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Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Pienta, K. J. ; Hammarlund, E. U. LU ; Brown, J. S. ; Amend, S. R. and Axelrod, R. M. (2021) In Proceedings of the National Academy of Sciences of the United States of America 118(7).
Abstract

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to... (More)

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
drug resistance, evolution, metastasis, tumor microenvironment, whole-genome doubling
in
Proceedings of the National Academy of Sciences of the United States of America
volume
118
issue
7
publisher
National Academy of Sciences
external identifiers
  • pmid:33504594
  • scopus:85100654450
ISSN
1091-6490
DOI
10.1073/pnas.2020838118
language
English
LU publication?
yes
id
7e6c7013-ea00-4216-beca-89fc56aeb698
date added to LUP
2021-02-23 08:52:51
date last changed
2024-05-03 03:16:18
@article{7e6c7013-ea00-4216-beca-89fc56aeb698,
  abstract     = {{<p>We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.</p>}},
  author       = {{Pienta, K. J. and Hammarlund, E. U. and Brown, J. S. and Amend, S. R. and Axelrod, R. M.}},
  issn         = {{1091-6490}},
  keywords     = {{drug resistance; evolution; metastasis; tumor microenvironment; whole-genome doubling}},
  language     = {{eng}},
  number       = {{7}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells}},
  url          = {{http://dx.doi.org/10.1073/pnas.2020838118}},
  doi          = {{10.1073/pnas.2020838118}},
  volume       = {{118}},
  year         = {{2021}},
}