CELL-INTRINSIC AND CELL-EXTRINSIC BIOPHYSICAL FORCES IN CANCER AGGRESSION
- Author(s): Miroshnikova, Yekaterina Andreevna;
- Advisor(s): Weaver, Valerie M;
- et al.
Tumors are mechanically-corrupted tissues. Although a role for tissue force in malignancy is slowly becoming appreciated, the molecular mechanisms underlying this phenotype remain poorly understood. Moreover whether similar relationships exist across distinct tumor types is not known. This motivated me to conduct a number of mechanobiological studies in breast, pancreatic, and brain cancers. To begin with I first developed the necessary tools with which to quantitatively assess tumor biology. This involved the development of a highly-controlled in vitro 3-dimensional hydrogel system that recapitulates biophysical stiffening of epithelial cancers and a bioreactor system that is able to model the compressive forces observed in intracranial cancers.
Epithelial malignancies contain abundant cross-linked collagen that increases tissue tension to promote malignant transformation by inducing focal adhesions and potentiating PI3 kinase signaling. In a context of breast cancer collagen cross-linking requires fibronectin and tumors contain abundant fibronectin and frequently express high levels of its ligand α5β1 integrin. I detected that fibronectin-bound α5β1 integrin is essential for collagen-dependent, stiffness-driven malignant transformation and explained why α5β1 integrin and fibronectin are consistently up-regulated in tumors and correlated their expression with breast cancer aggression. In a context of pancreatic ductal carcinoma I undertook collaborative studies which revealed that the cellular genotype tuned the tension of the malignant epithelium to mechanically prime the stroma and promote tumor progression through epithelial pSTAT3 and YAP. Highly aggressive pancreatic phenotypes developed within a highly stiff, matricellular-enriched and fibrotic tissue, and exhibited increased epithelial myosin activity with elevated cytokine, JAK, ROCK, FAK and Yap signaling, as well as STAT3-dependent inflammation. My work in these tumor tissues illustrated how tissue tension can force malignancy, drive tumor aggression, and compromise patient survival in the context of a collagen-rich microenvironments.
To detect whether these same principles apply to tissues lacking collagen-induced fibrosis, I extended my studies to glioblastoma multiforme (GBM). GBM brain tumors develop within a mechanically-challenged microenvironment that is characterized by high intracranial pressure, elevated solid stress and a dense hyaluronic acid (HA)-rich extracellular matrix that compromise vascular integrity to induce hypoxia and activate HIF1α. Interestingly, the presence of an R132H mutation in the metabolic regulator isocitrate dehydrogenous 1 (IDH1) improves patient prognosis in aggressive GBMs brain tumors and I hypothesized that IDH1 mutant GBM tumors would be less mechanically active than the more aggressive IDH WT tumors and that elevation of matrix mechanics could induce HIF1α and HIF1α-dependent gene expression in IDH1 mutant context to bypass the protective activity of the mutation and foster tumor aggression. Indeed, my studies showed that a stiff HA-rich ECM enhanced the aggressiveness of IDH1 mutant GBMs by inducing HIF1α-dependent tenascin C expression.
Taken together with the currently available data, my findings point to new possibilities for cancer intervention by normalizing tumor mechanobiology as they highlight the existence of a conserved mechanosignaling mechanism across the different tumor tissues towards which therapies might be developed.