A Lung Organotypic Coculture Reveals a Role for TFEB-Lysosomal Axis in the Survival of Disseminated Dormant Cancer Cells

SIMPLE SUMMARY: One of the worst aspects of tumors is the relapse of metastatic lesions several years after the removal of the primary tumor and after the patient has been considered disease-free. This particular aspect is called “metastatic dormancy”. Unfortunately, this behavior is particularly hard to study because disseminated cancer cells are technically not detectable by current imaging techniques. We developed a culture of breast cancer cells and lung epithelial cells that recapitulates in vitro several aspects of what is observed in the real lung. With this tool we identified a specific feature: a lysosomal process that is activated in breast cancer cells and which might be used in the future to target those cells before they wake up. ABSTRACT: (1) Background: metastatic relapse following a prolonged period of disease-free survival is a common cause of mortality for many cancer patients. Disseminated dormant cancer cells (DDCCs) lie below the radar before waking up years, or even decades, after the removal of the primary tumor. This implies that they are able to survive in a latent state in a foreign environment for an extended period of time supported by intrinsic and extrinsic factors still to be elucidated. (2) Methods: we employed a coculture of DDCCs with lung epithelial cells together with RNA sequencing analysis to understand the overlap in gene transcription between in vivo and cocultured DDCCs. (3) Results: we found a significant overlap between the processes activated in DDCCs from lungs and in the coculture, as well as in alveolar type I cells in vivo and in coculture. We identified the transcription factor EB (TFEB)-lysosomal axis as a relevant process activated in DDCCs upon dissemination to the lung and confirmed the results in our lung coculture. Interestingly, breast cancer patients with a higher expression of TFEB targets show increased likelihood of developing relapses. (4) Conclusions: we propose that lysosomal accumulation following TFEB activation is an important feature of breast cancer DDCCs that might be exploited for future therapeutic interventions.