Role of Hippo Pathway-TAZ signaling in the bone marrow environment of multiple myeloma
University of New Brunswick
The Hippo pathway (HP) is a highly conserved signaling pathway recently implicated in cancer development. TAZ is a transcriptional co-activator and downstream component of the HP. Our lab recently showed that TAZ plays a tumour suppressor role in multiple myeloma (MM). Previous studies suggest that the myeloma bone marrow (BM) microenvironment is characterized by distinct miRNA signatures, oxidative stress, and crosstalk between myeloma cells and their surrounding BM mesenchymal stromal cells (MSC). In line with these findings, emerging reports further suggest a potential link between TAZ and miRNAs. Interestingly, several miRNAs have been implicated in oxidative stress in solid tumours. Therefore, we sought to determine the role of TAZ in the oxidative stress and BM microenvironment of MM. Using TAZ knockout and wild-type myeloma cell models generated by CRISPR-Cas9 genome editing, we show that TAZ is associated with distinct microRNA profiles in MM. TAZ promotes myeloma cells' sensitivity to oxidative stress by inducing miR-224 to downregulate NRF2 transcriptional programs. Furthermore, we identified MST1 as a negative regulator of TAZ expression. Specifically, we provide evidence that MST1 negatively correlates with TAZ expression, and high MST1 expression is associated with poor clinical outcomes. Genetic and pharmacological inhibition of MST1 upregulate TAZ or miR-224 to sensitize myeloma cells to frontline antimyeloma therapies. Using the Transwell coculture system, we examined the effect of TAZ on myeloma cells and MSC interaction. We show that TAZ decreases the invasive and migratory ability of myeloma cells toward chemoattractant. RNA-sequencing analysis revealed that cell adhesion molecules that mediate cancer invasion and metastasis are enriched in the TAZ-knockout myeloma cell model. We identified ANXA1 as a cell adhesion molecular target of TAZ that mediates migratory and invasive behaviour of myeloma cells. TAZ regulates ANXA1 at transcriptional level. We show that TAZ expression negatively correlates with ANXA1 expression in both cell-line models and patient samples. Our findings uncover an unexpected role for TAZ in regulating BM oxidative stress and tumour – BME interaction in MM. Importantly, it also provides a compelling rationale to explore the therapeutic potential of upregulating TAZ expression via MST1 inhibition to restore sensitivity to specific therapeutics in MM.