Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 7, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2020838118
Keywords
metastasis; drug resistance; tumor microenvironment; whole-genome doubling; evolution
Categories
Funding
- Swedish Research Council [2019-05254]
- Crafoord Foundation
- European Union [949538]
- NIH/National Cancer Institute (NCI) [R01CA170595, U54CA143970-05]
- Patrick C. Walsh Prostate Cancer Research Fund
- Prostate Cancer Foundation
- NCI [U54CA143803, CA163124, CA093900, CA143055]
- European Research Council (ERC) [949538] Funding Source: European Research Council (ERC)
- Swedish Research Council [2019-05254] Funding Source: Swedish Research Council
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The theory introduces a new mechanism for cancer drug resistance, highlighting the importance of PACC formation and repopulation in treatment failure.
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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