The Role of mitotic slippage in creating a “female pregnancy-like system” in a single polyploid giant cancer cell
The Role of mitotic slippage in creating a “female pregnancy-like system” in a single polyploid giant cancer cell
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.
budding, cancer, female pregnancy system, innate immune response, maternal germ cell, mitotic slippage, parthenogenesis, placental developmental genes, polyploid giant cell, resistance to treatment, soma-germ transition
Salmina, Kristine
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Vainshelbaum, Ninel M.
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Kreishmane, Madara
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Inashkina, Inna
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Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Pjanova, Dace
cc905f38-5439-47da-b4ba-6e1311fa6785
Erenpreisa, Jekaterina
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6 February 2023
Salmina, Kristine
00a98b4d-8de8-4e78-99f7-a8834851d209
Vainshelbaum, Ninel M.
069ba573-1a06-49be-8f06-06e2446a6a4a
Kreishmane, Madara
7f584ce6-e889-47ab-adb0-7ddc7b0f915a
Inashkina, Inna
24b235f4-a65e-4e63-ba8f-17bfecfa4e4e
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Pjanova, Dace
cc905f38-5439-47da-b4ba-6e1311fa6785
Erenpreisa, Jekaterina
70b5fecb-7208-431f-bd35-ec498edc0033
Salmina, Kristine, Vainshelbaum, Ninel M., Kreishmane, Madara, Inashkina, Inna, Cragg, Mark, Pjanova, Dace and Erenpreisa, Jekaterina
(2023)
The Role of mitotic slippage in creating a “female pregnancy-like system” in a single polyploid giant cancer cell.
International Journal of Molecular Sciences, 24 (4), [3237].
(doi:10.3390/ijms24043237).
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.
Text
ijms-24-03237
- Accepted Manuscript
Text
ijms-24-03237-v2
- Version of Record
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Accepted/In Press date: 31 January 2023
Published date: 6 February 2023
Additional Information:
Funding Information:
This research was supported by a grant from the European Regional Development Fund (ERDF) project No. 1.1.1.2/VIAA/3/19/463 for K.S. and the 8.2.2.0/20/I/006 “University of Latvia Doctoral Study Program Capacity Enhancement Through a New PhD Model” project for N.M.V.
Publisher Copyright:
© 2023 by the authors.
Keywords:
budding, cancer, female pregnancy system, innate immune response, maternal germ cell, mitotic slippage, parthenogenesis, placental developmental genes, polyploid giant cell, resistance to treatment, soma-germ transition
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Local EPrints ID: 476030
URI: http://eprints.soton.ac.uk/id/eprint/476030
ISSN: 1422-0067
PURE UUID: e812ef25-0ccd-4573-9328-2e91f83204fa
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Date deposited: 04 Apr 2023 16:52
Last modified: 17 Mar 2024 02:46
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Contributors
Author:
Kristine Salmina
Author:
Ninel M. Vainshelbaum
Author:
Madara Kreishmane
Author:
Inna Inashkina
Author:
Dace Pjanova
Author:
Jekaterina Erenpreisa
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