Mechanisms of Tumor Evolution During Therapy Resistance

smoothened resistance in basal cell carcinoma

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. 

Read Paper
haensel-fig

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.

Read the Nature Medicine Paper
scam

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.   

Read the Cell Paper

Chromatin Dynamics driving iPS-derived Skin Grafts for Epidermolysis Bullosa

thera1

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. 

Read the Science Translation Medicine Paper
  • cover-gibbin

    Early Embryonic Patterning and Congenital Malformations

    Syndromic congenital malformations often encompass seemingly unrelated comorbidities. We’ve identified Gibbin, the product of the Xia-Gibbs Syndrome locus, as a chromatin regulator of early mesoderm lineage commitment that underlies microcephaly, autism, muscular weakness, aplasia cutis, and obesity. Gibbin localizes on key promoters and interacts with connected upstream enhancer complexes to read embryonic positional and timing information, suggesting malformations come from embryonic tissues “misreading” where and when to differentiate.

  • cover-ESO

    Spatiotemporal and Machine-Learning Platform Accelerates hPSC-derived Esophageal Mucosa Manufacturing

    We’ve developed a versatile platform to accelerate human tissue manufacturing by employing single cell and spatial technologies to generate a spatiotemporal multi-omics cell atlas for human esophageal development. Using Manatee, an innovative machine-learning algorithm, we prioritize the combinations of candidate human developmental signals for in vitro derivation of esophageal basal cells. Functional validation of the Manatee predictions leads to a clinically-compatible system for manufacturing human esophageal mucosa, validating this exciting tissue engineering approach.

join-the-lab-photo

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.

Inquire about joining the lab