The transcription factor MITF regulates many essential functions in both melanocytes and melanoma. It controls differentiation, proliferation and survival in a dose dependent manner; therefore it is under tight regulation. Many signalling pathways and transcription factors have been identified to control the expression and activity of MITF, however, there is little known about how the surrounding microenvironment could impact on MITF function. It is now well appreciated that stromal components also have an important role in determining disease progression, and in fact the extracellular matrix (ECM) is a key regulator of cellular differentiation, growth and survival, similarly to MITF. Therefore, we aimed to identify a potential crosstalk between ECM mediated adhesion signalling and MITF in order to better understand melanoma biology. By conducting transcriptomal analysis of cells in different microenvironments, we discovered that MITF levels and function is affected by collagen signalling in a matrix stiffness dependent manner. We demonstrated that increased matrix stiffness or collagen abundance leads to upregulation of MITF and consequently cells become more proliferative and differentiated and this is mediated by YAP1/PAX3. In addition, we found that in melanoma patients increased collagen abundance correlates with nuclear YAP1 localization. However, using large patient datasets we discovered that tumour-microenvironment mediated YAP1 signalling is more complex. In the absence of fibroblasts, YAP1/PAX3 drives MITF expression, but in the presence of fibroblasts, TGFÎ² induces a switch from YAP1/PAX3 driven transcription to YAP1/TEAD/SMAD driven transcription and consequently a de-differentiated phenotype. Furthermore, we show that high collagen expression is linked to poor survival, however the worst prognosis is seen in patients with high collagen expression, who also express MITF target genes such as the differentiation markers TRPM1, TYR and TYRP1 as well as CDK4. In summary, while a lot of effort has gone into identifying factors that induce the de-differentiated/invasive phenotype, it is not well understood how the switch to the differentiated/proliferative phenotype is controlled. Here we provide a novel mechanism whereby matrix signaling can induce MITF expression through YAP1 and show that this high matrix/differentiation/proliferation phenotype is predictive for poor survival.
|Date of Award||1 Aug 2018|
- The University of Manchester
|Supervisor||Adam Stevens (Supervisor) & Claudia Wellbrock (Supervisor)|