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When Three Isn't a Crowd: A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers
Kristine Salmina1, Bogdan I Gerashchenko2, Michael Hausmann3
1Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
Abstract:
Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a conceptual framework of the digyny-like origin of this karyotype based on the germline features of malignant tumors and adaptive capacity of digyny, which supports survival in adverse conditions. Studying how the recombinatorial reproduction via diploidy can be executed in primary cancer samples and HeLa cells after DNA damage, we report the first evidence that diploid and triploid cell sub-populations constitutively coexist and inter-change genomes via endoreduplicated polyploid cells generated through genotoxic challenge. We show that irradiated triploid HeLa cells can enter tripolar mitosis producing three diploid sub-subnuclei by segregation and pairwise fusions of whole genomes. Considering the upregulation of meiotic genes in tumors, we propose that the reconstructed diploid sub-cells can initiate pseudo-meiosis producing two "gametes" (diploid "maternal" and haploid "paternal") followed by digynic-like reconstitution of a triploid stemline that returns to mitotic cycling. This process ensures tumor survival and growth by (1) DNA repair and genetic variation, (2) protection against recessive lethal mutations using the third genome.
Insights
Near-triploid tumors may survive radio/chemotherapy via a digyny-like process. Diploid and triploid cells exchange genomes, with triploid cells undergoing pseudo-meiosis to generate diploid and haploid gametes, ensuring tumor survival and variation.
Area of Science:
- Cancer Biology
- Genetics
- Cell Biology
Background:
- Near-triploid human tumors often exhibit resistance to radio/chemotherapy.
- The underlying mechanisms for this resistance remain largely unclear.
- Previous work linked male tumor triploidy to XXY karyotypes.
Purpose of the Study:
- To propose a conceptual framework for the digyny-like origin of XXY karyotypes in tumors.
- To investigate genome exchange between diploid and triploid cell populations after DNA damage.
- To explore the role of pseudo-meiosis in tumor survival and adaptation.
Main Methods:
- Analysis of primary cancer samples and HeLa cells.
- Induction of DNA damage and observation of cellular responses.
- Microscopy to study mitosis and genome segregation.
- Gene expression analysis focusing on meiotic genes.
Main Results:
- Diploid and triploid cell subpopulations constitutively coexist and exchange genomes.
- Genotoxic stress induces endoreduplication and polyploid cell formation.
- Irradiated triploid HeLa cells can undergo tripolar mitosis, forming diploid sub-subnuclei.
- Evidence suggests reconstructed diploid cells initiate pseudo-meiosis, producing "gametes".
Conclusions:
- A digyny-like process involving genome exchange and pseudo-meiosis may explain tumor survival and adaptation.
- This mechanism promotes DNA repair, genetic variation, and protection against recessive lethal mutations.
- The findings offer a new perspective on the resistance of near-triploid tumors to cancer therapies.