). Overall, the clock proteins play an important role in cancer and cellular differentiation with significant involvement of the Wnt/β-catenin pathway.

4.3. Clock and c-Myc: The complex relationship in cancer

MYC, a member of the bHLH transcription factor family and primarily located in the nucleus, is crucial for regulating cell growth by suppressing the activity of specific cell-division inhibitors (Fig. 2), thereby repressing the growth-inhibitory effects of TGFβ. MYC disruption of the molecular clock is also known to influence metabolic reprogramming, chromatin state and accessibility, and immune infiltrate (Burchett et al., 2021). The interaction between MYC and the circadian clock is such that it causes the repression of BMAL1 by the upregulation of REV-ERBα (Altman et al. 2015). Altman and colleagues showed that MYC and N-MYC (responsible for the expression of genes, involved in ribosome biogenesis and protein synthesis) upregulated REV-ERBα, which hinders BMAL1 expression (Altman et al. 2015). This N-MYC-related effect on REV-ERBα is also a prediction of poor prognosis in neuroblastoma (Altman et al. 2015). Mutations in BMAL1 and CRY1/2 have different effects on c-MYC transcription, with the former upregulating c-MYC transcription and protein levels while the latter causing a downregulation (Liu et al. 2020). Liu et al. (2020) also reported that circadian clock controls c-MYC through an indirect pathway involving the core circadian clock-controlled gene β-catenin. This is supported by Huber et al. (2016), where the authors draw a connection between circadian rhythms and cancer prevention, suggesting that CRY2-driven degradation cycles of c-MYC are part of normal physiological processes. They highlighted that loss of CRY2 led to enhanced susceptibility to cancer, particularly because the absence of CRY2 allows for elevated levels of c-MYC, disrupting normal daily cycles of cell regulation. Data shows that CRY2 binds to phosphorylated MYC to promote its degradation. In CRY2 mutants, MYC is stabilized (Huber et al. 2016).

More updates were reported by the Altman group (2023) where they explained how the c-MYC oncoprotein altered clock gene expression, suppressing these rhythms. Their study hypothesized that c-MYC suppresses oscillations to upregulate biosynthetic pathways in a constant, non-oscillatory manner. Using RNA sequencing and metabolomics in cancer cells with inducible c-MYC activation, it was found that c-MYC disrupts over 85 % of oscillating genes, enhances ribosomal and mitochondrial biogenesis, and suppresses cell attachment pathways. c-MYC also increases nutrient transporter expression and disrupts metabolite oscillations, suggesting that it releases metabolic processes from circadian control to benefit cancer cells (Cazarin et al. 2023).

4.4. Crosstalk between circadian clock and metabolism

Metabolic reprogramming is one of the hallmarks of cancer and defines how metabolic pathways can be enhanced or inhibited by mutations resulting in tumorigenesis. Oncometabolites are metabolites that are increased in tumor cells (DeBerardinis and Chandel, 2016; Yong et al., 2020) and can serve as valuable prognostic tools for cancer. The clock controls daily rhythms in metabolic pathways, and metabolites can feedback to the clock to adjust its amplitude and phase (Zhang et al. 2015). Substantial evidence supports the relationship between the clock and metabolism, including alteration in clock function that affects glucose tolerance in adults and BMAL1 disruption in skeletal muscles upregulating hypoxia-inducible factor 1α (HIF1α), which, in turn, regulates circadian clock oscillation (Peek et al. 2017).

The timing of food intake is a powerful synchronizer of peripheral clocks, such as the liver, with metabolic cues like feeding and caloric content playing crucial roles in synchronizing these clocks (Gagliano et al. 2021). These nutrient-sensing pathways are essential for regulating the circadian expression of peripheral clocks, independent of SCN (Damiola et al. 2000; Hara et al. 2001). Chronic circadian disruption, often driven by modern lifestyle changes like social jet lag, is a major risk factor for hepatocellular carcinoma (HCC) (Kettner et al. 2016). Circadian misalignment induces non-alcoholic fatty liver disease (NAFLD), progressing to non-alcoholic steatohepatitis (NASH), fibrosis, and HCC. These conditions occur via persistent hepatic gene deregulation, oxidative stress, and metabolic reprogramming, mimicking patterns in night-shift workers. Mechanistically, bile acid dysregulation plays a central role. Elevated intrahepatic bile acids, coupled with deregulated nuclear receptors like FXR and CAR, drive NAFLD progression and oncogenic signaling. Circadian disruption also promotes sympathetic dysfunction and peripheral clock suppression, activating transcription factors such as AP1 and CREB, which sustain oncogenic pathways. Therapeutic strategies include restoring bile acid homeostasis through FXR agonists and CAR inverse agonists, alongside lifestyle changes to enhance circadian alignment (Kettner et al. 2016).

More recently, Padilla et al. (2024) also reported similar findings that chronic circadian disruption, modeled experimentally in mice through chronic jet lag (CJL), leads to metabolic dysfunction-associated steatotic liver disease (MASLD), which is a predominant causative factor for HCC (Padilla et al. 2024). Recent studies indicated that hepatocyte nuclear factor 4α (HNF4α), which regulates lipid and carbohydrate metabolism, nutrient storage, and tumor-promoting genes in the liver, has variable expression patterns for its different isoforms. Two HNF4α isoforms, "P1-HNF4α" and "P2-HNF4α," are regulated by the circadian clock in the liver. While the P1 isoform represses expression of tumor-promoting genes in a circadian manner and, therefore, acts as a tumor suppressor, the latter represses BMAL1 expression. The P2 isoform is overexpressed in HNF4α-positive hepatocellular carcinoma and deregulation of this isoform is also associated with colitis-induced colon cancer (Fekry et al. 2018).

The circadian clock regulates iron metabolism in colon tumors, promoting cancer growth and metastasis. Mouse studies show that tumor cells increase iron uptake to support DNA synthesis, with a 24-hour rhythm observed in iron-regulatory protein 2 (IRP2) levels in colon-26 tumors with a mutated Clock gene (Clock^Δ19; a Clock mutation with dominant negative activity intracellularly). Clock and Bmal1 genes drive Irp2 transcription, which in turn regulates transferrin receptor 1 (Tfr1) mRNA expression. Tumors with the Clock^Δ19 mutation exhibit reduced growth and diminished time-dependent iron fluctuations compared to wild-type tumors. These findings suggest that circadian rhythms promote cancer by regulating iron metabolism, highlighting a potential target for cancer prevention by disrupting this link(Okazaki et al. 2016).

A recent study by Liu et al. (2024) used CRC metastasis models to demonstrate that circadian disruption promotes metastasis by influencing immune cells in the TME, particularly myeloid-derived suppressor cells (MDSCs). Notably, gut microbiota and their metabolite taurocholic acid (TCA) play a crucial role in promoting MDSC accumulation and function. TCA enhances MDSC glycolysis through epigenetic changes and inhibits PDL1 degradation, linking the circadian clock, microbiota, and immune suppression in metastasis. This study connects circadian rhythms, gut microbiota, and immune suppression in the TME, revealing a mechanism driving CRC metastasis (Liu et al. 2024).

More recently, Peng et al. (2024) reported that CR disruption in sleep deficiency (SD) drives lung tumorigenesis via fatty acid oxidation (FAO). FAO senses CR disruption through increased palmitoyl-coenzyme A (PA-CoA) production by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-altered CLOCK hyperactivates ACSL1, producing PA-CoA, which promotes CLOCK S-palmitoylation and prevents its degradation, sustaining cancer stemness. The group also demonstrated that a timed β-endorphin resets Clock and Acsl1 expression, reducing SD-enhanced tumorigenesis, thereby highlighting β-endorphin as a potential chronotherapy for SD-related cancer (Peng et al. 2024).

In summary, all these reports show that CR disruption and ensuing metabolic cues play a significant part in the progression and prognosis of tumorigenesis, and they can also be utilized as potential strategy for chemotherapy.

4.5. Circadian clock and immune modulation

The tumor microenvironment (TME) comprises different cell types, including cancer cells, cancer-associated fibroblast, epithelial cells, and immune cells, which together play a vital role in tumor progression, metastasis, and drug resistance (Anderson and Simon, 2020). The immune response within the TME depends on the type of immune cells present. For instance, M1 macrophage and cytotoxic T cells promote antitumor responses. In contrast, M2 macrophages, regulatory T (Treg) cells, and myeloid-derived suppressor cells (MDSCs) lead to an immunosuppressive microenvironment (Aiello et al. 2020). There is growing evidence of the circadian control of some immune cells, such as macrophages and dendritic cells, which may provide avenues for improving immunotherapeutic approaches for treating cancer (Wang et al. 2024; Fortin et al. 2024). In a study that explored the impact of infusion time of certain immunotherapeutic drugs such as nivolumab, pembrolizumab, and ipilimumab on melanoma patients, the authors found that morning infusion had a more beneficial effect on women, older patients, and also patients with low tumor burden (Goncalves et al. 2023). Teixeira and colleagues demonstrated that Bmal1 and Per2 levels were disrupted in intraperitoneal macrophages isolated from doxorubicin (DOX)-treated mice when compared to untreated mice, implying a CR disruptive action of DOX in vivo (Teixeira et al. 2020). This effect was concomitant to NF-κB induction, which acted as a positive signal for anti-inflammatory IL10 transcription in the macrophages from tumor-bearing mice treated with DOX, and which related the anti-inflammatory effects of DOX to the high expression of Bmal1 and Rev-erbα (Teixeira et al. 2020). Another study found that PD-1 is diurnally expressed on tumor-associated macrophages (TAMs) in B16/BL6 melanoma mice, and BMS-1, a PD-1/PD-L1 inhibitor, is more effective when administered at the time of day when PD-1 is highly expressed on TAMs (Tsuruta et al. 2022). Several studies have reported that tumor growth in mice is more significant under jet lag conditions (Papagiannakopoulos et al. 2016; Hadadi et al. 2020). This could explain how increased tumor growth and misalignment of the macrophage internal clock can lead to alterations in the immune microenvironment (Aiello et al. 2020). Furthermore, a recent study demonstrated that dendritic cells have a circadian anti-tumor function that controls the tumor volume in melanoma (Wang et al. 2023). This finding indicates that circadian rhythms control anti-tumor immune components, which affect tumor size and provide novel therapeutic strategies for cancer treatment. More recently, Fortin et al. (2024) described the role of the circadian clock in modulating immunosuppression. They reported the rhythmic pattern of MDSCs in a colorectal cancer model and showed that a timed treatment with anti-PDLI treatment at the peak accumulation of MDSCs is more effective (Fortin et al. 2024). Altogether, circadian clock control of immune cell function provides an opportunity for timing the regulation of immunotherapy to increase efficacy.

4.6. Circulating tumor cells and the Circadian Clock: The time that controls metastasis

Circulating tumor cells (CTCs) are migrating cells with stem cell-like features that detach from primary tumors, intravasate into circulation, and disseminate at distant sites, leading to metastasis (Pantel and Speicher, 2016). An increase in CTC count is predictive of cancer progression with shorter overall survival, as observed in several cancer types, including prostate (Lorente et al. 2018), small-cell lung (Bendahl et al., 2023), and early and metastatic breast cancer (Muller et al. 2021). Similarly, an increase in the number and tightness of CTC clusters is associated with poor overall and progression-free survival (Paoletti et al. 2019), underscoring the importance of longitudinal sampling of CTCs for prognosis (Fig. 3).

Fig. 3.

Circadian rhythm controls the circulatory tumor cells. CTCs are cancer cells that detach from the primary tumor and travel through the bloodstream, potentially forming secondary tumors at distant sites. The initial portion of the image illustrates how CTCs infiltrate the bloodstream and establish secondary growths. It also demonstrates the heightened metastatic potential of CTCs during periods of rest and highlights the implications of studying CTCs and their synchronization with CR in cancer diagnosis, prognosis, and chronotherapy interventions.

Similarly, in the pursuit of optimizing personalized time-of-day treatment strategies, researchers have begun to investigate the role of the circadian clock in CTC dissemination. A recent study by Diamantopoulou et al. (2022) in mouse models and patients with breast cancer demonstrated that rest-phase CTCs are more metastatically competent than those of the active phase (Fig. 3), implying a higher tendency of these cells to spontaneously intravasate during sleep (i.e., resting phase) (4:00 a.m.), possibly due to key CR regulated growth factors. Given that CRs and sleep (i.e., resting phase) have a notable impact on the regulation of hormone secretion, it is plausible to hypothesize a correlation between these factors and time-dependent CTC behavior (Vaughn and Vaughn, 2023; Diamantopoulou et al., 2023). Various other studies revealed the rhythmic variations in CTC circulation dynamics (Zhu et al. 2021; Paiva et al. 2013) and their interactions with immune cells to facilitate cell cycle progression and influence metastasis (Szczerba et al. 2019; Diamantopoulou et al. 2022; Gu et al., 2024). Thus, circadian clock–regulated processes may influence CTC movement, offering the potential for chronotherapy.

5. Chronotherapy: Where timing meets therapy

Chronotherapy is a scientifically based treatment based on their 24-hour circadian rhythm to enhance the efficacy and tolerability of drugs administered at their maximum tolerated doses (Giacchetti et al. 2006). This approach capitalizes on the delivery of the chemotherapeutic agents at a time that is better adapted to treat the disease, leveraging the fact that numerous cellular and physiological processes targeted by these drugs are regulated by the circadian clock. This concept of leveraging the circadian clock in treating diseases is termed “circadian medicine”. It encompasses three concepts, which include (1) exploiting the clock; (2) targeting the clock, and; (3) detecting the clock. The use of circadian medicine although not very vast has been reported by several studies (de Assis and Kramer, 2024; Kramer et al. 2022; Panda, 2019).

A phase III trial of chronomodulated infusion of fluorouracil (FU), leucovorin, and oxaliplatin for 4 days (chronoFLO4), in comparison with conventional 2-day delivery of the same drug (FOLFOX2), did not show any difference in efficiency. The role of sex in the chronotherapeutic delivery of anticancer drugs was observed in a study by Innominato et al. (2020), where the adverse effect of neutropenia was mitigated when men were administered irinotecan in the morning compared to women, who showed a lower burden of neutropenia when administered in the afternoon (Innominato et al. 2020). A retrospective study by Catozzi et al. (2024) analyzed 361 patients with metastatic or advanced solid tumors treated with immune checkpoint blockers (ICB) to assess the impact of infusion timing on outcomes. Early morning Immune Checkpoint Blockade (ICB) administration was linked to improved survival and treatment response as the patients receiving ICBs at the best time of day had a 4.8-fold lower mortality risk compared to those treated at the worst time. Additionally, ICB toxicities were strongly timing-dependent in women, but not in men (Catozzi et al. 2024).

Recent research by Hill et al. (2020) presents a mathematical framework designed to analyze patient pharmacokinetics (PK) data accurately. The model was applied to chronomodulated administration of three cancer drugs—irinotecan, oxaliplatin, and 5-fluorouracil—via the Mélodie infusion pump to the patient’s hepatic artery. By leveraging the model, innovative infusion profiles were created to ensure precise drug delivery into the bloodstream by filling the gap between intended and actual drug exposure (Hill et al. 2020). Cisplatin-based chronotherapy has shown to reduce toxicity in patients with melanoma and NSCLC (Li et al. 2015; Dakup et al. 2018). More recently, Campian et al. (2022) showed the effect of timed delivery of temozolomide in patients with glioma; however, they faced the challenge of a small study cohort (Campian et al. 2022). Zhang et al. (2022) more recently used telemonitoring to analyze circadian rhythms and sleep patterns in nightshift (NS) and dayshift workers (DS). Key findings from tracked activity and temperature by wearable sensors, over a week, revealed that NS had poorer circadian rhythm stability (48 %) and sleep quality than DS (70 %), despite similar rest durations. Nightshift work and past exposure to night shifts were linked to worse rhythm stability and sleep quality, suggesting telemonitoring could identify workers at higher health risk for personalized prevention strategies (Zhang et al. 2022). Given the regulatory role of circadian rhythms in key cellular processes, understanding how their disruption influences cancer progression in the context of new hallmarks of cancer - phenotypic plasticity, cancer stem cells, epithelial-mesenchymal transition, and cellular senescence could enhance chronotherapy approaches (Zhou et al. 2024).

The interaction between radiotherapy and chronotherapy has been the subject of numerous reviews and studies, and it has been hypothesized that the ‘time-of-day’ affects the adverse side effects of radiation toxicity. A study by Chan et al. (2017) reported that the timing of radiation therapy affected patients differently. For patients with breast and cervical cancer, radiation worked better when administered in the morning. Prostate cancer patients treated in the evening experienced increased toxicities and biochemical failure i.e., disease recurrence. They explicitly stated that female patients who underwent radiotherapy between 11:01 a.m. and 2:00 p.m. had superior treatment tolerance (Chan et al. 2017). Taken together, these data reflect a need for well-designed clinical trials with well-defined times of treatment for different cohorts to determine the clinical relevance of chronoradiation therapy.

While we are progressing toward achieving precision medicine in the treatment of cancer, future trials need to consider an individual patient’s chronotype to match the appropriate ‘time-of-day’ for effective therapy. Chronotype, influenced by the circadian clock is defined as an individual’s natural preference for the timing of their daily activities such as the sleep-wake cycles (Starreveld et al. 2021). It determines whether an individual is a morning (owl) or evening person (lark) (Jones et al. 2019). Several studies have reported different factors that could affect chronotype, which include age, gender, and the environment (Pagani et al. 2011; Randler and Engelke, 2019). Other studies also looked at the impact of sleep and genetic variation on chronotype. A genome-wide study by Jones et al. (2019) identified 327 loci that are believed to have a function in circadian rhythm and sleep timing, which could be explored in patients’ that have disrupted rhythms and devastating health problems (Jones et al. 2019). A study by Starreveld et al. (2021) reported that cancer patients with severe fatigue experience circadian rhythm disruption and suggests that clinicians should pay more attention to patients’ sleep quality as they found that fatigue is more related to sleep quality than chronotype (Starreveld et al. 2021).

Although numerous studies have reported on the mechanism that governs circadian rhythms, there is still a lack of how to adapt these findings into translation medicine. CYCLOPS (cyclic ordering by periodic structure) developed by Anafi et al. (2017), is an algorithm that uses global descriptors of gene expression patterns to identify periodic oscillations in both human and mouse data. In this study, the researchers reconstructed molecular rhythms in human lungs and livers, and assessed circadian function in hepatocellular carcinoma samples using this method. Finally, they reported the effect of the dosing time of chemotherapeutic drug, streptozocin (Anafi et al. 2017). Another study by Talamanca et al. (2023) used an algorithm, CHIRAL, to determine circadian phases in human tissues using data from the Genotype-Tissue Expression (GTEx) project transcriptome. CHIRAL can assign donor internal phases (DIPs) and tissue internal phases (TIPs) by correlating circadian gene expression across tissues. Overall, this research study reported that molecular rhythms were sexually dimorphic, with females reporting more sustained rhythms that dampen with age (Talamanca et al., 2023). The knowledge of circadian biology and assessing these rhythms through chronotype can help achieve personalized medicine in the treatment of cancer.

6. Conclusion

CR plays a key role in the initiation and progression of cancer. In this review, we summarized studies that explored the influence of light- or dietary timing–mediated disruptions of biological oscillations on the development and progression of multiple cancers. Because core clock genes have a drastic impact on the stemness-related signaling pathway, CR is believed to have a considerable influence on the dissemination of tumor cells to distant sites. This role was elaborated by several clock-related gene interactions with the canonical Wnt signaling pathway and the subsequent enhancement of c-MYC expression. Moreover, the core clock gene, BMAL1, is consistently associated with altered cellular metabolism, causing the Warburg effect by affecting genes such as GLUT and HK (Hexokinase) in cancer cells. Another major clock-related gene, PER2, is closely associated with the cell-cycle protein cyclin D, which affects the proliferative potential of mammalian cells.

Nevertheless, the roles of oncometabolites in impeding tumor-promoting genes and initiating tumorigenesis under the influence of BMAL1 require further research. One of the promising strategies for monitoring tumor levels in prognosis is enumerating CTCs in the peripheral blood and identifying the periods of the day when CTC levels peak. Chronotherapy which looks at the timely delivery of drugs is a therapeutic strategy that needs to be well characterized. Further research is essential to untangle the complexities of individual circadian variabilities and establish chronotherapeutic avenues for prognostication and improved progression-free survival. Although there is evidence supporting the tumor-suppressing functions of specific clock-related genes and the tumor-promoting roles of others, the current understanding of studies related to circadian rhythms is insufficient to address fundamental questions regarding the interaction between core clock genes and the genetic changes that play a role in the development of cancer hallmarks. Nevertheless, developments in understanding the interactions between clock genes and tumor-associated genes will likely continue to lead to new approaches for cancer treatment and novel therapeutic strategies.

Biographies

Olajumoke Ogunlusi, B.Sc Cell Biology and Genetics (University of Lagos, Nigeria), and a Ph.D. Candidate in Biology (Texas A&M University, USA) with experience in cancer biology, circadian biology, and tumor microenvironment. Research focuses on the role of circadian rhythm disruption in aggressive mammary tumorigenesis.

Abantika Ghosh, MSc Immunology (University of Oxford), and a current Ph.D. student in Biology (Texas A&M University) has experience working on projects in immunology, microbiology, and cancer biology.

Mrinmoy Sarkar, Ph.D., served as a Postdoctoral Research Associate at Texas A&M University, specializing in cancer biology. His research focuses on therapeutic immuno-modulation within the tumor microenvironment.

Kayla Carter, B.Sc. in Microbiology (Mississippi State University), and a current Ph.D. student in Biology (Texas A&M University), has experience in cancer biology, cancer-associated fibroblasts, and the tumor microenvironment. Research focuses on the role of cancer-associated fibroblasts in tumor progression and drug response.

Harshini Davuluri, B.E. in Biotechnology from Vellore Institute of Technology, India and a current graduate student in the Master of Biotechnology program at Texas A&M University, College Station. Has experience in cancer biology, and tumor microenvironment and currently focusing on the role of nanoparticles in tumor growth and metastasis in Sarkar Lab.

Mahul Chakraborty, Ph.D. is an assistant professor at Texas A&M University. He has expertise in genomics and evolutionary biology. His lab studies the role of genome structure in phenotypic variation and diseases, including cancer.

Kristin Eckel-Mahan, Ph.D. is an Associate Professor at McGovern Medical School, The University of Texas Health Science Center. The main focus of her lab is to identify the role of the circadian clock in health and disease

Alex Keene, Ph.D. is a Professor and Department Head at Texas A&M University. He has expertise in neurogenetics and behavior. The focus of his lab is to identify the genetic basis of this shift in behavioral choice in the fruit fly and Mexican cavefish.

Jerome S Menet, Ph.D. is an associate professor in the Department of Biology at Texas A&M University. Research in his lab aims at uncovering the mechanisms underlying 24hour rhythms in gene expression, with a focus on defining the role of the molecular circadian clock and the daily rhythm of food intake in this process.

Deborah Bell-Pedersen, Ph.D. is a Distinguished Professor at Texas A&M. She has expertise in circadian clock control of gene expression, and her research currently focuses on clock control of mRNA translation and translation fidelity and the role of the clock in healthy aging.

Tapasree Roy Sarkar, Ph.D. is an Assistant Professor at Texas A&M University. She has expertise in cancer biology. Her lab is focusing on the role of tumor microenvironment in tumor progression and metastasis.