Abstract 2548: Elucidating the significance of senescent tumor microenvironment in progression of pancreatic adenocarcinoma

Abstract Background: Oncogenes, oxidative stress, DNA damage response are typical stimulators for cellular senescence in tumor microenvironment (TME). The recent literature emphasizes on the dual nature of senescence where its tumor-promoting effects can outweigh the initial tumor-suppressive effects, especially when senescent cells accumulate and are not efficiently cleared. This study aims to see whether senescence in TME plays any role as contributing factor for the progression and relapse in pancreatic adenocarcinoma. Methodology: In 30 pancreatic adenocarcinoma tissue specimens, senescence was assessed by lysosomal mass quantification, immuno-staining of DNA damage foci, gene expression of cell cycle arrest markers and SASP factors profiling by ELISA. The relevant transcripts of metastasis, stemness and Wnt signaling were evaluated by gene and protein expression. In-vitro Doxorubicin induced senescence model (Panc-1 cells) was created and evaluated for validation of results. Results: The senescence was markedly elevated in tumor tissue, demonstrated by increased positivity of SA-β-gal, Ɣ-H2AX foci, cell cycle arrest markers (p16, p53, p21), pro-inflammatory cytokine (IL-10>0.0547*). The accumulated senescence was found significantly correlated with increased expression of invasiveness markers (Vimentin, and N-cadherin) stemness (Sox2, Oct4, Nanog). The co-localization of Ɣ-H2AX and Sox2 as seen in immunofluorescence microscopy concludes the presence of senescence along with stemness. Genes of Wnt signaling cascade (Wnt2<0.0039**; c-Myc< 0.0039**) which are involved in both senescence and stemness were significantly raised in pancreatic adenocarcinoma. Conclusion: Our findings highlight the critical role of metabolically active senescent cells in remodeling tumor microenvironment through secretory factors and presence of active stemness within. The senescence has positive influence on tumor promoting features like invasion, metastasis and tumor proliferation. Selective elimination of senescence can be a promising therapeutic implication considering the balance between beneficial and harmful effects of senescence in cancer treatment. Citation Format: Ankita Semwal, Anjali Aggarwal, Vinit Sharma, Mayank Sharma, Rajesh Gupta, Ritambhra Nadda. Elucidating the significance of senescent tumor microenvironment in progression of pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2548.