Mercurio Lab News
After a successful defense of her thesis back in March of this year, our very own Dr. Dimpi Mukhopadhyay joined the UMass Chan Class of 2024 in the commencement ceremony earlier this month.
We are so proud of Dimpi and so happy we were able to celebrate this moment with her!!
Congratulations to the Class of 2024 graduates!!!
Dr. Dimpi Mukhopadhyay has successfully defended her thesis on the Functional Role of the Calcium Channel TRPC6 in Breast Cancer Therapy Resistance and Metastasis. Dimpi will be continuing to expand her training and will be joining Dr. Evanna Mills lab at Dana Farber Cancer Institute for her postdoctoral research on immunometabolism. We are so proud of Dimpi and excited to see all she will achieve in her future!!
Photos of our celebration can be found on the Mercurio Lab Events page!
Ayush was selected as one of nine finalists to compete in this year's 3 Minute Thesis Competition (3MT). He was awarded with the second place prize! Congrats Ayush!!
ABSTRACT
We are interested in the contribution of integrins and the extracellular matrix to epithelial differentiation in carcinomas. This study was motivated by our finding that the Hippo effectors YAP and TAZ can sustain the expression of laminin 332 (LM332), the predominant ECM ligand for the integrin β4, in breast carcinoma cells with epithelial differentiation. More specifically, we observed that YAP and TAZ regulate the transcription of the LAMC2 subunit of LM332. Given that the β4/LM332 axis is associated with epithelial differentiation and YAP/TAZ have been implicated in carcinoma de-differentiation, we sought to resolve this paradox. Here, we observed that the β4 integrin sustains the expression of miR-200s that target the transcription factor ZEB1 and that ZEB1 has a pivotal role in determining the nature of YAP/TAZ-mediated transcription. In the presence of β4, ZEB1 expression is repressed enabling YAP/TAZ/TEAD-mediated transcription of LAMC2. The absence of β4, however, induces ZEB1 and ZEB1 binds to the LAMC2 promoter to inhibit LAMC2 transcription. YAP/TAZ-mediated regulation of LAMC2 has important functional consequences because we provide evidence that LM332 enables carcinoma cells to resist ferroptosis in concert with the β4 integrin.
Goel HL, Karner ER, Kumar A, Mukhopadhyay D, Goel S, Mercurio AM. YAP/TAZ-mediated regulation of laminin 332 is enabled by β4 integrin repression of ZEB1 to promote ferroptosis resistance. Journal of Biological Chemistry. 2024 March 18. PMID: 38508310
ABSTRACT
Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca2+-dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing.
Mukhopadhyay D, Goel HL, Xiong C, Goel S, Kumar A, Li R, Zhu LJ, JClark JL, Brehm MA, Mercurio AM. The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing. Cell Reports. 2023 October 31. PMID: 37910503
