Minimization of thermodynamic costs in cancer cell invasion

Abstract

Metastasis, the truly lethal aspect of cancer, occurs when metastatic cancer cells in a tumor break through the basement membrane and penetrate the extracellular matrix. We show that MDA-MB-231 metastatic breast cancer cells cooperatively invade a 3D collagen matrix while following a glucose gradient. The invasion front of the cells is a dynamic one, with different cells assuming the lead on a time scale of 70 h. The front cell leadership is dynamic presumably because of metabolic costs associated with a long-range strain field that precedes the invading cell front, which we have imaged using confocal imaging and marker beads imbedded in the collagen matrix. We suggest this could be a quantitative assay for an invasive phenotype tracking a glucose gradient and show that the invading cells act in a cooperative manner by exchanging leaders in the invading front.T umor metastasis is obviously of enormous clinical importance.A fundamental physiologic and clinical difference between benign and malignant tumor cells is that the former are usually neither invasive nor fatal. It is currently difficult to predict the probability of metastasis from the morphological or phenotypic properties of tumor cells observed within a primary cancer. Invasive tumor growth, at both primary and secondary sites, requires tumor cells to break through the stromal tissue barrier, evade the immune system, and coordinate signaling among tumor and mesenchymal cells to promote formation of tissue infrastructure, such as angiogenesis, to maintain tumor viability in its newly invaded space (1). We test two hypotheses: (i) The extreme thermodynamic costs of the oxidative Warburg cycle used by cancer cells forces them to follow glucose gradients; and (ii) minimization of the thermodynamic costs can be achieved by collective invasion strategies.Invading cells are subject to significant potential fitness costs that may be minimized by collective behavior. Metastatic tumor cells that leave the primary tumor have to break through the stromal tissue barrier, evade the immune system, and coordinate with other local cells during angiogenesis to finally set up a viable remote tumor. It has been estimated that less than 1% of the primary tumor cells are able to finish the metastasis cycle (2), and yet they contribute to more than 90% of the cancer-related deaths (3). Although the molecular details are still unclear, it is significant that the malignant transition is accompanied by a change in the metabolism pathway from the mitochondrial oxidation of pyruvate in mitochondria (an aerobic process) to the far less energy-efficient and ancient anaerobic pathway of glycolysis followed by lactic acid fermentation in the cytosol (4), known as the Warburg cycle (5).Most, if not all, metastatic cancer cells use the Warburg cycle, which is a far less efficient metabolism in terms of ATP production (6), consuming glucose (glycolysis) rather than using the usual oxidative Krebs phosphorylation cycle, although, thermodynamically, the process is efficient in the storage...

Cell motility and drug gradients in the emergence of resistance to chemotherapy

“…A further consideration in using the MDA-MB-231 cell line is the connection between metastasis, motility, and metabolic energy consumption. Metastatic breast cancer MDA-MB-231 uses the aerobic glycolysis, compared with the usual mitochondrial oxidative phosphorylation cycle, consuming glucose less efficiently in terms of ATP production but more efficiently in storage of chemical energy (21,22). Although cancer invasion and resistance have been discussed separately for a long time, the two phenotypes reveal substantial overlaps on bimolecular pathways and demand in energy consumption.…”

“…Conventional chemotaxis would be expected to drive the cells away from the high-drug region. However, from a fitness advantage perspective it is advantageous for a cell to move toward regions of higher stress if resistance emerges because of reduced competition for resources such as glucose, oxygen, or space (22). (iii) The third scenario is local evolution of resistance to the drug without any influence of migration of the cells.…”

Mechanotransduction of mesenchymal melanoma cell invasion into 3D collagen lattices: Filopod-mediated extension–relaxation cycles and force anisotropy

“…As 3D environments for migration and traction analysis, cells are embedded in either synthetic substrate, typically elastic polyethylene glycol hydrogels [13,14], or scaffolds composed of physiological, in vivo-like polymers, such as fibrillar collagen matrices [15]. The forces generated by individual cells or cell populations are detected as displacement of co-embedded reference markers, such as beads, followed by mathematical postprocessing [5,9,16,17]. Alternatively, or in addition, ECM fibrils are directly detected by differential interference contrast [18] or 3D confocal reflectance microscopy [19][20][21] to track the kinetics of reversible or irreversible displacement and transport [22,23].…”

Ancient hot and cold genes and chemotherapy resistance emergence

“…Recent studies of the bone marrow represent an ideal ecology to be reproduced by microfluidic systems, with designed in vitro complex environments with a functional hematopoietic niche (3). Glucose gradient or chemotherapy gradients have been used to study the phenotypic progression of cancer in complex environments (4,5); now we add the compartmentalization of small, possibly clonal, communities within the gradient. Just as rapid fixation of drug-resistant bacterial mutants in a metapopulation can occur in an environment with drug gradients and connected microhabitats (6)(7)(8), we demonstrate that an ecologically designed microenvironment, with drug gradients and connected microhabitats, can drive the rapid emergence of resistance in MM.…”