title: A mechanism for asymmetric cell division resulting in proliferative asynchronicity.
abstract: 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.
  
  
  CONCLUSIONS
  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-14-0474/F1.large.jpg.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Dey-Guha
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Cleidson P
authors.initials: CP
authors.lastname: Alves
authors.affiliation: Harvard Medical School, Boston, Massachusetts.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Yeh
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.lastname: Salony
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sole
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Revati
authors.initials: R
authors.lastname: Darp
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Harvard-Ludwig Center for Cancer Research, Boston, Massachusetts. sridhar@mgh.harvard.edu.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
mesh_terms: D060049:Asymmetric Cell Division; D060965:Clonal Evolution; D018740:Genetic Heterogeneity; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt