Role of the different Semaphorin-3C isoforms in cancer-associated desmoplasia.

• Applicant: Dr. Juan Rodriguez Vita
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419966437

Cancer research is mainly focused in neoplastic cells despite the fact that the number of processes regulated by the tumor microenvironment is constantly increasing. This is of particular importance in pancreatic cancer where the stromal compartment accounts for up to 90% of the total tumor mass. In this specific tumor the majority of stromal cells are fibroblasts. Fibroblasts can be reversibly activated to myofibroblasts during wound healing. Thereby they adopt a contractile, migratory and secretory phenotype. In cancer, the activation of fibroblasts is more stable and associated with an even stronger secretory phenotype, immunomodulatory properties and proliferation. These so-called cancer-associated fibroblasts (CAF) contribute to tumor progression by secreting extracellular matrix (ECM) molecules, cytokines and other tumor-promoting factors. The mortality of pancreatic cancer is nearly equal to its incidence mainly due to high resistance of these tumors against chemotherapy. In the last years, the massive stromal component was identified as a main cause of progression and resistance in pancreatic cancer. The accumulation and activation of fibroblasts, resulting in ECM deposition, is called desmoplasia. Additional to their contribution to cancer progression by secreting pro-tumorigenic factors, CAF shield the tumor from chemotherapeutics by increasing the interstitial fluid pressure, thereby decreasing the infiltration of drugs into the tumor resulting in resistance. Targeting the ECM could help to regain vascular homeostasis within tumors to improve the distribution of chemotherapy and in turn increase its therapeutic effect. We propose that SEMA3C, a member of the Semaphorin protein family, could be employed to interfere with desmoplasia. It has recently been described that increased SEMA3C expression correlates with enhanced tumor growth and metastasis in pancreatic ductal carcinoma (PDAC). Our preliminary data show that SEMA3C expression increases during fibrosis while expression of Furin proteases, which cleave SEMA3C, disappears. The Furin-cleaved SEMA3C-p60 isoform inhibits TGF-β-mediated myofibroblast transdifferentiation and fibrosis. SEMA3C represses TGF-β receptor II expression through PARP1.This project is aimed at better understanding how Semaphorin-3C contributes to fibroblast activation in pancreatic cancer and to develop preclinical strategies interfering with this. We will decipher how SEMA3C isoforms transmit signals in fibroblasts and how this affects their behavior. We have developed several tools to deliver SEMA3C-p60 into PDAC mouse models. This will allow analyzing its effects on tumor progression, tumor-associated desmoplasia, immunosuppression, delivery of chemotherapy and metastasis. In summary, we will obtain valuable information on how SEMA3C isoforms control tumor-associated desmoplasia to pave the way towards novel strategies interfering with the tumor stroma.

• DFG Programme: Research Grants