EphB6 regulates TFEB-lysosomal pathway and survival of disseminated quiescent breast cancer cells

Late relapse of disseminated cancer cells is a common feature of some types of tumors. Several intrinsic and extrinsic factors have been shown to affect reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes persistence of DDCCs from estrogen receptor positive (ER+) breast tumors. Here we show that TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct contact of DDCCs with alveolar type I-like lung epithelial cells drives lysosomal accumulation and EphB6 induction. EphB6 contributes to TFEB transcriptional activity and lysosome formation in DDCCs in vitro and in vivo, and supports survival of DDCCs in coculture and in vivo. Furthermore, signaling from EphB6 promotes the proliferative response of surrounding lung parenchymal cells in vivo.