A mechanism for asymmetric cell division resulting in proliferative asynchronicity.

Mol Cancer Res
Authors
Keywords
Abstract

UNLABELLED: All cancers contain an admixture of rapidly and slowly proliferating cancer cells. This proliferative heterogeneity complicates the diagnosis and treatment of patients with cancer because slow proliferators are hard to eradicate, can be difficult to detect, and may cause disease relapse sometimes years after apparently curative treatment. While clonal selection theory explains the presence and evolution of rapid proliferators within cancer cell populations, the circumstances and molecular details of how slow proliferators are produced is not well understood. Here, a β1-integrin/FAK/mTORC2/AKT1-associated signaling pathway is discovered that can be triggered for rapidly proliferating cancer cells to undergo asymmetric cell division and produce slowly proliferating AKT1(low) daughter cells. In addition, evidence indicates that the proliferative output of this signaling cascade involves a proteasome-dependent degradation process mediated by the E3 ubiquitin ligase TTC3. These findings reveal that proliferative heterogeneity within cancer cell populations, in part, is produced through a targetable signaling mechanism, with potential implications for understanding cancer progression, dormancy, and therapeutic resistance.

IMPLICATIONS: These findings provide a deeper understanding of the proliferative heterogeneity that exists in the tumor environment and highlight the importance of designing future therapies against multiple proliferative contexts. VISUAL OVERVIEW: A proposed mechanism for producing slowly proliferating cancer cells. http://mcr.aacrjournals.org/content/early/2015/01/09/1541-7786.MCR-14-0….

Year of Publication
2015
Journal
Mol Cancer Res
Volume
13
Issue
2
Pages
223-30
Date Published
2015 Feb
ISSN
1557-3125
URL
DOI
10.1158/1541-7786.MCR-14-0474
PubMed ID
25582703
PubMed Central ID
PMC4336804
Links
Grant list
R01 CA185086 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States