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 cancer patients 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 AKT1low 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.

AKT Inhibition Promotes Nonautonomous Cancer Cell Survival

“…Interestingly, we have also found that human cancer cell lines treated with allosteric small-molecule AKT inhibitors (e.g., Akti-1/2, MK-2206), at a sub-therapeutic dose (i.e., which only partially suppresses AKT signaling by about 80–90%), dramatically increase their fraction of AKT low , MCM2 low , H3K9me2 low , HES1 high cancer cells (6, 9–11). These quiescent cancer cells rapidly resume their cell cycle with inhibitor washout, consistent with a temporary rather than permanent cell cycle arrest, which is identical to spontaneously arising AKT low slow proliferators (10).…”

“…We recently discovered that epithelial cancer cells growing in culture occasionally divide asymmetrically by suppressing AKT signaling in one emerging “AKT low ” daughter cell (9, 10). This unusual type of cell division is triggered by an asymmetric decrease in Type I collagen-β1-integrin-FAK signaling, resulting in activation of the mTORC2 signaling complex, partial phosphorylation of AKT1 kinase, and its activation-induced degradation mediated by the E3-ubiquitin ligase TTC3 and the proteasome (9).…”

“…This unusual type of cell division is triggered by an asymmetric decrease in Type I collagen-β1-integrin-FAK signaling, resulting in activation of the mTORC2 signaling complex, partial phosphorylation of AKT1 kinase, and its activation-induced degradation mediated by the E3-ubiquitin ligase TTC3 and the proteasome (9). Asymmetric signaling thus produces one normally proliferating daughter cell and another AKT1 low daughter expressing a MCM2 low , H3K9me2 low , HES1 high marker profile (9, 10). Importantly, suppression of AKT signaling is both necessary and sufficient to produce these slow proliferators (9).…”

“…Asymmetric signaling thus produces one normally proliferating daughter cell and another AKT1 low daughter expressing a MCM2 low , H3K9me2 low , HES1 high marker profile (9, 10). Importantly, suppression of AKT signaling is both necessary and sufficient to produce these slow proliferators (9). AKT1 low cancer cells are not apoptotic, autophagic, or senescent, nor do they express cancer stem cell markers or differentiate (10).…”

“…These quiescent cancer cells rapidly resume their cell cycle with inhibitor washout, consistent with a temporary rather than permanent cell cycle arrest, which is identical to spontaneously arising AKT low slow proliferators (10). In fact, malignant cells of various types can be made quiescent this way regardless of their PTEN / PI3K / AKT mutation status or general dependency on PI3K / AKT signaling pathway for their growth (9). Based on these observations, we sought to understand this AKT-induced quiescent cancer cell state in further molecular detail using a combined RNA, protein, and metabolite profiling approach to develop an integrated, multi-scale, molecular snapshot of small molecule AKT inhibition.…”