Feedback loops involving AMPK, ERK and TFEB in matrix detachment leads to non-genetic heterogeneity

Cancer cells metastasize by evading apoptosis induced due to the detachment from the extracellular matrix. Deciphering the adaptive strategies employed by cancer cells in matrix-deprived condition can help design novel therapeutic strategies to tackle metastasis. Here, we provide evidence for non-genetic heterogeneity in matrix-detached cells enabled by feedback loop among AMPK, ERK and TFEB that determines autophagy maturation and cell survival. The subpopulation of matrix-detached cells with pAMPKlow/pERKhigh/TFEBlow state show autophagy maturation arrest and elevated cell death. Conversely, pAMPKhigh/pERKlow/ TFEBhigh cells show high autophagy maturation and better cell survival. We show