Mechanics & malignancy: Physical cues and changes that drive tumor progression
McGrail, Daniel James
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Despite advances in the molecular regulators of cancer, patient survival rates have stagnated. Mechanical cues from the extracellular matrix can induce a malignant phenotype, and the spread of cancer which results in 90% of cancer-related deaths is also a mechanical process. This work first shows that metastatic ovarian cancer cells, which preferentially metastasize to soft tissue, become more malignant on soft matrices by increasing adhesion, growth, chemoresistance, and migration as well as undergoing epithelial-to-mesenchymal transition (EMT). However, most cancers such as breast become more malignant on stiff matrices, so we next contrasted metastatic ovarian cancer cells with breast cancer cells. We show that matrix preference is dependent on basal levels of cytoskeletal tension and can be reversed or blocked by modulating cytoskeletal tension. To understand the biophysical changes associated with the phenomena observed on soft substrates, we next utilized matched cell lines that were either chemoresistant or had undergone EMT independent of substrate rigidity. To analyze chemoresistance, cells resistant to microtubule-targeting Taxol were isolated from ovarian cancer cell lines. We found that these cells altered their adhesion to produce down-stream changes in microtubules culminating in Taxol resistance. Next, in a genetically-induced EMT model we found near-identical phenotypic changes as seen with substrate-induced EMT. Moreover, these studies also revealed that mesenchymal cells are softer and can no longer support solid stress. Finally, we identify an actin-sodium channel pathway responsible for supporting solid stress. Taken together, this biophysical analysis reveals key pathways associated with cancer progression and identifies multiple pathways that could be targeted to reverse these changes, paving the way for novel therapeutic strategies.