Stem Cells, Tumor Evolution, and Novel Cellular and Molecular Therapeutics
Mechanisms of Tumor Evolution During Therapy Resistance
How do tumors change to allow them to keep growing despite our best treatment efforts? Basal cell carcinomas (BCCs) are perhaps the most common human tumor, are driven by the hedgehog signaling pathway, and a model for the pathogenesis and treatment of other human tumors. Advanced BCCs frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms, providing a unique opportunity to study human tumor and tumor environment evolution in vitro, in animal models, and in patients through multi-dimensional genomic and proteomic approaches. We have identified several novel but common resistance pathways that other tumors also use to escape therapy, and have developed candidate therapeutics to add to our treatment armamentarium.
Cytoskeletal/Fibrotic signaling through SRF-MRTF confers Drug resistance
Using multi-dimensional genomic analysis of animal models and our patients with drug-resistant BCCs, we have found that Serum Response Factor/Myocardin Related Transcription Factor (SRF/MRTF) activation is a common and powerful mechanism of drug resistance. SRF/MRTF have previosly been associated with fibrosis and inflammation, and MRTF inhibitors significantly slowed the growth of drug-resistant basal cell carcinomas in mice and signaling in primary patient tumors, highlighting the therapeutic potential of this approach.
Atypical Protein Kinase C in Gli Activation
We examined patients with Smo inhibitor resistant BCCs and proteins that interact with the primary cilium to demonstrate that the polarity kinase atypical protein kinase C iota/lamda (aPKC) is critical for Hh-dependent processes. aPKC acts in the nucleus directly on the Gli transcription factor complex, acting in concert with HDAC1 to promote chromatin association and tumor resistance. Our work implicates the kinase as a new, tumor-selective therapeutic target for the treatment of Smo-inhibitor resistant cancers and has led us to identify a potent a promising candidate aPKC inhibitor.
iPS-derived Skin Grafts for Epidermolysis Bullosa
Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. Our lab has developed a scalable and cGMP compatible protocol to generate patient-derived COL7A1 gene-corrected epithelial keratinocyte sheets for autologous grafting and use the system to study the mechanisms of human embryonic skin differentiation.
Morphogens and Lineage Selectors Cooperate to Fold Chromatin
Embryonic stem cell differentiation promises advances in regenerative medicine yet the conversion into transplantable tissues remains poorly understood. Here, we use a multi-dimensional genomics including Cohesin HiChIP visualized chromosome conformation to show that both p63 and the morphogens contribute to dynamic long-range interactions, as revealed on the TFAP2C locus. Our study demonstrates the unexpected dependency of p63 on morphogenetic signaling and provides novel insights into how a master regulator can specify diverse transcriptional programs depending on the chromatin conformation induced by specific morphogen exposure.
Join the lab
Exciting training opportunities for post-doctoral fellows, graduate students and undergraduates in stem cell biology and tissue engineering, cancer biology, genomics, proteomics, bioinformatics.