Philip H. Howe, Ph.D.
My research is focused on the role of transforming growth factor β1 (TGFβ1) in cellular models of differentiation and cancer. We have identified a signaling pathway whereby TGFb regulates epithelial-mesenchymal transitions (EMT) and metastasis through a post-transcriptional mechanism involving the regulation of an RNA binding protein, heterogeneous ribonucleoprotein E1 (hnRNP E1). TGFb regulation of hnRNP E1 phosphorylation not only mediates translational silencing of select mRNAs involved in EMT/metastasis but also of lncRNAs that may also contribute to tumor progression. One mRNA target, the cytokine ILEI/FAM3C, has been identified as a potent stem factor in breast epithelium and studies are focusing on the molecular mechanisms through which it elicits these progenitor effects. Another focus area, is the long intergenic non-protein-coding (LncEnc1), also known as Platr18 (pluripotency associated transcript 18). We have shown that Platr18 is not expressed in normal epithelium or adult somatic tissues but is highly induced by TGFb through the hnRNP E1 pathway and that it is highly upregulated during breast cancer progression. We find that Platr18 is functionally involved in the transcriptional program of tumor plasticity and metastasis to ultimately control: 1) the formation of tumor initiating cells; 2) T-cell mediated immune responses through the control of V-Set and Immunoglobulin domain containing 3 (VSIG-3); and, 3) primary tumor neurogenesis through the control of Sema4F, an axon guidance molecule involved in neuronal development and tumor innervation.