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 cellsII (AECIIs) to AECIs is a hallmark of alveolar epithelial stimulation. However, the role of AECII transdifferentiation during the reactivation of DTCs has not been fully elucidated. In the present study, we found that tumor cells promoted the transdifferentiation of AECIIs. Furthermore, the supernatant of the transdifferentiation of AECIIs to AECIs (Super-TDA) promoted the dormant-to-proliferating switch of DTCs via the autocrine effect of TGF-β1 on the 3D BME culture system invitro. 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 AECII transdifferentiation. Furthermore, the transdifferentiation of AECIIs 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.