Study of Lysosomal Function as a Mechanoregulated Determinant of Metastatic Dormancy and Aggressiveness in Breast Cancer

Breast cancer survivors can develop metastases even decades after having successfully been treated. One of the hypotheses to explain late recurrences is cancer dormancy, characterized by disseminated dormant breast cancer (DDTCs) cells that survive for a prolonged period in a quiescent state. We implemented, as our model systems for studying breast cancer metastatic dormancy, D2.0R and D2A1 cell lines, with characteristics of DDTCs. Transcriptome analysis of DDTCs revealed an upregulation in gene signatures related to TFEB/TFE3 signalling, lysosomal accumulation and vesicle transport in both. Bioinformatic analysis showed that YAP1/TAZ might take part in the genetic regulation of lysosomal gene expression. We propose that YAP1/TAZ signalling pathway may act as a repressor of the lysosomal pathway. By using TEAD pharmacological inhibitors we showed the role of YAP1/TAZ-TEAD axis in repressing lysosomal gene expression. Furthermore, our data showed that TEAD inhibition treatment led to an increased and functional lysosomal compartment in dormant cells that is associated with an increased initiation of autophagy.