The Role of Mitotic Slippage in Creating a “Female Pregnancy-like System” in a Single Polyploid Giant Cancer Cell

Abstract

In our recent work, we observed that triple-negative breast cancer MDA-MB-231 cells respond to doxorubicin (DOX) via “mitotic slippage” (MS), discarding cytosolic damaged DNA during the process that provides their resistance to this genotoxic treatment. We also noted two populations of polyploid giant cells: those budding surviving offspring, versus those reaching huge ploidy by repeated MS and persisting for several weeks. Their separate roles in the recovery from treatment remained unclear. The current study was devoted to characterising the origin and relationship of these two sub-populations in the context of MS. MS was hallmarked by the emergence of nuclear YAP1/OCT4A/ MOS/EMI2-positivity featuring a soma-germ transition to the meiotic-metaphase-arrested “maternal germ cell”. In silico, the link between modules identified in the inflammatory innate immune response to cytosolic DNA and the reproductive module of female pregnancy (upregulating placenta developmental genes) was observed in polyploid giant cells. Asymmetry of the two subnuclei types, one repairing DNA and releasing buds enriched by CDC42/ACTIN/TUBULIN and the other persisting and degrading DNA in a polyploid giant cell, was revealed. We propose that when arrested in MS, a “maternal cancer germ cell” may be parthenogenetically stimulated by the placental proto-oncogene parathyroid-hormone-like-hormone, increasing calcium, thus creating a ”female pregnancy-like” system within a single polyploid giant cancer cell.

Cdc42 Regulates the Expression of Cytoskeleton and Microtubule Network Proteins to Promote Invasion and Metastasis of Progeny Cells Derived from CoCl2-induced Polyploid Giant Cancer Cells

“…The small GTPases Cdc42 can regulate the expression of cytoskeletal proteins which are involved in regulating cell polarity, microtubule dynamics, and asymmetric cell division 5 , 27 , 28 . In the present study, we confirmed that Cdc42 and its related proteins in the regulation of cytoskeleton are involved in the asymmetric generation of PGCCs to generate progeny cells with enhanced invasion and migration abilities.…”

Special Issue “Advances in Genome Regulation in Cancer”

“…With regards the embryonic nature of cancer exhibited by PGCCs as supported by the TCGA database in [13] and previous studies [33,34], the most recent paper in this Issue by Salmina et al [14] added an unexpected aspect to the characteristics of PGCCs. As created by repeated mitotic slippage in a breast cancer cell line in response to doxorubicin treatment, the transcriptome analysis of the resulting PGCCs revealed not only female meiosis but also stark upregulation of the invasive "female pregnancy" Gene Ontology module elaborated in the innate immunity network.…”

“…Currently, there are several converging and parallel hypotheses of how the cancer genome is regulated. New ideas for therapies and various facets of these hypotheses are explored in the ten articles presented in this Special Issue [5][6][7][8][9][10][11][12][13][14].…”

“…Complex network analytical tools allow the detection of the most relevant nodes of the networks (hubs, high-centrality nodes) for signal processing. Complex network approaches are used here in several articles [7,10,[12][13][14]. Moreover, this network approach provides a new paradigm for drug discovery [18].…”

Self-organisation of early stress response in the biology of cancer

“…4A) and in particular the system of embryo invasion and "female pregnancy" (Fig. 4B) [35]. It is pioneered by the AP-1 complex.…”