Cancer cell-microenvironment communication in tumor progression and therapy resistance

Despite effective treatments, the prognosis of patients with metastatic cancer remains poor due to the recurrence of chemotherapy-resistant cancer. Genomic instability and the accumulation of mutations in progressive tumors drive cancer cell inherent features, such as invasion and proliferation. However, tumor progression and treatment resistance are not isolated events due to cancer-genetic and epigenetic alterations but also require a permissive tumor microenvironment (TME). Transduced into cancer cells by cell surface receptors, such as integrins and receptor tyrosine kinases (RTKs), the signaling cascades from the TME and extracellular matrix (ECM), promote the development of metastases as well as resistance to treatments by regulating cancer growth, tissue penetration, and apoptosis evasion. However, the key mechanisms and pathways activated during cancer evolution, including invasion, metastasis, and tissue responses to chemotherapy, remain to be systematically identified. The aim of this thesis was to study the cancer cell-ECM interactions and cancer cell-intrinsic factors enabling tumor progression and treatment resistance. In this thesis, we found that disease progression and chemotherapy treatment induce desmoplastic reaction in the TME of high-grade serous ovarian cancer (HGSC), both in the primary tumor and metastatic tissues. The results indicate that the stiff fibrotic tumor ECM, specific ECM substrates, and chemotherapy itself promote tumor cell proliferation, spreading, and chemoresistance. In particular, we demonstrated that in response to stiffness, platinum treatment, and collagen VI, the activation of focal adhesion kinase (FAK)-integrin β1-YAP signaling enhances the apoptosis evasion of HGSC cells harboring intrinsic treatment resistance. We also found a robust mechanism, whereby HGSC cells gain platinum resistance via platinum treatment-induced, adaptive RSK1/2-EphA2-GPRC5A signaling switch. Mechanistically, this signaling switch was blocked by the inhibition of RSK kinase, resulting in platinum re-sensitization of HGSC cells. In addition, by using a fibrotic tumor stroma-mimicking 3D model, we found that RTK RET proto-oncogene-mediated Ras-MAPK pathway activity, responsible for multiple tumor progression features, such as cancer invasion, is inhibited by PTPRA phosphatase. Using this analysis, we found a novel driver gene, ECHDC1, acting as a tumor-suppressor that inhibits invasive cancer growth. To summarize, the studies compiled in this dissertation support the need for precision medicine approaches to target novel cancer cell-intrinsic tumor progression regulators, as well as to target the ECM-signaling pathways and their effects on disease development and chemoresistance.