Abstract PR003: Fibroblast plasticity driven by Prrx1 interferes the tumor cells - tumor microenvironment crosstalk towards a more aggressive pancreatic ductal adenocarcinoma
Authors: Karin Feldmann, Carlo Maurer, Katja Peschke, Steffen Teller, Kathleen Schuck, Katja Steiger, Thomas Engleitner, Rupert Öllinger, Aristeidis Papargyriou, Rim Sabrina Jahan Sarker, Wilko Weichert, Anil K. Rustgi, Roland M. Schmid, Roland Rad, Günter Schneider, Dieter Saur, Maximilian Reichert
Journal: Cancer Research (2021)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibroblast-rich desmoplastic stroma which plays a critical role in the progression and therapeutic resistance of PDAC. The stroma is composed of extracellular matrix proteins, mainly deposited by the cancer-associated-fibroblasts (CAFs) and various types of immune cells. Cancer-associated fibroblasts display a high degree of interconvertible states including quiescent, inflammatory and myofibroblastic phenotypes. However, the mechanisms by which this plasticity is achieved are poorly understood. Here, we demonstrate that CAF plasticity promotes PDAC cell aggressiveness through multiple mechanism, particularly promoting Epithelial-to-Mesenchymal Transition and immune cell infiltration. Methods: To manipulate fibroblast plasticity in PDAC, we generated genetically engineered mouse models (GEMMs) in which CAF plasticity is modulated by genetical depletion of the transcription factor Prrx1 in fibroblasts by using orthotopic implantation models (Sm22-CreERT, Prrx1fl/fl, Rosa26mTmG) as well as dual recombinase-driven GEMMs (Pdx-Flp, FSF-KrasG12D/w t, p53fr/wtt, Sm22-CreERT, Prrx1fl/fl). To characterize the impact of CAFs on tumor differentiation, immune cell infiltration and response to chemotherapy various in vivo and in vitro co-culture experiments were performed. Results: Our in vivo results demonstrate that restraining CAF plasticity by Prrx1-depletion leads to more differentiated tumors, disrupts systemic tumor dissemination, including circulating tumor cells as well as metastases. Interestingly in tumors with Prrx1-deficient stroma, infiltration of macrophages and lymphocytes was increased. Specifically, we observed more B-cells as well as cytotoxic T-cells. Gene expression profiling of primary murine fibroblast samples revealed that Prrx1-deficient CAFs express myofibroblastic gene signatures characterized by ECM secretion phenotype. Indeed, on a functional level Prrx1-deficient CAFs secret more collagen and are highly migratory. Additionally, co-culture experiments of tumor cells and CAFs revealed that Prrx1-driven CAF-derived hepatocyte growth factor confers to a more invasive PDAC cell phenotype and resistant to therapy-induced apoptosis by inducing EMT in vitro. Importantly, in line with our in vitro and in vivo findings, compartment specific-gene expression analysis of human data revealed that pancreatic cancer patients with high stromal expression of Prrx1 display the squamous, most aggressive, subtype of PDAC. Conclusions: Here, we define that the Prrx1 transcription factor is critical for CAF plasticity, allowing a dynamic switch between different states. This work demonstrates that Prrx1-mediated CAF plasticity has significant impact on PDAC biology and therapeutic resistance. Citation Format: Karin Feldmann, Carlo Maurer, Katja Peschke, Steffen Teller, Kathleen Schuck, Katja Steiger, Thomas Engleitner, Rupert Öllinger, Aristeidis Papargyriou, Rim Sabrina Jahan Sarker, Wilko Weichert, Anil K. Rustgi, Roland M. Schmid, Roland Rad, Günter Schneider, Dieter Saur, Maximilian Reichert. Fibroblast plasticity driven by Prrx1 interferes the tumor cells - tumor microenvironment crosstalk towards a more aggressive pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PR003.