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

Abstract

To understand how malignant tumors develop, we 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. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. At the cellular level, the development of PGCCs was associated with forming 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. 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. Our data support that PGCCs may represent a central regulator in malignant histogenesis, intratumoral heterogeneity, immune escape, and macroevolution via the de-repression of suppressed pre-embryogenic program in somatic cells.

Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

“…The endoreplication cycle eventually resulted in the development of PGCCs (mostly mononucleated PGCCs). Here, we found that PGCCs divided into daughter cells through diverse variants of mitosis, such as multipolar mitosis and RMEM as we recently reported ( 22 ). These aberrant mitoses generated multiple micronuclei and inevitably increased chromosomal instability, genomic chaos, and cancer macroevolution ( 22 , 39 , 52 , 53 ), which is known to contribute to chemotherapy resistance ( 54 , 55 ).…”

“…S4E and movie S8). In addition, during division, PGCCs can undergo restitution multipolar endomitosis (RMEM) ( 22 ), resulting in a massively fragmented multinucleated PGCC (Fig. 4D, fig.…”

“…Our previous studies showed that PGCCs dedifferentiate from mature somatic cells by recapitulating a blastomere-stage cleavage program that augments the nucleus and gives rise to embryonic life ( 16 , 20 , 22 ). Because they mimic early embryonic development, we propose that PGCCs may represent “somatic blastomeres” ( 28 , 40 – 42 ).…”

“…These senescent cells contain either a highly enlarged nucleus or multiple nuclei, often accompanied by markedly increased cell size and genomic content, and are now referred to as polyploid giant cancer cells (PGCCs) (15,16). Although PGCCs were often overlooked or mispresented as "dead cells" in the past owing to their inability to execute mitosis, they are now known to generate therapy-resistant daughter cells via nuclear budding or bursting (16)(17)(18)(19)(20)(21)(22), forming transient cell-in-cell structures called fecundity cells (22,23). It has been recently shown that PGCCs recapitulate properties of the blastomere-stage embryonic program of dedifferentiation (16,20,22,24,25).…”

“…Although PGCCs were often overlooked or mispresented as "dead cells" in the past owing to their inability to execute mitosis, they are now known to generate therapy-resistant daughter cells via nuclear budding or bursting (16)(17)(18)(19)(20)(21)(22), forming transient cell-in-cell structures called fecundity cells (22,23). It has been recently shown that PGCCs recapitulate properties of the blastomere-stage embryonic program of dedifferentiation (16,20,22,24,25). PGCCs are also known to contribute to therapy resistance in various types of solid tumors, including ovarian (16), prostate (19,(26)(27)(28), colon (29), and breast cancers (30) and melanoma (31).…”