期刊
MOLECULAR CANCER RESEARCH
卷 13, 期 2, 页码 223-230出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-14-0474
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资金
- Stand Up to Cancer Innovative Research Grant [SU2C-AACR-IRG0911]
- National Cancer Institute
- Howard Hughes Medical Institute
- CNPq Ciencia sem Fronteiras-Brazil [202620/2012-3]
- HHMI Medical Student Research Fellowship
- Bolsa de Ampliacion de Estudios, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad [BA12/00021]
- NATIONAL CANCER INSTITUTE [R01CA185086] Funding Source: NIH RePORTER
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 beta 1-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. (C) 2015 AACR.
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