Ongoing, Future and Possible Projects

Our research focuses on Smad-mediated and non-Smad mechanisms of TGF-β signaling, and their roles in epithelial-mesenchymal transdifferentiation (EMT). 

Upon ligand binding to the receptor complex, Smads regulate transcription in cooperation with DNA-binding, sequence-specific transcription factors, and co-activators and co-repressors. Now that we have insight into the mechanisms of transcription activation and repression by Smads, we aim to understand the functional crosstalk of Smads with epigenetic regulation of gene expression and methyltransferases. TGF-β proteins also activate non-Smad signaling pathways, and we aim to define the mechanisms of TGF-β-induced activation of the Akt-mTOR pathway, resulting in translation regulation, and TGF-β-induced Erk MAP kinase signaling, and their roles in the cell’s response to TGF-β. Finally, we are examining the regulation of receptor presentation and activity at the cell surface and how this regulation affects the TGF-β response. 

Considering the key roles of the TGF-β family in cell and tissue differentiation, and in development, we address the roles of TGF-β family signaling, through Smad and non-Smad pathways, in epithelial-mesenchymal transdifferentiation, primarily in carcinoma progression, and the initiation of TGF-β signaling at the level of the cell surface receptor complexes, where different receptor complex differently control the TGF-β/BMP response. Below is an outline of ongoing and future projects.

Functional interactions of methyltransferases with Smads. We found that Smads associate with lysine and arginine methyltransferases. These interactions allow for inducible Smad methylation, and for methylation to participate in TGF-β- or BMP-induced signaling. We reported that BMP- and TGF-β-induced Smad6 and/or Smad7 methylation on Arg by PRMT1 initiates and enables BMP-and TGF-β-induced Smad signaling. We also found that activated Smads can recruit the methyltransferase SETDB1 to target genes, where it directs Smad-mediated epigenetic changes and thus participates in transcription control. Further studies on functional interactions of Smads with methyltransferases will provide insight into (1) the roles of methylation in TGF-β/BMP signaling, in particular by inhibitory Smads, and (2) the resulting participation of these novel methylation-mediated signaling mechanisms in EMT.

Functional roles of TGF-β​-induced EMT in cancer progression and susceptibility to cancer drugs and immunotherapy. In breast carcinomas and other carcinomas, TGF-β/Smad signaling drives the acquisition of mesenchymal cell characteristics by carcinoma cells with an initial epithelial phenotype, and does so through collaboration with other signaling pathways. While short-term treatment with TGF-β confers a reversible EMT in the sense that withdrawal of TGF-β allows the cells to revert to an epithelial phenotype, long-term exposure to TGF-β stabilizes the EMT phenotype and confers independence of added TGF-β. EMT is accompanied by extensive changes beyond the phenotypic changes that are implied by the term EMT. Specifically, EMT confers increased expression of immunosuppressive cytokines and ligands, including PDL-1 (the ligand of the PD1 receptor) and TGF-β1. EMT is also linked to acquisition of cancer stem cell properties, and increased resistance to established anti-cancer drugs. We aim to evaluate how cancer cell TGF-β responsiveness and EMT are functionally connected at the signaling level to increased acquisition of stem cell properties and cancer drug resistance, taking advantage of differential properties of carcinoma cells with reversible versus stabilized EMT.

     In immuno-oncology, successful treatment of carcinomas using anti-PD1 or anti-PDL1 antibodies is seen in only a fraction of patients, and the resistance to these treatments correlates with high levels of TGF-β signaling in the cancers. In this context, we aim to evaluate the roles of TGF-β signaling and TGF-β-driven EMT in cancer cells in the susceptibility and resistance of cancers to anti-PD1/PDL1 using cell and mouse models. Studies using mouse models are performed in collaboration with the lab of Rosemary Akhurst at UCSF.