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

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.

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

“…Research on the underlying mechanisms through which breast disseminated dormant cancer cells (DDCCs) survive in new environments is rare, but Zangrossi et al recently published a study showing that the TFEBlysosomal axis activates DDCCs and promotes relapses. In these experiments, the increase in lysosomal flux was essential for the survival of breast DDCCs, and important targets of TFEB that regulate known lysosomal functions were found to be highly enriched in DDCCs, suggesting an important role for TFEB and its value as a therapeutic target [150].…”

Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern

“…Cells were harvested 48 h post-transfection, their total RNA was purified and retrotranscribed as in Ref. (85). Real-time PCR was performed as in Ref.…”

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].…”