In densely populated cells, the perinuclear pool of LC3 was significantly reduced by at least 50% (Supplementary Fig. We noticed that isolated or well-spread out (“sparse”) MCF10A cells (non-tumorigenic epithelial cells) on coverslips had more LC3 endogenous puncta (autophagosomes), compared to the cells in the middle of confluent cell patches-described here as “dense” (Supplementary Fig. Here we show that YAP and TAZ promote autophagy thorough transcriptional regulation of myosin-II and conversely, autophagy is crucial in maintaining both the cell survival and proliferative status downstream of the Hippo signaling hubs, YAP/TAZ–TEAD.Īutophagosome formation is reduced at high cell density Autophagy is also a key player in assisting cell survival during nutrients or oxygen deprivation conditions, important stresses associated with cancerous environments 14, 15. As Hippo signaling impacts cancer initiation/progression, organ development, and stem cell maintenance and regeneration 10, 11, 12, 13, it is important to understand relevant effector processes downstream of YAP/TAZ, as cell proliferation and survival. When cells are at low density and are flat/well-spread on a stiff extracellular matrix (ECM), YAP/TAZ localize in the nucleus and are active, while when the cells are round/compact at high-cell density or plated on soft matrix with minimum adhesion area to the ECM, YAP/TAZ are redistributed to the cytosol and are inactive 7, 8, 9. The mechanism behind these mechanical signals (of contact inhibition or cell shape deformation generated by the pulling forces of the ECM) has only recently been linked to Hippo signaling 5, 6, 7, a pathway comprising two interconnected core modules: kinases (MST1/2, LATS1/2 kinases) and transcriptional regulators (YAP/TAZ co-transcriptional regulators and TEADs transcription factors). Pathologically, loss of contact inhibition leads to uncontrolled cell growth (characteristic of solid tumors) and increases the abilities of cells to invade host tissues (as in metastasis) 2, 3, 4. CIP is reversed in physiological conditions requiring rapid cell growth and proliferation, such as embryonic development and wound healing or tissue regeneration.
This arrest of cell proliferation is seen in most epithelial cells, and is associated with a halt in cell division and the initiation of differentiation. High-cell density/confluency leads to contact inhibition of proliferation (CIP), a fundamental property whereby normal cells cease proliferation and cell division when they occupy all the space allocated to them upon reaching confluence 1.
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