The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis

Abstract

Tumours evolve to cope with environmental stresses or challenges such as nutrient starvation, depletion of survival factors, and unbalanced mechanical forces. The uncontrolled growth and aberrant deregulation of core cell homeostatic pathways induced by genetic mutations create an environment of stress. Here, we explore how the adaptations of tumours to the changing environment can drive changes in the motility machinery of cells, affecting migration, invasion, and metastasis. Tumour cells can invade individually or collectively, or they can be extruded out of the surrounding epithelium. These mechanisms are thought to be modifications of normal processes occurring during development or tissue repair. Therefore, tumours may activate these pathways in response to environmental stresses, enabling them to survive in hostile environments and spread to distant sites.

Phenotypic Plasticity of Cancer Cells Based on Remodeling of the Actin Cytoskeleton and Adhesive Structures

“…The most common sequence of events nesessary to successfully colonize distant organs is termed “the invasion-metastasis cascade” and includes the following steps: (1) invasion at the local site through BM; (2) migration in surrounding tissues; (3) entrance into a circulatory system (blood or lymph vessel) and traveling through circulation; (4) arrest at a distant site and exit from the circulatory system; (5) survival and proliferation in a distant organ, resulting in formation of micro- and macrometastases [ 30 ]. In cancer, EMT is activated by signaling pathways from TGFβ (Transforming Growth Factor Beta), EGF (Epidermal Growth Factor), HGF (Hepatocyte Growth Factor), Notch, FGF (Fibroblast Growth Factor), Wnt, and IGF (Insulin-Like Growth Factor), signals from tumor microenvironment (e.g., cancer-associated macrophages or fibroblasts), hypoxia and increased matrix stiffness [ 29 , 31 , 32 , 33 , 34 ].…”

Metabolic Potential of Cancer Cells in Context of the Metastatic Cascade

“…Lung cancer cells are able to bypass such mechanical inhibition through adapting their cytoskeleton and hence maintain high glycolytic rates while other cells in the TME cannot [ 116 ]. In general, the composition of the ECM has an impact on the cell’s metabolic phenotype and also impacts the adhesion and migration efficiency of cells [ 117 , 118 , 119 , 120 , 121 , 122 ].…”

Interpretable deep learning uncovers cellular properties in label-free live cell images that are predictive of highly metastatic melanoma

“…Recent work has suggested mechanistic links between enhanced branched actin formation in lamellipodial and enhanced cell-cycle progression (Mohan et al, 2019;Molinie et al, 2019), especially in micro-metastases. Therefore, we offer as a hypothesis that the connection between pseudopod formation and metastatic efficiency predicted by our analysis relates to the lamellipodia-driven upregulation of proliferation and survival signals (Nikolaou and Machesky, 2020;Swaminathan et al, 2021).…”