Reciprocal effects of BRCA-mutated Pancreatic Cancer and tumor microenvironment in Therapeutic Resistance
2Faculty of medicine, Tel-Aviv University
3Pathology department, Sheba Medical Center
4Department of Molecular Cell Biology, Weizmann Institute of Science
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Most patients are diagnosed with metastatic disease and have limited treatment options. BRCA1/2-mutated (BRCAmut) PDAC is a unique subgroup with exceptional responses to platinum chemotherapy and PARP inhibition. However, despite this promising strategy, most patients eventually develop resistance. Several resistance mechanisms, both cell-intrinsic and cell-extrinsic, were previously described. Our main objective is to interrogate cell-extrinsic mechanisms of resistance in BRCAmut-PDAC tumor microenvironment (TME), specifically in cancer-associated fibroblasts (CAFs), a major component of the PDAC TME, and to identify key-interactions that support resistance.
Materials and methods: We developed preclinical patient-derived models recapitulating the clinical scenarios of sensitive and resistant BRCAmut-PDAC. Moreover, we developed paired “in-vivo acquired resistant” models from initially sensitive tumors. We characterized the TME, histologically and molecularly, using spatial pathology, RNAseq and FACS analyses. PDAC and CAFs reciprocal interactions and their effect on immune cells were explored in co-culture systems.
Results and discussion: The resistant TME demonstrated a more cellular stroma and altered expression of factors related to resistance and immune system activation. Spectral FACS analysis revealed a shift in CAFs subtypes during emergence of resistance in-vivo and in in-vitro. Moreover, co-culture of patient-derived PDAC, CAFs and PBMCs demonstrated immune inhibition effects of the resistant PDAC that was lost using targeted inhibition. CAFs increased proliferation of BRCAmut PDAC organoids.
Conclusions: Overall, in-vivo and in-vitro analyses demonstrate the interplay between CAFs and PDAC. These interactions may highlight key-pathways contributing to therapeutic resistance. Developing targeted treatments for these interactions have the potential to improve survival of PDAC patients.