Spatiotemporal view of malignant histogenesis and macroevolution via formation of polyploid giant cancer cells

To understand how malignant tumors develop, the authors tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging. At the cellular level, the development of PGCCs was associated with forming of transient intracellular cells, termed fecundity cells. The fecundity cells can be decellularized to facilitate nuclear fusion and synchronized with other nuclei for subsequent nuclear replication. In addition, PGCCs can undergo several rounds of entosis to form complex tissue structures, termed fecundity structures. The formation of PGCCs via multiple modes of nuclear replication in the absence of cytokinesis leads to an increase in the nuclear-to-cytoplasmic (N/C) ratio and intracellular cell reproduction, which is remarkably similar to the mode of nuclear division during pre-embryogenesis. The study data support that PGCCs may represent a central regulator in malignant histogenesis, intra-tumoral heterogeneity, immune escape, and macroevolution via the de-repression of the suppressed pre-embryogenic program in somatic cells.