Navigating the paradox of senescence and chemoresistance in pancreatic cancer

Abstract

Cellular senescence, described as a mechanism of irreversible cell cycle arrest, has emerged as a complex and multifaceted process with significant implications in cancer biology, particularly in pancreatic ductal adenocarcinoma (PDAC). This literature review aims to explore the intricate role of senescence in PDAC, focusing on its dual nature during tumorigenesis, in addition to therapy resistance, and its potential as a therapeutic target. Senescence escape was found to play a crucial role in PDAC progression, prompting the development of various pro-senescence therapies. However, recent studies have revealed a paradoxical aspect of the senescence-associated secretory phenotype, revealing its pro-tumorigenic effects and contribution to immune evasion in PDAC. By integrating insights from recent molecular studies, this review synthesizes current knowledge on the role of senescence in PDAC tumorigenesis and chemoresistance, with an emphasis on the emerging role of the tumor microenvironment and explores current and promising avenues for future research and potential therapeutic interventions.

Keywords: Chemoresistance; Hypoxia; Metabolism; Oncogene-induced senescence; Pancreatic ductal adenocarcinoma; Senescence; Senescence-associated secretory phenotype; Stroma; Therapy-induced senescence; Tumor microenvironment.