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. Author manuscript; available in PMC: 2026 Oct 18.
Published in final edited form as: Curr Opin Biomed Eng. 2025 Oct 18;36:100624. doi: 10.1016/j.cobme.2025.100624

Fuel, form, and memory: The motility-driven journey of cancer cells

Carolina Trenado-Yuste 1,2, Celeste M Nelson 1,3,*
PMCID: PMC12646604  NIHMSID: NIHMS2113093  PMID: 41306346

Abstract

Tumor progression is a complex, multi-stage process that involves tumor formation, cancer cell invasion, and metastasis and colonization of distant sites. Each stage is driven in part by cell motility and interactions between cancer cells and their surrounding microenvironment. In this review, we describe how cell motility contributes to each stage of cancer progression, with a focus on cell metabolism, nuclear mechanics, and mechanical memory. Throughout, we highlight the mechanisms used by cancer cells to move and adapt during the metastatic cascade. Understanding how cancer cells migrate can provide valuable insights into novel approaches to disrupt metastasis and improve outcomes of cancer treatments.

Keywords: Energy metabolism, morphogenesis, tissue morphodynamics

Introduction

The process of tumor progression relies in part on cancer cell migration. For a cancer to spread, cells must detach from their primary tumor, locally invade adjacent tissues, intravasate into the nearby lymphatic or circulatory system, and colonize distant organs to form secondary tumors (Figure 1). The surrounding three-dimensional (3D) tumor microenvironment (TME) affects cancer cell migration and, thus, the ability of cells to contribute to disease progression. Therefore, understanding the migratory strategies of cancer cells could suggest new means of slowing disease progression.

Figure 1. Cancer cell motility during the metastatic spread.

Figure 1.

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(A) Schematic of solid primary tumor containing cells that use different migratory strategies. Migration is influenced by cell-ECM interactions. (B) Cancer cell migration to distant sites involves cell detachment from the primary tumor and intravasation into the circulatory system. During this stage of tumor progression, cancer cells encounter a variety of mechanical and physical constraints that impact their survival. (C) In the final stages of metastasis, cancer cell motility enables immune evasion, detachment from endothelial cells, and organ colonization.

During their migratory journey, cancer cells encounter a variety of challenges [1]. To successfully overcome these challenges, cancer cells need to adapt their metabolism to meet fluctuating energy demands [2–4], undergo nuclear deformation to navigate confined spaces [5–7], and develop mechanical memory to prepare for more efficient navigation of future microenvironments [8]. Recent innovations in metabolic reporters, synthetic substrata, and microfluidic platforms have uncovered new roles for these features not only in sustaining tumor progression, but also in directly regulating cancer cell migration.

In this review we highlight the latest findings on cancer cell motility across different stages of tumor progression, through the lenses of cell metabolism, nuclear mechanics, and mechanical priming. Focusing primarily on findings enabled by technical advances within the past five years, we explore how these cellular adaptations impact cell migration and discuss how targeting them could help slow or disrupt metastatic spread.

Fueling the journey: effects of metabolism on metastatic spread

Abnormal proliferation leads to the formation of a neoplastic lesion and eventually a frank tumor. As tumors grow, their demand for energy increases to sustain the metabolic requirements of rapid proliferation and adaptation to microenvironmental conditions such as low oxygen, nutrient deprivation, and changes in extracellular matrix (ECM) stiffness. Once the primary tumor is established, cancer cells acquire a motile phenotype (Figure 1A) [2,3,9], and growing evidence indicates that cancer cells actively adapt their metabolism to support migration [9–11].

Many cancer cells within solid tumors shift toward aerobic glycolysis, a phenomenon known as the Warburg effect. Elevated glycolytic metabolism leads to an acidic TME, which promotes cancer cell migration [4,12] at least in part by activating proteases such as matrix metalloproteinases (MMPs) that degrade the ECM. Migratory cancer cells transport MMPs toward their leading edge to degrade the ECM, facilitating their ability to migrate and invade through dense microenvironments [13]. While glycolysis is the dominant mode of energy production, cancer cells also rely on alternative metabolic pathways to enable migration and adaptation [14,15]. For instance, glutamine metabolism promotes colorectal cancer migration, invasion, and metastasis, particularly under hypoxic conditions [16]. These findings highlight that the metabolic flexibility of cancer cells supports their invasive and adaptive capacities during tumor progression.

During detachment from the primary tumor, cancer cells can migrate as individual cells with mesenchymal or amoeboid-like morphologies, or as collectives in clusters, sheets, strands, or fluid-like formations. Metabolic heterogeneity exists across these modes of migration. Individual cells adapt dynamically to mechanical changes in the ECM, which influences cytoskeletal organization and contractility [13]. Individual cells apply forces to widen and squeeze through pores within the ECM. To meet these energy demands, cancer cells localize energy production where it is most needed. Mitochondria accumulate at the leading edge of migrating cells, enhancing ATP production to support migration [13] (Figure 2A). Given these energy constraints, cancer cells also prioritize energy-efficient pathways to sustain invasion.

Figure 2. Effects of metabolism on cancer cell migration.

Figure 2.

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(A) Metabolic reprogramming supports the transition from a proliferative to a migratory state. During local invasion, leader cells rely on OXPHOS while follower cells depend on glycolysis; these states are interchangeable. (B) Metabolism is flexible as cancer cells circulate. For instance, elevated ROS levels can induce cell death. Circulating cancer cells reduce ROS by relying on lactate, glutamine, and oleic acid. (C) To establish secondary tumors, disseminated cancer cells often enter a dormant state, similar to their original state in the primary tumor.

Although glycolysis is the primary mode of ATP production in many cancer cells, the role of mitochondria cannot be overlooked. To sustain long-term energy demands, oxidative phosphorylation (OXPHOS), the metabolic pathway by which ATP is generated in the mitochondria, is activated in cells at the leading edge of migrating collectives (leader cells). Leader cells function similarly to individual migrating cells, as they exhibit a higher ATP/ADP ratio than the follower cells that trail after them [9]. In contrast, follower cells exhibit elevated glucose uptake and rely more on glycolysis [9]. Leader and follower cell states are dynamic (Figure 2A). As leader cells deplete their energy stores, follower cells may transition into leader roles, ensuring continued invasion and adaptation to the TME [17]. Consistently, targeting metabolic heterogeneity, such as by inhibiting pyruvate dehydrogenase (PDH) and glucose transporter 1 (GLUT1), can disrupt collective invasion, offering a potential therapeutic strategy to hinder metastasis [18]. As a result, metabolic heterogeneity among cancer cells can increase the efficiency of metastasis [19].

The intravasation of cancer cells into the circulation is also highly influenced by the relative ease of migrating through confined spaces. MDA-MB-231 breast carcinoma cells migrate to areas of lower confinement, likely to reduce energetic costs. This migratory strategy aligns with observed shifts in their ATP/ADP ratio, which is higher in dense matrices and lower in aligned collagen matrices. Both melanoma and breast cancer cells undergo metabolic reprogramming during metastasis, shifting toward fatty acid oxidation to sustain migration [20]. ECM stiffness also influences mitochondrial respiration, ATP/ADP ratios, and migration in pancreatic cancer cells [21].

Once inside the vasculature, overcoming oxidative stress is a critical step in tumor progression (Figure 2B). Circulating cancer cells must enhance their antioxidant defenses to survive, as the bloodstream exposes them to high levels of reactive oxygen species (ROS). Excessive levels of ROS induce cytotoxicity, leading to DNA damage and cell death. To counteract ROS, cancer cells activate metabolic pathways that promote survival. A key mechanism is the production of NADPH, which mitigates oxidative stress by regenerating ROS-detoxifying metabolites [22]. Nonetheless, ROS are not solely detrimental; at controlled levels, they are essential for cell survival and motility, suggesting that they must be tightly regulated for successful metastasis. Consistently, studies in lung cancer and melanoma suggest that regulated ROS levels play a critical role in regulating cancer cell proliferation, resistance to anoikis, and invasiveness, which are crucial for successful metastatic dissemination [23]. ROS levels are tightly connected to metabolism. Glutamine serves as a key fuel source for migrating cancer cells, feeding the TCA cycle and sustaining redox balance. Increased glutamine metabolism correlates with a higher risk of metastasis in colorectal cancer [16]. Metabolic plasticity thus enables cancer cells to withstand oxidative stress and sustain their migration towards distant sites.

Upon arrival at distant sites, cancer cells must adapt to the new microenvironment in order to establish secondary tumors and drive disease progression (Figure 1C). Different organs provide unique metabolic landscapes, influencing cancer cell migration and growth. Metastatic cancer cells originating from the same tumor can adopt distinct metabolic profiles depending on their site of secondary colonization. In melanoma, specific metabolic adaptations have been shown to limit metastasis to the brain while allowing efficient colonization of the lung, suggesting that metabolic plasticity plays a crucial role in organ-specific metastasis [24]. Specifically, primary melanoma tumors in mice treated with an OXPHOS inhibitor were prevented from metastasizing to the brain but not the lung, suggesting that melanoma metastasis to the brain involves increased utilization of OXPHOS. A recent study elucidated the role of tumor heterogeneity in the metastasis of breast cancer cells to the lung during the seeding stage of micro-metastatic lesions. The authors identified OXPHOS as a top pathway upregulated during metastatic seeding [25], which implies that successful colonization requires metabolic flexibility, enabling cancer cells to acquire organ-specific metabolic adaptations (Figure 2C) [26].

After seeding, cancer cells may cease to divide and migrate but still retain the ability to re-enter the cell cycle, an adaptation known as dormancy. Cancer cells can remain in a dormant state for months or even years during which they may exhibit reduced metabolic activity and potentially lower ATP levels. Regulation of ROS accumulation also appears to be important for long-term survival. Dormancy is sustained by autophagy, which manages the intracellular accumulation of ROS [27]. Some dormant cells have the capacity to reactivate and re-enter a proliferative state and acquire migratory properties to start metastasizing again. Thus, understanding the mechanisms that regulate cell dormancy and reactivation is important for developing strategies to prevent metastatic reactivation.

Shaping the journey: the effects of nuclear form on metastasis

During primary tumor formation, the cancer cell nucleus–the largest and most rigid organelle in the cell body–undergoes significant physical changes, often displaying differences in size or shape compared to that of normal cells. The nucleus may be stretched due to abnormal cancer cell proliferation or compressed by the TME during primary tumor formation (Figure 3A). The nucleus also undergoes significant deformation during cancer cell invasion, which both influences and can limit cell motility through the TME [6,28].

Figure 3. Effects of nuclear mechanics on cancer cell migration.

Figure 3.

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(A) Nuclear deformations occur during tumor overgrowth and cancer cell migration through confined spaces. (B) Nuclei undergo significant deformation as cancer cells intravasate and flow through small-diameter capillaries. (C) Nuclear alterations during cell extravasation include nuclear softening within 24 hours, with nuclei undergoing various deformations in response to the new microenvironment.

While tumor cells soften when navigating through 3D confined spaces [29], the nucleus cannot soften to the same extent as the cytoplasm. As a result, MDA-MB-231 human breast cancer cells adjust their movement in 3D confinement by shifting from a pulling mechanism to a combination of pulling and pushing forces [6]. Deformations of the nucleus during confined migration can sometimes compromise nuclear envelope integrity or induce replication stress, ultimately leading to DNA damage [30,31]. Such damage can promote genomic instability, which may contribute to tumor heterogeneity, cancer progression, or resistance to therapy.

As cancer cells invade from the primary tumor, they squeeze through pores smaller than their average diameter. Nuclear lamins play a crucial role in the ability of cells to navigate through these confined spaces. Variations in lamin expression can alter nuclear stiffness and deformability, impacting how cancer cells respond and migrate through the TME [32]. Nuclear stiffness depends on the composition and organization of the nuclear lamina, which provides structural support. Cells with higher levels of lamin A/C typically have stiffer nuclei, making confined migration more challenging [33]. Abnormal nuclear mechanics lead to dome-like deformations in the nuclei of MDA-MB-231 cells, which are reduced by overexpression of lamin A/C [34]. B-type lamins also control nuclear mechanics by coupling lamin networks that regulate nuclear integrity, cell migration, and overall tumor progression. Overexpression of lamin B1 inhibits the connection between the nuclear envelope and actin filaments, promoting migration in melanoma cells [35]. In addition to regulating cancer cell migration, A- and B-type lamins also protect against rupture of the nuclear envelope, DNA damage, and cell death.

During the process of intravasation, cancer cells must breach the ECM and migrate through blood vessel walls, which leads to nuclear and constriction and deformation [36] (Figure 3B). Forces exerted on the nucleus promote the translocation of transcription factors that drive epithelial-mesenchymal transition (EMT), a key process in tumor cell dissemination [37,38]. Epithelial breast cancer cells undergoing constricted migration that induces nuclear envelope rupture exhibit changes in gene expression consistent with a transition to a more mesenchymal phenotype, whereas mesenchymal cells experience only transient effects [39]. Several studies, particularly in colon cancer cells, have shown that nuclear softening enhances metastatic potential [40,41]. One mechanistic example is the knockdown of the nuclear envelope protein lamin A, which reduces nuclear stiffness and, in turn, enhances cell motility and migration [42]. Additionally, cells navigating physical constraints experience unfolding of the nuclear membrane, which triggers an influx of calcium ions, increasing contractility and allowing the cells to sense and respond to mechanical stress [43].

Once in the circulatory system, cancer cells must resist shear stress and navigate narrow constrictions within the bloodstream before eventually attaching to endothelial cells [44]. While migration through tissue pores occurs over hours, movement through the circulatory system is governed by fluid forces, allowing cancer cells to travel large distances within seconds. The nucleus can also be deformed when cancer cells flow through narrow capillaries, potentially leading to cell-cycle arrest [45]. While increased nuclear deformability gives a migratory advantage, soft nuclei are more susceptible to rupture and nuclear damage. Excessive nuclear deformation can generate nuclear blebs, requiring time for nuclear envelope repair and potentially resulting in DNA damage. In extreme cases, such deformation may induce EMT, further enhancing the migratory and invasive capacity of cancer cells [46].

As cancer cells begin to colonize secondary organs, they become significantly deformed in order to traverse endothelial junctions and escape the circulatory system (Figure 3C). The extravasation of cancer cells involves cancer cell adhesion to the endothelium, transendothelial migration, and migration through the ECM of the new organ. Transendothelial migration is affected by the properties of the subendothelial ECM and endothelial actomyosin contractility, which influence the resistance of the endothelium to cells squeezing through the monolayer [47]. Cancer cells and their nuclei also soften upon extravasation, and this softening persists for at least 24 hours, facilitating further migration and invasion [48].

Recording the journey: the effects of mechanical memory

Alterations in the mechanical properties of the TME are a hallmark of cancer [49], requiring cancer cells to adapt along their journey (Figure 4A). The migration of cancer cells is inherently coupled to the mechanical properties of the TME [50], and their responses and adaptations are important for survival. However, it remains unclear whether cancer cells retain a memory of these adaptations and, if so, how this memory influences tumor progression [8]. Recent studies have proposed the term “mechanical memory”, an ability to sense, retain, and respond to mechanical signals, even when external conditions shift [51].

Figure 4. Effects of mechanical memory on cancer cell migration.

Figure 4.

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(A) Mechanical memory of cancer cells during primary tumor formation influences their migratory behavior. High ECM stiffness is a common hallmark of early stage tumors. (B) Cancer cells rapidly adapt to fluid shear stress, hypoxia, and solid stresses over minutes to hours until they extravasate. (C) Factors secreted from the primary tumor condition distant organs, creating a permissive niche for incoming cancer cells to colonize.

During primary tumor formation, proliferating cancer cells recruit lymphatic and blood vessels that surround the primary tumor, increasing interstitial fluid pressure, compromising drainage, and altering fluid viscosity. Elevated extracellular fluid viscosity has been found to enhance breast cancer cell motility on 2D surfaces [52]. Increased stiffness is another characteristic of solid tumors, and cancer cells exposed to high stiffness exhibit increased motility, even in metastatic sites where the surrounding microenvironment is softer [53]. These findings suggest that targeting the mechanical properties of the ECM could be a potential strategy for modulating tumor invasion.

Cells preconditioned on a stiff matrix not only adopt a more mesenchymal-like morphology but also retain this phenotype for several days on softer substrata, influencing their migration [54]. Furthermore, breast cancer cells conditioned on a stiff substratum metastasize to bone more frequently than those conditioned on a soft substratum, demonstrating that prior mechanical exposure can influence metastatic potential [55]. The persistence of this mechanically conditioned state was found to be regulated by RUNX2, an osteogenic transcription factor and a well-established driver of bone metastasis. Together, these studies show how the physical properties of the tumor microenvironment can precondition cancer cells for successful dissemination.

Characteristics of the ECM in primary tumors are often mirrored in metastatic lesions [8] (Figure 4B). A recent study characterized ECM organization in both human patients and murine models, identifying region-specific ECM patterns in melanoma and breast cancer tissues [56]. Metastatic lesions contained similar ECM features as the primary tumor, suggesting a conserved influence of ECM architecture on cancer progression. To further investigate the role of mechanical conditioning, a PEG-based hydrogel system was used to tune the modulus of the matrix on demand, allowing researchers to study how the culture history of human mesenchymal stem cells (hMSCs) influences cellular responses [51]. Culturing hMSCs on stiff and soft hydrogels revealed that chromatin remodeling occurs in response to the mechanical properties of the microenvironment, reinforcing the concept that cells can retain a memory of their previous mechanical microenvironments.

Mechanical memory acquired in the primary tumor enhances the extravasation of circulating cancer cells at secondary sites (Figure 4C). For example, the stiffness of the matrix in primary breast tumors modulates invasion and metastasis, influencing breast-to-bone colonization in vitro [57]. Metastasis is a selective process that favors cells that are motile and soft. Cancer cells have been found to soften after they migrate through confined spaces [29] or endothelial barriers [48]. A recent study found that metastatic lung cancer cells adopt a softer phenotype after extravasation, leading to increased migration [58]. Further research is needed to elucidate the persistence, intensity, and duration of mechanical memory obtained from the primary tumor microenvironment.

Conclusions

Cancer cell migration plays an important role in driving disease progression. Recent studies suggest that migratory strategies arise from cellular adaptation to metabolic demands [9], microenvironmental constraints requiring nuclear deformation, and memory of past mechanical microenvironments. However, it remains unclear whether the impact of each of these features is cancer-type specific. Moreover, many studies often overlook intratumoral heterogeneity and the functional role of migrating cancer cells.

Emerging treatments target cancer cell migration by exploiting tumor-specific metabolic adaptations [25]. One adaptation during metastasis is an increase in ATP production [24], which is believed to fuel the energetic demands of cancer cells. However, whether OXPHOS represents the dominant source of ATP that facilitates migration essential for metastatic progression remains uncertain. Further research is needed to elucidate the contributions of various metabolic pathways to cell motility across different tumor types, as the role of metabolism cell migration remains less well characterized than its role in proliferation.

Investigating cancer cell migration in capillary-like microenvironments is particularly challenging due to geometric constraints and physiological fluid flows [45,52], which influence nuclear deformation and add complexity to migration dynamics [39]. Additionally, nuclear mechanics may evolve during tumor progression, raising the question of whether only cells with specific nuclear properties can successfully migrate and metastasize. Recent studies also suggest that cancer cells may retain memory from the primary tumor [8,54], with evidence indicating that matrix organization can predict metastatic potential [59]. A deeper understanding of these mechanisms could provide valuable insights for patient prognosis and the development of targeted therapeutic strategies.

Biomedical engineering research provides powerful tools to enhance our ability to study cancer cell migration during disease progression, particularly through the lenses of metabolism, nuclear mechanics, and mechanical priming. 3D real-time imaging of cell metabolism, for example, is starting to enable researchers to investigate how cell metabolic activity dynamically influences migration during invasion and metastasis. Similarly, recent advances have led to approaches that explore potential anticancer drugs aimed at rectifying nuclear size, with the primary goal of reducing cancer cell migration. We also believe that engineering microfluidic devices such as multi-organ-on-a-chip will not only enable the modeling of primary tumors but also facilitate the study of their connections to metastatic niches, allowing researchers to investigate how mechanical memory influences organ-specific metastasis [60]. As we continue to combine engineering principles with cancer biology, we open new avenues for novel diagnostics and therapies offering more effective and personalized cancer treatment strategies.

Acknowledgements

The authors were supported in part by grants from the Ludwig Institute for Cancer Research Princeton, the National Institutes of Health (CA187692, CA21492, HL164861, HD099030, HD111539), and the National Science Foundation (2134935). CT was supported in part by the New Jersey Department of Health, the Division of Office of Research Initiatives, and the New Jersey Commission on Cancer Research (NJCCR) through a 2023 NJCCR Postdoctoral Research Grant, as well as the Damon Runyon Cancer Research Foundation through the Quantitative Biology Postdoctoral Fellowship.

Abbreviations:

3D

Three-dimensional

CAF

cancer-associated fibroblast

ECM

extracellular matrix

EMT

epithelial-mesenchymal transition

OXPHOS

oxidative phosphorylation

ROS

reactive oxygen species

TME

tumor microenvironment

Footnotes

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Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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