EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells

Abstract

Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the 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 coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs.

A new glance at autophagolysosomal-dependent or -independent function of transcriptional factor EB in human cancer

“…Latent and advanced recurrence of disseminated cancer cells for up to 20 years is common in breast and prostate cancer, and from ~20%-40% of breast cancer patients present with recurrence in distant organs, sometimes decades after the initial cancer diagnosis [147,148]. With the increased development and advances in cancer treatment, early detection and treatment have improved the survival rate of cancer patients, and the course of cancer has been prolonged, but an increase in late recurrence is gradually affecting more patients [149].…”

Lysosomes at the Crossroads of Cell Metabolism, Cell Cycle, and Stemness

“…Resistance to ferroptosis is a feature of metastasis-initiating cells (MICs), which have CSC properties [236]. Interestingly, MIC progenies are characterized by high TFEB expression and accumulation of lysosomes, which help them survive the metabolic stress they encounter during metastasis [237,238].…”

Current challenges in metastasis research and future innovation for clinical translation

“…Induction of DTC dormancy has been achieved through CDK4/6 inhibition (e.g. Palbociclib) [109] or by inhibiting outside-in pro-proliferative signaling [95,110]. Immunotherapy that harnesses immunological surveillance to control DTCs also has great potential to both eradicate and control metastatic disease since neutrophils and myeloid subtypes regulate microenvironmental cues that control dormancy [55][56][57].…”