Understanding paracrine interactions induced by morphogens in PDAC

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by extreme chemotherapeutic resistance and the lack of effective immune response, fueling the need for effective treatment strategies. PDAC features include a complex desmoplastic stroma comprising cancer-associated fibroblasts (CAFs), a variety of lymphoid and myeloid cell lineages, and a plethora of paracrine signals that communicate between them. Malignant cells attract and reprogram stromal cells through morphogens like Sonic Hedgehog (SHH) and Transforming Growth Factor beta (TGFβ), creating a hospitable tumor microenvironment (TME) conducive to survival, growth, invasion, and escape from immune response. However, the underlying mechanisms mediating stromal reprogramming are understudied. This proposal aims to identify how active morphogen signaling shapes local immunosuppression in the pancreatic TME by focusing on the interaction of malignant epithelial cells, CAFs, myeloid cells, and T cells. In the past, targeting either of these populations has been insufficient to reverse immunosuppression, demonstrating that the complexity of crosstalk between diverse cell types in PDAC is insufficiently understood. By combining in vivo and ex vivo studies with a novel PDAC tumor explant platform, we are able to study cell-cell communication in an intact TME by manipulating morphogen signaling through targeted drugs, recombinant proteins, and neutralizing antibodies. These experimental approaches are guided by sophisticated computational analyses based on single cell RNA sequencing data. The overarching goal is to understand how CAFs and myeloid cells collaborate to maintain local immunosuppression within the pancreatic TME and leverage this understanding to reactivate anti-tumor immune response in PDAC. I hypothesize that combinatorial CAF and myeloid targeting will disrupt local immunosuppression and lead to partial reinstatement of T cell action that can be pushed further by immunomodulators. I will pursue this hypothesis through the following interrelated Specific Aims: In Aim 1, I will focus on how SHH-activated CAFs regulate the expansion of the myeloid cell population in PDAC. Aim 2 centers around building and testing a novel treatment regimen to reactivate exhausted T cells. Aim 3 seeks to identify differences between SHH and TGFβ-mediated CAF activation and downstream paracrine effects in the pancreatic TME. These studies will identify how malignant epithelial cells, CAFs, and myeloid cells work together to maintain immunosuppression through an intricate communication network. Successful completion of this proposal will both expand our basic understanding of PDAC immunosuppression and also produce a practical advance in the therapeutic targeting of this devastating disease. Concurrently, this work will facilitate my pathway towards an independent NIH-funded tenure-track faculty investigator by advancing my long-term objective of dissecting paracrine signaling cascades in PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is one of the most lethal cancers due to its extreme chemotherapeutic resistance and the lack of effective immune response. Local immunosuppression in the dense desmoplastic stroma is governed by morphogen signaling. This proposal aims to investigate how morphogen signaling influences the communication between epithelial tumor cells, cancer-associated fibroblasts, myeloid cells, and cytotoxic T cells, and exploit these findings for targeted therapy.