Identification and Characterization of Cellular Senescence in Pancreatic Ductal Adenocarcinoma

Most cancers present a complex system of interactions between heterogenous tumor cell populations and diverse components of the microenvironment. Different types of damage and stress within tumors provoke some cells to undergo cellular senescence, a state that involves cell-cycle arrest, and a secretory phenotype that can have diverse effects on tumorigenesis. The involvement of cellular senescence in the deadly pancreatic ductal adenocarcinoma is poorly understood. Our goal is to identify which cell types are in a senescent state, particularly in the tumor stroma. We aim to characterize their features and functions in modulating the tumor microenvironment. To uncover the prevalence of senescence, we stained a panel of human pancreatic cancer sections of different stages for the senescence marker p16INK4a. We found that most samples contained p16+ cells, with a high degree of variation between and within lesions. Interestingly, in premalignant lesions p16+ cells were mostly in the tumor epithelial compartment whereas in carcinomas a stromal p16+ fraction was more prominent, mostly representing fibroblasts. In mouse models, we found a similar pattern of p16 expression. Our ongoing work includes a detailed characterization of senescent cells presence in human tumors and their expression profiles by analysing scRNA-seq datasets of pancreatic cancer, understanding the effects of senescence induction on the tumor and its microenvironment, and uncovering potential signals that activate senescence in the stroma. Elucidating the roles of senescent cells in the tumor microenvironment will provide the basis for the targeting of such cells as a novel therapeutic approach in cancer therapy.