Transdifferentiation of type II alveolar epithelial cells induces reactivation of dormant tumor cells by enhancing TGF-β1/SNAI2 signaling

Abstract

Dormant tumor cells (DTCs) serve a crucial role in the pathogenesis of metastasis and may compromise the efficacy of existing therapeutic modalities aimed at fully eradicating cancer. However, the mechanisms underlying the dormant-to-proliferating switch of DTCs remain largely unknown. The lung is one of the most common sites of metastatic recurrence. The transdifferentiation of alveolar epithelial cells II (AEC IIs) to AEC Is is a hallmark of alveolar epithelial stimulation. However, the role of AEC II transdifferentiation during the reactivation of DTCs has not been fully elucidated. In the present study, we found that tumor cells promoted the transdifferentiation of AEC IIs. Furthermore, the supernatant of the transdifferentiation of AEC IIs to AEC Is (Super-TDA) promoted the dormant-to-proliferating switch of DTCs via the autocrine effect of TGF-β1 on the 3D BME culture system in vitro. Monensin and LY2109761 blocked the dormant-to-proliferating switch of DTCs induced by Super-TDA. Although lipopolysaccharide did not directly stimulate the reactivation of DTCs, it promoted DTC reactivation by increasing the secretion of TGF-β1 in the Super-TDA. We further demonstrated that the upregulation of SNAI2 expression was required for Super-TDA facilitating the DTC dormant-to‑proliferating switch. Taken together, our findings demonstrated that tumor cells may promote AEC II transdifferentiation. Furthermore, the transdifferentiation of AEC IIs may, in turn, induce the reactivation of 3D-established DTCs by promoting TGF-β1/SNAI2 signaling. Targeting this process may provide novel therapeutic strategies for the inhibition of the dormant‑to-proliferating switch.

Molecular Aspects of Regeneration Mechanisms in Holothurians

“…PCGF2 is a chromatin-modifying protein that inhibits EMT and negatively regulates stem cell-like properties [ 195 , 196 ]. SNAI proteins play a crucial role in EMT and in repressing the mesenchymal-epithelial transition, being important in embryonic and tumor development [ 197 , 198 , 199 ]. On the other hand, a complex of SNAI and ID2 inhibits EMT [ 200 , 201 ].…”

The Eupentacta fraudatrix transcriptome provides insights into regulation of cell transdifferentiation

“…SNAI proteins play a crucial role in the epithelial-mesenchymal transition (EMT) and in repressing the mesenchymal-epithelial transition (MET), being important in embryonic and tumour development [43][44][45] . The co-expression of Ef-snai2 and Ef-id2 (see below) may indicate partial involvement of the EMT mechanisms in the transformation of coelomic epithelial cells into enterocytes in E. fraudatrix.…”

The role of respiratory epithelium in host defence against influenza virus infection

“…In the alveolar epithelium, the initial repair process is re-epithelialization of the denuded basement membrane and reassembly of tight junctions. This is accomplished primarily by type II alveolar epithelial cells, which are relatively resistant to injury [213] , [214] , [215] , [216] , [217] , [218] . Type II cells spread, proliferate, and transdifferentiate into type I cells to restore normal alveolar structure and barrier function [213] .…”

“…Type II cells spread, proliferate, and transdifferentiate into type I cells to restore normal alveolar structure and barrier function [213] . Various signaling pathways have been identified that promote type II cell spreading [219] , [220] , proliferation [214] , [221] , and trans-differentiation [218] , [222] . A recent study shows that a subset of type II alveolar epithelial that is specifically responsive to Wnt and Fgf signalling may be the dominant progenitor cells during injury in mouse and humans [223] .…”