Therapeutic Stress-induced Activation of PGCC Life Cycle Drives the Resistance Acquisition and Structured Tissue Differentiation

To elucidate how cancer cells generate resistance and defined forms of tissue structure in response to therapeutic stress, we tracked the temporal dynamics of life cycle of polyploid giant cancer cells (PGCCs) induced by the mitotic destabilizer vincristine (VCR). Live-cell fluorescence imaging revealed that VCR activated a distinct endoreplication-based life cycle, which replaced canonical mitosis. PGCCs exhibited reduced proliferative activity, enhanced epithelial-mesenchymal transition (EMT), progressive acquisition of blastomere-like features, and broad multilineage differentiation potential. Both PGCC populations and single PGCC-derived progeny displayed time- and dose-dependent acquisition of malignant traits in vitro and tumorigenic capacity in vivo. PGCC-derived spheroids exhibited ability to differentiate into the cells of origin from three germ layers. Importantly, pre-budding PGCCs induced by higher VCR concentrations exhibited enhanced ability for glandular structure formation and tissue differentiation. Morphologically, the nuclei of PGCC-derived spheroids underwent growth in size, formation of luminal structure, and followed by maturation of lumen. Mechanistically, PGCCs entered a senescent state characterized by elevated senescence-associated secretory phenotype (SASP)-manifested by rich proinflammatory cytokines. Notably, silencing IL1{beta}, IL6, or IL8, or pharmacological inhibition of their receptors, suppressed PGCC formation, budding, EMT, and blastomere-like reprogramming into structured tissue. Our studies provide novel mechanistic insights into early embryogenesis and tumorigenesis at the tissue structural developmental level.