Receptor tyrosine kinase signaling and extracellular matrix cues in ovarian cancer metastasis and drug resistance

Sammanfattning: Albeit many studies have contributed towards understanding the origin, development, treatment response and evolution of high-grade serous ovarian carcinoma (HGSC), the exact supporting mechanisms are still not fully understood, and the disease remains a clinical challenge with low 5-year survival and high recurrence rate. The purpose of this thesis was to study the dynamic communication between the cancer cells and the tumor microenvironment (TME) to understand how these influence and are affected by disease progression and chemotherapy in the context of HGSC. In Paper I we uncovered a robust platinum chemotherapy-induced ERK1/2-RSK1/2-EphA2- GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, RSK inhibition halted this signaling switch and even restored the canonical, tumor-suppressive EphA2 signaling, resulting in the efficient sensitization of HGSC cells to platinum treatment in vitro and in vivo. In addition, we described GPRC5A association to chemotherapy response, overall and progression-free survival in HGSC patients. In Paper II we reported that the ligand ephrinA5 was highly expressed in the most aggressive ovarian cancer type (i.e. HGSC) and further upregulated both at the protein and mRNA levels upon disease progression. Functionally, ephrinA5 left unaffected or even impaired EphA2 tumorsuppressive signaling. In Paper III we characterized the matrisome of HGSC solid tumors (primary and different metastatic sites) and ascites, pre- and post-chemotherapy. We showed that extracellular matrix (ECM) stiffness promoted cell proliferation and spreading (via focal adhesion kinase and YAP/TAZ signaling), and protected HGSC cells against cisplatinmediated, apoptosis-inducing DNA damage. In addition, we reported that different ECM components altered cell adhesion, migration and chemoresistance in diverse ways. In particular, collagen VI enhanced the chemoresistance of disease-recurrent, patient-derived organoids, was upregulated in HGSC patients upon chemotherapy and associated to poor survival. In conclusion, the findings of this thesis help us to better understand how ovarian cancer cells activate specific signaling mechanisms and engage in altered ECM remodeling and TME interactions that enhance cancer cell growth, metastatic and chemoresistance capabilities.