Acquisition of Therapeutic Resistance and Structured Tissue Differentiation via Activation of the Life Cycle of Polyploid Giant Cancer Cells.

Authors

Zhiqian Zhang, Xiaoran Li, Xinxin Tian, Limin Deng, Jin-Tang Dong, Jinsong Liu

Published in

Cancer letters. Pages 218928. Oct 29, 2026. Epub Oct 29, 2026.

Abstract

To elucidate the mechanisms underlying therapy-induced resistance, we investigated the temporal dynamics of the polyploid giant cancer cell (PGCC) life cycle following treatment with the microtubule-destabilizing agent vincristine (VCR). Longitudinal live-cell fluorescence imaging revealed that VCR-induced mitotic suppression activated a distinct PGCC life cycle characterized by nuclear amplification and progressive cellular reprogramming. At the cellular level, PGCCs entered a senescence-like state accompanied by an enhanced senescence-associated secretory phenotype (SASP), increased epithelial-mesenchymal transition (EMT), acquisition of early embryonic-like features, and multilineage differentiation potential into ectoderm, mesoderm, and endoderm. PGCC-derived progeny exhibited dose- and time-dependent changes in proliferative behavior, aggressive phenotypes in vitro, along with time-dependent tumorigenic potential in vivo. Remarkably, at the tissue level, PGCCs also underwent spatial nuclear reorganization and self-organization into morphologically defined glandular epithelial structures exhibiting varying degrees of tissue maturation, reminiscent of early embryonic development. Silencing IL1β, IL6, or IL8, or pharmacologically inhibiting their receptors, suppressed PGCC formation, budding, EMT, and embryonic-like reprogramming associated with tissue morphogenesis. Furthermore, NAMPT emerged as a key regulator of embryonic-like stemness, glandular morphogenesis, and structural expansion. Together, these findings reveal that therapeutic stress activates a PGCC life cycle capable of generating two divergent outcomes: resistant tumor regeneration through clonal selection of undifferentiated tumor cells and organized tissue differentiation through spatial nuclear reprogramming. Our study establishes a conceptual framework linking therapy-induced polyploidization, developmental plasticity, and resistance generation at both cellular and tissue levels.

PMID:
42956987
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.

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