Stromal Senescent Cells: Mechanisms of Formation and Action in the Pancreatic Tumor Microenvironment

Cellular senescence is a cell state acquired in response to various endogenous and exogenous stress signals and damages, where the cells enter a stable non-proliferative state and undergo alterations in their morphology, metabolism and secretory profile. In the context of cancer, both cancer and stromal cells can become senescent during disease progression and exert pro- and anti-tumorigenic functions. The deadly disease of pancreatic ductal adenocarcinoma (PDAC) has a rich tumor microenvironment (TME) that is immune “cold” and characterized by high abundance of cancer-associated fibroblasts (CAFs). While the presence of stromal cell senescence in PDAC has been observed, little is known about their identity, formation and action in the pancreatic TME. I aim to identify which stromal cells in the PDAC TME are in a senescent state, uncover the triggers for their formation and investigate their characteristics and roles in TME modulation. Additionally, I aim to explore the potential of targeting senescent cells as a therapeutic strategy. We found that most PDACs contain cells expressing the senescence marker p16 in tumor and stromal compartments, and that most of the stromal senescent cells are CAFs. Gene expression analysis of senescent CAFs, isolated from mouse and human pancreatic cancers, and identified within scRNA-seq datasets, revealed that these cells express elevated levels of genes that modulate the tumor immune microenvironment. Depletion of senescent CAFs in mouse PDACs increased the proportion of activated CD8+ T cells and improved the responses of mice carrying PDACs to immune checkpoint therapy. My ongoing and future work includes a detailed characterization of stromal senescence in mice models and human samples and the effects of their elimination on the TME, including the immune and vascular systems. I will test combinations of senolytic and immunotherapy treatments on PDAC models to elucidate potential therapeutic avenues. Furthermore, I aim to explore potential signals that induce senescence in the PDAC TME. Collectively, elucidating the signals that trigger stromal senescence and their roles in the pancreatic tumor microenvironment will provide the basis for their targeting as a novel therapeutic approach to treat pancreatic cancer in the clinic.