Modulation of fibrosis in pancreatic cancer by key players of the tumor microenvironment

• Applicant: Professorin Dr. Véronique Orian-Rousseau
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524774652

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer. Late diagnosis, aggressive local invasion, early systemic dissemination and resistance to chemo- and radiotherapy account for its poor prognosis. Pancreatic tumors are characterized by a desmoplastic stroma which occupies up to 80 % of the total tumor area. The pancreatic tumor microenvironment rich in extracellular matrix (ECM), and stromal cells comprised of cancer-associated fibroblasts (CAFs) –among which there are pancreatic stellate cells (PSCs), bone marrow-derived cells and resident fibroblasts –, immune cells, as well as endothelial and nerve cells, promotes cancer-cell proliferation, survival, invasion and metastasis. The highly fibrotic environment prevents vascularization and lymphocyte infiltration, thereby decreasing the success of chemotherapy. Modulation of the activation of PSCs/CAFs, the main actors in the desmoplastic reaction in PDAC, might have an impact on fibrosis, immunoregulation and cancer cells invasion. We propose, to investigate the potential of CD44 as a regulator of these processes through its pleiotropic functions as a co-receptor for several classes of cell surface receptors like CXCR4, LRP6, MET, VEGFR-2, EGFR and TGFbetaR the latter being relevant for special properties of PDAC. CD44 has been shown to interact with TGFbetaRI promoting or negatively regulating its signaling in different cell types, being still controversial. Based on our preliminary results showing a promoting effect of CD44 on TGFbeta signaling in PSCs, we aim at further dissecting the CD44/ TGFbeta crosstalk. We hypothesize that the removal of CD44 isoforms in PSCs/CAFs will have a global impact through the modulation of TGFbeta–as a central microenvironmental regulator in PDAC– as well as through its co-receptor function on receptor tyrosine kinases and GPCR signaling. To address the possible involvement of CD44 in the pancreatic tumor microenvironment, we will make use of Cd44 floxed mice crossed with PDGFRCreERT2 mice thus globally targeting CAFs, and GFAP-Cre mice more specific for PSCs. We will study the influence of the loss of Cd44 in these cell types on tumor growth and metastasis. We will characterize the phenotypical changes in the tumor stroma upon removal of Cd44, the ECM deposition, its physical effects and its consequences on the immune landscape. We will examine the crosstalk between fibroblasts devoid of Cd44 and cancer cells in terms of migration. Given the notable influence of specific isoforms such as CD44v6 on RTK signaling, we will also remove Cd44v6 in the same stromal cells using the Cd44v6 floxed mice. Finally, we will explore the effect on resistance to gemcitabine of pancreatic tumors lacking Cd44 on CAFs as compared to wild-type CAFs. The rescue of past treatment regimens that are less toxic than the current standard of care, may benefit a majority of patients with poorer performance status, highlighting its translational value.

• DFG Programme: Research Grants