Abstract 6015: Senescence-associated secretory phenotype drives PGCC‘s lifecycles and blastomere-like reprogramming to promote therapeutic resistance

Abstract Background: Polyploid giant cancer cells (PGCCs) are stress-responsive tumor subpopulations linked to treatment resistance and poor prognosis. While prior studies have characterized their senescent-like phenotypes and capacity for developmental reprogramming, two core questions remain poorly understood, including the temporal dynamics governing PGCC's lifecycle progression and the precise mechanistic role of senescence in shaping their biology. Methods: We induced PGCC formation using vincristine (VCR), a mitotic destabilizer, and tracked their lifecycle via live-cell fluorescence imaging. We assessed proliferative activity, EMT, blastomere-like features, and differentiation potential in vitro, alongside tumorigenicity in vivo. Mechanistically, we interrogated SASP cytokines using genetic silencing and pharmacologic inhibition. Results: VCR activated an endoreplication-based lifecycle in PGCCs, replacing canonical mitosis. PGCCs progressively exhibited reduced proliferation but enhanced EMT, progressive blastomere-like stemness, and multilineage differentiation. Both PGCC populations and their progeny acquired time/dose-dependent malignant traits and tumorigenic capacity. PGCCs partially adopted senescence, marked by elevated SASP cytokines. Silencing IL1β/IL6/IL8 or inhibiting their receptors suppressed PGCC formation, budding, EMT, and stemness, thus identifying SASP as critical for PGCC homeostasis and fate. Conclusion: Our work delineates PGCCs’ lifecycle evolution and establishes SASP as a key driver of their lifecycle and the emergence of aggressive, therapy-resistant progeny, bridging senescence, developmental reprogramming, and cancer progression. Citation Format: Zhiqian Zhang, Xiaoran Li, Xinxin Tian, Limin Deng, Jin-Tang Dong, Jinsong Liu. Senescence-associated secretory phenotype ​drives PGCC‘s lifecycles and blastomere-like reprogramming to promote therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6015.