Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation

Abstract

'Neosis' describes the process whereby p53 function-deficient tumour cells undergo self-renewal after genotoxic damage apparently via senescing ETCs (endopolyploid tumour cells). We previously reported that autophagic digestion and extrusion of DNA occurs in ETC and subsequently revealed that self-renewal transcription factors are also activated under these conditions. Here, we further studied this phenomenon in a range of cell lines after genotoxic damage induced by gamma irradiation, ETO (etoposide) or PXT (paclitaxel) treatment. These experiments revealed that chromatin degradation by autophagy was compatible with continuing mitotic activity in ETC. While the actively polyploidizing primary ETC produced early after genotoxic insult activated self-renewal factors throughout the polygenome, the secondary ETC restored after failed multipolar mitosis underwent subnuclei differentiation. As such, only a subset of subnuclei continued to express OCT4 and NANOG, while those lacking these factors stopped DNA replication and underwent degradation and elimination through autophagy. The surviving subnuclei sequestered nascent cytoplasm to form subcells, while being retained within the confines of the old ETC. Finally, the preformed paradiploid subcells became released from their linking chromosome bridges through autophagy and subsequently began cell divisions. These data show that 'neotic' ETC resulting from genotoxically damaged p53 function-deficient tumour cells develop through a heteronuclear system differentiating the polyploid genome into rejuvenated 'viable' subcells (which provide mitotically propagating paradiploid descendents) and subnuclei, which become degraded and eliminated by autophagy. The whole process reduces aneuploidy in descendants of ETC.

The “virgin birth”, polyploidy, and the origin of cancer

“…Various proposals have been made including; meiosis-like reduction divisions [15, 22]; reduction through diplochromosomes and haploidy [28, 29]; multi-polar mitoses [16, 46, 47]; and “a-mitotic budding” of descendent sub-cells [48-51]. Recently, we attempted to unite and order most of these various events as a necessary sequence of steps in a prolonged process of specific rearrangements [31, 52]. However, the mechanisms associated with survival of resistant tumour cells after the emergence of reversible polyploidy under genotoxic stresses remain hitherto ill-defined, at least in part because of the complexity, extension in time, and rarity of the process (as most cells die), and so the full picture remains obscure.…”

“…; Why is stemness induced in somatic tumour cells by DNA damage, and why is it associated with transient (reversible) polyploidy? ;Why do the sub-nuclei of polyploid giants cells behave autonomously and undergo asymmetric divisions [31, 54, 55];How and why do multinucleated tumour cells sequestrate cytoplasm to their individual sub-nuclear descendants [31]? ; How do they identify and sort the sub-nuclei containing viable or non-viable genetic material [31, 42, 55]?…”

“…;Why do the sub-nuclei of polyploid giants cells behave autonomously and undergo asymmetric divisions [31, 54, 55];How and why do multinucleated tumour cells sequestrate cytoplasm to their individual sub-nuclear descendants [31]? ; How do they identify and sort the sub-nuclei containing viable or non-viable genetic material [31, 42, 55]? ; Why does the extent of reversible polyploidisation have an apparent limit of ~32C which coincides with the cell number in the morula (blastulation) stage of embryogenesis [42] and are these somehow related?…”

Neoplastic-Like CELL Changes of Normal Fibroblast Cells Associated with Evolutionary Conserved Maternal and Paternal Genomic Autonomous Behavior (Gonomery)

“…They stressed the similarity in the cellular processes to offspring cells from giant-cells and budding yeast, and to amitotic cleavage of polyploid "simple organisms" (see Eudorina, ameba-above). They concluded in unison with earlier scientist's views and pledges [26] [79]- [81] that giant cells "---have not attracted much attention in the cancer research community and their roles in tumorigenesis have been largely untested." This is a sentiment, that should include lower endo-polyploid levels (4n/8C & 8n/16C), which occur in gynecological specimens and in Barrett' esophagus, recognized to be: "---beginning/pre-cancerous tissue ---" [22].…”

“…These somatic cell divisions are peculiarly similar in some details to meiosis (meiotic-like) as for instance [ Figure 3 & Figure 4 above] of Wilkins and Holiday [5]. Moreover, in tumor progression associated with depolyploidization to lower ploidy-levels the meiotic specific gene-products DMC1, Rec8 and MOS were up-regulated [26]. The uniqueness of this meiotic-like endo-two-step division-system is illustrated from fibroblastic growth showing the perpendicular orientation of co-segregating whole complements in the first division (Figure 1(C)).…”