Metabolic landscape of disseminated cancer dormancy

Abstract

Cancer dormancy is a phenomenon defined by cancer cells’ entry into a reversible quiescent, non-proliferative state, and represents an essential part of the metastatic cascade responsible for cancer recurrence and mortality. Emerging evidence suggests that metabolic reprogramming plays a pivotal role in enabling entry, maintenance, and exit from dormancy in the face of the different environments of the metastatic cascade. Here, we review the current literature to understand the dynamics of metabolism during dormancy, highlighting its fine-tuning by the host micro and macroenvironment, and put forward the importance of identifying metabolic vulnerabilities of the dormant state as therapeutic targets to irradicate recurrent disease.

Metabolism at the nexus of entrance and exit from dormancy

Metastases (see Glossary) arise following a strenuous process of cancer spreading beyond the primary site and formation of new growths in distant organs. Many patients with cancer experience a long lag (years to decades) between diagnosis of the primary tumor and clinical detection of metastases. This pause in progression results from disseminated tumor cells (DTCs) that go into dormancy until they awaken into metastases[1, 2]. Dormancy may arise in two forms: cellular dormancy, referring to solitary DTCs that remain in a long-term quiescent, non-proliferative state; and population dormancy, referring to small cell clusters or micrometastases that equilibrate cell proliferation and death, resulting in net-constant size[3]. Because metastatic relapse is still largely incurable, understanding what switches DTCs from dormancy to metastatic outgrowth is one of the most significant and urgent quests in cancer research today.

The conventional view on the pathogenesis of metastasis is a series of interrelated steps dependent on both the intrinsic properties of the DTCs and those of the host micro and macroenvironment. While the requirement for specific mutations to exit dormancy has not been shown, there is now ample evidence that host factors control metastatic outgrowth. These include attrition by the immune system and tissue-specific properties, such as blood supply, oxygenation, nutrient and growth factor availability, extracellular matrix composition, and interactions with key cell types within particular niches, all of which are embedded in a broader organismal context[4-14]. The constraints of this new environment lead DTCs to a constant struggle for adaptation. By serving as both a sensor of environmental conditions and an effector of physiological changes, metabolism stands at the nexus of the complex fate decisions that ensure enough resources for DTC survival and outgrowth at distant sites.

Despite the rich history of research in metabolic reprogramming during cancer initiation and metastasis[15, 16] there is much to learn about how rare, quiescent DTCs rewire their metabolism to switch between quiescent and proliferative states. In physiology, these state transitions hinge on the cell’s ability to strike a balance between energy production and its expenditure. This is achieved through an equilibrium in the combustion of fuel sources, such as proteins, carbohydrates, and lipids (catabolism), and the use of energy to synthesize them (anabolism). Thus, while quiescent cells are wired toward catabolic processes that provide energy to sustain cellular integrity and function, proliferative cells rewire towards anabolic metabolism to empower the generation of building blocks needed for rapid cell division (Fig.1). Evidence supporting metabolic reprogramming as a critical trait of dormant DTCs came from the observation that dormancy is driven by hypoxia, a condition of low oxygen tension that drives profound metabolic changes [17] and is often present in the primary tumor. Indeed, post-hypoxic DTCs were found quiescent and upregulated genes associated with long-term dormancy in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner[18, 19], demonstrating a clear connection between major metabolic regulatory pathways and dormancy induction. While the role of hypoxia in the awakening of DTCs remains controversial[18, 19], additional studies have provided evidence for metabolism as an important regulator of metastatic outgrowth. For example, breast DTCs activate de novo lipid synthesis to outgrow in the brain[20, 21]. Similarly, while unknown if through direct resuming of proliferative capacity, increased fatty acid uptake by the fatty acid translocase, CD36, fuels the initiation of oral[22] and breast[23] cancer metastasis in lymph nodes and lungs. Additionally, cells from the microenvironment at distant sites support the metabolic crosstalk with the DTC, as illustrated by immune- and stromal-derived lipid mediators that support dormancy exit and metastasis across organ sites[24-28]. When put into context these observations suggest that DTCs respond to the metabolic state of the environment to coordinate successful cell fate transitions during metastasis. Importantly, the metabolic landscape differs across distant sites[29], as well as with the broader complexities of the host (e.g., age, race, gender)[30, 31] and external factors (e.g., diet, stress)[32, 33], all of which may impose specific metabolic adaptations to lingering DTCs.

Figure 1: Metabolic reprogramming as a coordinator of cell fate decisions of DTCs.

Schematic representation of the metabolic switch between catabolic energy-producing pathways (e.g. fatty acid oxidation, autophagy, oxidative phosphorylation) and anabolic energy-consuming pathways (e.g. glycolysis, TCA cycle anaplerosis, serine synthesis, pentose phosphate pathway) that allows DTCs’ fate transitions between quiescent and proliferative states. This reversible switch between catabolism and anabolism is rapidly engaged by DTCs depending on the metabolic state of the surrounding environment, enabling DTCs to retain homeostasis and control the decision to either enter and remain dormant or proliferate and thrive as overt metastases.

Here, we search for evidence that metabolic rewiring drives DTC entrance and exit from dormancy. What metabolic traits do DTCs have or gain to survive and grow at distant sites? Do DTCs and cells within the microenvironment compete for the same metabolites? How does organ-specific metabolite composition determine metastatic outgrowth? And, can systemic metabolism affect local metabolite availability at distant sites, and thus metastatic relapse? Addressing these questions will expand our understanding of DTC dormancy and provide therapeutic windows for preventing metastatic relapse.

DTC-intrinsic metabolic traits that empower dormancy

Metabolic oscillation ensures survival in the different phases of the cell cycle[34]. Dormancy is a quiescent state in which DTCs temporarily arrest in G0 phase of the cell cycle, and that is characterized by the activation of the cell cycle inhibitory axis through p38 mitogen-activated protein kinase (MAPK) activation and induction of the major restriction point regulator, p27^Kip1[35, 36]. Consequently, the dormant state inversely correlates with the presence of cell cycle inducers, such as Ki67[37] and cyclin-dependent kinases (CDKs)[38]. CDKs are the major link between cell cycle progression and metabolic reprogramming that guarantees enough resources throughout the different cell cycle phases[39, 40]. But how does CDKs’ metabolic activity enable cell survival in a quiescent state?

CDK4/6 activity, a well-known mediator of the transition from the G1 to DNA replicative S phase whose suppression induces long-term G0 cell cycle arrest[41, 42], also regulates mitochondrial metabolism in melanoma, dictating whether cancer cells rely on glutamine catabolism and fatty acid oxidation (FAO) to sustain energy production via OXPHOS in the mitochondria[43]. Likewise, suppression of CDK2 activity, a key repressor of p27^Kip1 that builds up to commit cells into proliferation[38], negatively regulates aerobic glycolysis in gastric cancer cells, powering OXPHOS-mediated quiescence through induction of the homeostatic regulator sirtuin 5 (SIRT5)[44]. A similar OXPHOS dependence sustains dormant pancreatic cancer cells[45] and breast cancer micrometastasis in the lung[46], rendering them vulnerable to OXPHOS inhibitors. These observations support a paradigm where dormant DTCs shift their metabolism away from aerobic glycolysis, a staple of anabolism[47], to catabolic pathways that fuel mitochondrial OXPHOS to maintain energetic and redox homeostasis, thereby enabling their survival[48]. Another aspect of catabolism that seems important to the dormant state is elevated autophagy[49, 50]. A recent report showed that breast DTCs rely on autophagy to enter and remain dormant in the lung[51]. Moreover, mitophagy, a specialized autophagy mechanism that eliminates dysfunctional and damaged mitochondria[52], was recently shown to grant breast dormant DTCs a healthy mitochondrial network necessary not only to power the heightened need for OXPHOS, but also to prevent the buildup of reactive oxygen species (ROS) and its associated toxicity, thereby empowering dormant DTC survival in the lung[53].

AMPK is an energetic sensor that promotes catabolic pathways. These include autophagy (through direct regulation of the mammalian autophagy inducer ULK1), FAO (through its target acetyl-CoA carboxylase (ACC)), and OXPHOS (through direct control of the master regulator of mitochondrial biogenesis PGC-1α)[54]. Consequently, AMP-activated protein kinase (AMPK) signaling is also frequently upregulated in quiescent cells across various tissues and cell types[54]. Consistent with the importance of catabolic pathways in powering the dormant state in DTCs, AMPK activation promotes the survival of estrogen receptor-positive (ER⁺) breast cancer dormant cells through increased FAO-powered OXPHOS[55]. Moreover, it drives the activation of antioxidant defense mechanisms through phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2) to limit ROS accumulation and accelerate breast cancer recurrence[56]. Together, these studies put forward catabolic pathways as homeostatic regulators of the dormant state (Fig.2) and pinpoint specific metabolic liabilities of dormant DTCs with therapeutic potential to be explored.

Figure 2: Intrinsic metabolic networks that empower dormant DTCs homeostasis and survival.

Schematic representation of the link between metabolic pathways, cell cycle progression and the dormant state. In order to retain cellular integrity and allow for survival in the face of induction of the restriction point of cell cycle driven by the induction of p27Kip1, cyclin-dependent kinases (CDKs) rewire metabolism towards glutaminolysis, fatty acid oxidation (FAO) and induce SIRT5-dependent switch from anaerobic glycolysis to oxidative phosphorylation (OXPHOS). Dormant DTCs also utilize cellular recycling processes like autophagy or mitophagy to obtain important nutrients and energy. These catabolic pathways enable DTCs to meet energetic demands necessary for survival in dormant state, and their inhibition causes cell death. Dormancy-induced metabolic reprogramming is internally governed by AMPK which acts as a rehost coordinating the induction of these catabolic processes through regulation of its direct targets ULK1 (autophagy), ACC (FAO) and PGC-1α (OXPHOS), while promoting detoxification of reactive oxygen species (ROS) through induction of NRF2 levels.

The DTC-microenvironment metabolic tug-of-war

Over the last decade, evidence has mounted pointing to a key role of the local microenvironment in the metabolism of cancer cells[57]. For example, proliferative and quiescent cells show distinct usage of glutamine. Whereas proliferative cells catabolize glutamine using transaminases to synthesize non-essential amino acids (NEAAs), such as glutamate and aspartate, quiescent cells have diminished expression of those enzymes and, therefore, rely on the presence of these amino acids within the local microenvironment[58]. Thus, it is anticipated that the microenvironment metabolic profile cooperates with DTCs intrinsic properties to dictate dormancy in distant sites.

The microenvironment is composed of diverse cell populations, including fibroblasts, adipocytes, pericytes, nerves, endothelial and immune cells, all embedded in extracellular matrix (ECM) components, and sharing secreted growth factors, cytokines, and metabolites[59]. Cancer-associated fibroblasts (CAFs), a subtype of stromal cells, are the most abundant cell population in the microenvironment, and the major regulators of ECM stiffness via deposition of collagens[60]. Increased deposition of specific collagen types and consequent stiffness-induced mechanical stress have been linked to dormancy in both breast and oral squamous cell carcinoma[61-63]. Interestingly, collagens are proteins rich in proline[64], an amino acid with important metabolic functions. In fact, pancreatic cancer cells have been shown to uptake CAF-produced collagen and metabolize it to proline to sustain the TCA cycle and, thereby, survive under nutrient-deprived conditions[65]. Likewise, proline catabolism has been linked to the ability of breast DTCs to thrive as metastases[66]. In addition to collagens, CAFs can be educated by cancer cells to produce energy-rich metabolites that support their survival and rapid proliferation. Lactate is likely the most well-recognized of these, being produced at high levels through excessive aerobic glycolysis that cancer cells induce in CAFs to use in return[67]. Similarly, cancer cells induce a lipid-rich phenotype in CAFs to power FAO and OXPHOS in support of pancreatic cancer initiation[68]. The metabolic crosstalk with the stroma extends to exchanges of pancreatic stellate cell-secreted alanine, which can be used by cancer cells as an alternative pyruvate source to fuel OXPHOS when glucose is limited[69]. Likewise, pancreatic stellate cells generate lysophosphatidylcholines, which support key components of cell membrane synthesis and stimulate the growth and migration of pancreatic cancer[70]. While these mechanisms are yet to be probed at distant sites, it is conceivable that dormant DTCs might take advantage of similar mechanisms to create an environment rich in the metabolites they need to survive and grow.

Besides being a source of important metabolites, the microenvironment can also create a scenario of competition, depriving DTCs of essential metabolites for growth and/or favoring their elimination by the immune system[71-74]. For example, glutamine is essential for tumor cell growth but also immune cell function and the competition for this metabolite within the microenvironment has gained attention. Preventing tumor cells from using glutamine enhanced glutamine levels in the microenvironment and favored its usage by the immune cells, thereby promoting T cell and dendritic cell function and overcoming immune evasion[75-77]. A similar competition for glucose[71] and cholesterol[78] exists between cancer and T cells in the microenvironment and drives cancer progression. This highlights the role of metabolite constraints and composition within the microenvironment as regulators of antimetastatic immunity, and suggests that boosting access to key metabolites by immune cells holds therapeutic promise. Indeed, using nanoparticles to accumulate essential nutrients and reduce the level of immunosuppressive metabolites in the microenvironment has proved efficient in attenuating the metabolic competition of tumor cells and favoring the nutritional demands of infiltrating immune cells[79].

The contribution of the microenvironment to the metabolic profile of DTCs might extend beyond the usage of metabolic substrates into the horizontal transfer of organelles among cells within the microenvironment. This is supported by the observation that cancer cells acquire mitochondria from the microenvironment to survive and thrive at primary[80] and metastatic[81] sites. Future studies focused on the functional characterization of DTC-microenvironment metabolic interactions should identify ways to defeat metastasis in this metabolic tug-of-war.

Organ-specific metabolic landscape dictates DTC’s fate

Only recently, we began to appreciate how the specific physiology, architecture, and resident cell types of each organ control DTC dormancy and outgrowth (reviewed in[82-84]). Because different organs also provide different nutrients[85-87], it is expected that metastases arising in different organs have distinct metabolic dependencies. For example, breast metastases show a distinct metabolic profile depending on the distant site where they arise. Whereas breast DTCs engage more in aerobic glycolysis in the liver, they prefer OXPHOS[88] or enhance glutamine uptake[89] in the bone. In the lung and the brain, breast DTCs afford flexibility to perform either glycolysis, FAO, or OXPHOS at high rates for successful colonization[88, 90, 91]. This raises the question of whether all DTCs are able to metabolically rewire according to their new site or a preference is already imprinted at the primary site with DTCs targeting organs that better fit their intrinsic metabolic capabilities. On one hand, specific cancer types metastasize consistently to certain tissues, and the tissue of origin was recently shown to metabolically constrain where metastases can grow[92]. On the other hand, the striking metabolic similarities between metastases and the organ where they arise[29], combined with the finding that organ-induced metabolic changes are reversed by DTC reinjection in the primary site[93], argue that organ-specific nutrient content is an important limiting factor for the outgrowth of any DTC (Table 1).

Table 1.

Site-specific metabolic availability and its contribution to DTC dormancy and metastasis.

Site of metastasis	Nutrient availability	DTC dormancy maintenance	DTC metabolic adaptation and metastasis
Lung	Well-oxygenated organ; produces large amounts of lactate and pyruvate that can be used as carbon sources; precisely controls the surfactant lipid pool by either synthesizing new lipids (e.g., palmitate) or recycling them from old surfactant [140].		De novo serine synthesis sustains breast cancer metastasis[141]; Increased proline catabolism supports breast cancer metastasis[66]; Breast DTCs exploit the pyruvate-rich lung to outgrow into metastases[94, 95]; Increased CD36 expression in oral and breast cancer cells fuels metastasis[22, 23]; Lung mesenchymal cells trigger lipid storage in neutrophils that fuel breast cancer metastasis[24]; Neutrophil-derived lipids contribute to pancreatic dormant DTC awakening[26]; Mesenchymal cell-derived lipids dampen NK cell immunity and facilitate breast cancer metastasis[27]; A palmitate-rich lung environment fosters breast cancer metastasis[98]; Breast DTCs rewire towards increased proline and ceramide production to establish micrometastases[110]
Liver	Glucose- and lipid-rich environment; metabolically zonated, featuring highly oxygen-consuming cell populations at the periportal region and glycolitic cell types at the perivenous areas; metabolic activity tightly controlled by insulin and other metabolic hormones[142].		Lung- and melanoma-derived lipids reprogram macrophages and facilitate metastasis[28]; A palmitate-rich liver environment fosters breast cancer metastasis[98]; High insulin levels dictate melanoma liver-tropic metastasis[99]
Bone	Storage for vital minerals and other essential ions (including calcium and phosphorus); highly hypoxic due to low oxygen tension; important site for fat storage[143].		Increased production of lactate and serine by breast DTCs fuels osteoclastogenesis in support of metastasis[104, 105];
Brain	Totally dependent on oxidative metabolism and nurtured exclusively by blood glucose and ketone bodies; rich in newly synthesized lipds; serine- and glycine-limited environment[144].		Increased serine synthesis sustains nucleotide production and cell proliferation of breast DTCs[96]; Use of acetate as an alternative source for breast, ovarian, kidney and lung cancer metastases[145]; De novo fatty acid synthesis drives breast cancer metastases[20, 21]; Breast DTCs co-opt GABA as an oncometabolite to outgrow into metastases[103];
Skeletal muscle	Explores energy depots to maintain contractile activity, including creatine phosphate, glycogen and intramyocellular lipids[146].	High oxidative stress prevents breast DCC outgrowth[100].

Evidence that the tissue microenvironment imprints differential cancer metabolism comes from comparisons of primary tumors and matched metastases. Indeed, whereas primary breast tumors feed on glutamine anaplerosis, breast DTCs exploit the pyruvate-rich lung to outgrow into metastases[94, 95]. Another example of site-specific adaptations is the increased lipid and serine/glycine synthesis of breast DTCs in response to the low levels of these metabolites in the brain[20, 21, 96]. Similarly, melanoma DTCs rewire towards FAO to uniquely colonize the lymph node[97]. Additionally, the default lipid-rich environments in lung and liver foster breast cancer metastatic outgrowth, and targeting lipid availability proved efficient in reducing lung metastatic burden[98]. The influence of organ-specific metabolism on metastasis extends also to metabolic hormones. An example is how naturally high insulin levels in the liver favor liver-tropic melanoma metastases[99]. These adaptations showcase the metabolic plasticity of dormant DTCs to meet the unique demands of the new limiting microenvironment (Fig.3).

Figure 3: Multi-tier regulation of metabolic landscape of the DTCs microenvironment and its consequences for metastatic disease.

DTCs are subjected to different metabolic pressures imposed by the metabolic landscape of the environment, which is regulated by the interplay of microenvironmental, organ-specific and systemic metabolic state. At the microenvironmental level, metabolic features of its various components (e.g., stroma, immune cells, etc), competition for nutrients and metabolites between DTCs and the local ecosystem and the differential composition of the matrix create a specific metabolic environment. These microenvironmental metabolic features are further shaped by organ-specific metabolism resulting from organ-specific functions, cell composition as well as architecture and metabolic zonation which is also shaped by the last tier of metabolic regulation – the systemic metabolic state of the organism (e.g., host factors like age, race, and obesity in combination with environmental factors like diet, stress and lifestyle). Together, these different tiers of metabolic regulation converge to dictate the metabolic landscape of the microenvironment where DTCs reside thereby controlling whether DTCs become and remain inactive in a dormant state or thrive and give rise to overt metastasis in a given organ.

While many studies have enumerated mechanisms facilitating DTC adaptation to common sites of metastasis, why DTCs fail to colonize certain sites has received far less attention. Skeletal muscle, spleen, and thyroid are three infrequent sites of metastasis, where vascular flow, immune composition, secreted factors, and incompatible metabolism have been proposed as mechanisms of suppression[82, 83]. A closer look into the skeletal muscle revealed that, despite seeding and persisting at a relatively high rate, breast DTCs encounter a profound metabolic barrier at this site[100]. In particular, constant hydrogen peroxide exposure coupled with insufficient antioxidant defenses limit DTC proliferation. These findings may provide new strategies to prevent metastasis by sustaining or reproducing metabolic microenvironments that naturally minimize DTC outgrowth.

Organ-specific colonization also demands different interaction strategies with the many tissue-specific resident cells to obtain nutrients required for DTC survival and proliferation. In the brain, breast DTCs form gap junctions with astrocytes[101], and synaptic connections with glutamatergic neurons[102]. Interestingly, they also develop a gamma-aminobutyric acid (GABA)-ergic phenotype — mimicking neurons — and convert GABA into succinate and NADH to fuel metabolic pathways[103]. On the other hand, in the bone, breast DTCs will undergo the well-described ‘vicious cycle’ of osteolytic bone metastasis. Through the release of large amounts of lactate and serine, DTCs fuel differentiation and metabolic fitness of osteoclasts, granting a niche with more space and nutritional resources[104, 105]. This again exemplifies the DTC metabolic plasticity required to colonize different sites (Fig.3) and reaffirms the need to better understand the DTC-microenvironment metabolic interactions underlying entry and exit from dormancy in an organ-specific manner.

In addition to inter-organ heterogeneity, different parts of the same organ feature spatially distinct microenvironments (that is, intra-organ heterogeneity) that disproportionally impact DTC outgrowth. For example, the inherent abundance of natural killer (NK) cells in the liver sustains breast DTC dormancy, while NK cell-deprived microenvironments catalyze metastatic outgrowth[5]. It is tempting to speculate that regional differences also reflect spatial metabolic heterogeneity. This is particularly evident in the liver, which is divided by metabolic zonation, corresponding to varying blood flow-generated gradients of oxygen, nutrients, hormones, and morphogens[106]. How metabolic liver zonation impacts the emergence of metastases remains unknown and ripe to study. Another example of intra-organ heterogeneity is physically distinct niches occupied by quiescent and proliferative breast DTCs within the bone marrow[107-109], yet any root to differential metabolism is to be explored. Likewise, even two DTCs on the same microvessel can experience different signaling environments; proximity to endothelial stalks sustains breast DTC quiescence, whereas endothelial tip cell-derived mitogenic factors ignite metastatic outgrowth[11]. Whether this dichotomy stems from spatial metabolic heterogeneity remains underexplored. A rare example is the recent finding that breast DTCs in micrometastases have different metabolic demands than co-evolving macrometastases in the lung[110]. This highlights that different metabolic niches exist even within the same distant site and may dictate DTC’s fate. Additional understanding of how regional metabolic heterogeneity determines the differential emergence of metastases will probe site-specific metabolic modulation as a strategy to effectively control dormant DTCs.

Systemic metabolism shapes DTC outgrowth

Systemic organismal metabolism integrates the physiological functions of all tissues and systems in the body (i.e., the overall metabolic state of an individual) with environmental factors (e.g., diet, stress, lifestyle) to ensure organismal homeostasis. This connection is facilitated by the circulation of metabolites, lipids, hormones, cytokines and other secreted factors that convey information throughout the body, thereby shaping the metabolic landscape of each organ microenvironment to reflect the physiological state of the organism. While strong indications that the metabolic landscape of the local microenvironment can regulate DTC entry and exit from dormancy, our understanding of the interplay between systemic metabolism and cancer dormancy is in its infancy. However, several lines of evidence support a potential role of systemic organismal metabolism in regulating DTCs cell fate. For instance, obesity, an organismal condition on the rise in developed countries, has long been linked to poorer prognosis in breast cancer patients. Patients with higher body mass index (BMI) have lower recurrence-free survival[111-114] and are up to 46% more likely to have late distant metastases when compared to patients with an ideal BMI[115]. This suggests that obesity might drive dormant DTC awakening and consequently promote metastasis. In support of this premise, breast cancer cells implanted in obese mice show a marked increase in proliferation[111], and a high-fat diet drastically increases metastatic burden[98, 116]. Diet-induced obesity also alters the landscape of the microenvironment at distant sites, as recently illustrated by the favoring of myeloid lineages and consequent lung neutrophilia that underlie breast cancer lung metastases[117, 118]. Postmenopausal obesity in mice has also been shown to promote escape from dormancy in breast tumors through induction of neovascularization[113]. Other conditions affecting organ-specific lipid metabolism, such as metabolic dysfunction-associated steatotic liver disease (MASLD), also predispose to metastasis. In particular, the lipid-rich microenvironment in MASLD activates de novo palmitate biosynthesis in colorectal DTCs via upregulating fatty acid synthase (FASN)[119], and sustains lipid transfer from hepatocytes to breast and melanoma DTCs in direct support of fatty acid β-oxidation[120]. In addition, accumulation of glucocorticoids (GCs)[121-124] or oncometabolites in circulation[125-127] were recently implicated in metastatic outgrowth.

Inflammation has emerged as another potent systemic regulator of cancer development by promoting metastasis[128-131]. Two different axes of action were described and exemplify the complexity of cancer disease. First, the primary tumor cells secrete cytokines to generate inflammation and increase the recruitment of immunosuppressive cell types in future sites of metastasis[132-134]. Second, other organs can promote inflammation to influence the immune system in the primary tumor site. In this scenario, the cancer-free liver secretes serum amyloid A (SAA) proteins, regulating the infiltration of immune cells in the primary tumor and consequently, remodeling the microenvironment[135]. Additional studies are necessary to precisely pinpoint the contribution of these and other aspects of host physiology (e.g., diet, race, age, Fig.3) with major systemic metabolic consequences to the fate of DTCs in different cancer types, as well as within different microenvironments, and ultimately leverage these insights into therapeutic intervention for patients with metastatic cancer.

Concluding remarks

The evidence presented above supports a paradigm where the ultimate success of a DTC thriving as overt metastasis is, in part, a function of how extensively it can adapt to the metabolic demands of its host environment. We have enumerated the metabolic principles that enable homeostasis of dormant DTCs, mechanisms by which metabolic rewiring facilitates DTC adaptation to common sites of metastasis, and metabolic bottlenecks that sustain DTC dormancy and impede colonization of specific sites. Critically, a systematic understanding of metabolic dependencies of DTCs versus tissue-resident cell types, and how they evolve in space and time and are shaped by the systemic metabolic state of an individual, is eagerly awaited (see Outstanding Questions) and essential to inform therapeutic intervention in patients at risk of developing metastases.

Outstanding Questions.

• Are the metabolic features of quiescent DTCs different than non-cancerous quiescent cells? Can these unique features create metabolic liabilities unique to quiescent DTCs?

• Does DTC intrinsic metabolic profile dictate organ-specific metastasis? Are there specific nutritional demands that are more fit to specific distant organs?

• Are there organ-specific metabolites inducing DTCs in and out of dormancy? Could site-specific metabolic modulation present an opportunity to effectively prevent outgrowth or eradicate dormant DTCs?

• Which metabolites do DTCs and tissue-resident cell types compete for? Can local metabolite availability be manipulated to steer DTC trajectory towards dormancy maintenance and/or increase immune surveillance?

• How do aspects of host physiology with major systemic metabolic consequences (e.g., diet, race, sex, age) influence DTC fate in different cancer types as well as within different and constantly evolving microenvironments?

• How can we translate metabolic regulation of dormancy research for clinical benefit?

A few challenges and exciting opportunities lie ahead before we successfully translate metabolic liabilities into antimetastatic therapies. One challenge is to continue expanding our understanding of the spatiotemporal regulation of the metabolic landscape of DTC dormancy. Here advanced technologies will be instrumental, spanning single-cell resolved imaging to identify metabolic states in rare populations of dormant DTCs (e.g., using biosensors[136], in vivo metabolic CRISPR screens to characterize requirements for early colonization across multiple sites[137], and single-cell and spatial metabolic profiling[138, 139] to resolve metabolic profiles of ecosystems hosting DTCs. Another consideration is the need to study DTC-microenvironment metabolic interactions using in vitro models that better recapitulate the physiological complexity of distant sites (including nutritional content and diverse tissue-resident populations), as well as pre-clinical animal models that reproduce nutrient availability and metabolic heterogeneity of human metastases. Finally, clinical validation that focuses on metabolic control of dormant DTCs at the different metastatic sites is needed. These combined efforts should pave the way for targeting metabolic liabilities as a new direction for long-lasting prevention of dormancy-powered metastatic relapse.

Highlights.

• Metabolic reprogramming enables the successful transition of DTCs from proliferation to quiescence and the survival of DTCs in the dormant state.

• The ultimate success of a DTC thriving as overt metastasis is a function of how extensively it can adapt to the metabolic demands of its host environment.

• Distinct metabolic landscapes of secondary organs dictate whether DTCs stay dormant or reawaken and colonize specific organs giving rise to metastatic tissue tropism.

• Identifying metabolic vulnerabilities of the dormant state is essential to essential to inform therapeutic intervention in patients at risk of developing metastases.

Glossary

Aerobic glycolysis

Metabolic process that converts glucose into lactate, even when oxygen is available.

Anabolism

Process of synthesis of complex molecules (such as DNA) from smaller units.

Anaplerosis

Synthesis of intermediates of the TCA cycle.

Autophagy

Degradation and recycling of cellular components through a lysosome-dependent regulated mechanism.

Catabolism

Set of metabolic pathways that break down complex molecules into simpler ones.

Dormancy

A state of pause in cancer progression in which individual DTCs are quiescent and reversibly arrested in G0 phase of the cell cycle.

Disseminated tumor cells (DTCs)

Cancer cells that have left the primary tumor and survived in the circulation to land in a distant organ.

Extracellular matrix (ECM)

Comprising molecules, specifically proteoglycans and fibrous proteins (fibronectin, collagen, elastin and laminin) secreted by stromal cells into the microenvironment, that generate an intricate network of macromolecules that fill the intercellular space.

Fatty acid β-oxidation (FAO)

Catabolic process by which fatty acids are broken down to generate energy.

Hypoxia

A condition of oxygen deficiency in a biotic environment.

Metabolic dysfunction-associated steatotic liver disease (MASLD)

Previously known as non-alcoholic fatty liver disease, is a condition characterized by excessive fat build-up in the liver.

Metastases

Outgrowths of DTCs that are histologically or radiologically detectable.

Micrometastases

A small group of DTCs that are too few to be picked up in a screening or diagnostic test.

Oxidative phosphorylation (OXPHOS)

Metabolic pathway driving the reduction of oxygen to generate high-energy phosphate bonds in the form of adenosine triphosphate (ATP) through an electrochemical transmembrane gradient.

Tricarboxylic acid (TCA) cycle

A series of reactions to release stored energy from carbohydrates, fats, and proteins through oxidation of acetyl-CoA.