Mechanisms of Tumor Evolution During Therapy Resistance

smoothened resistance in basal cell carcinoma

How do tumors evolve to keep growing despite our best treatment efforts? Basal cell carcinomas (BCCs) are the most common human tumor, are driven by the hedgehog signaling pathway, and a model for the pathogenesis and treatment of other human tumors.  We have shown that advanced BCCs frequently acquire resistance to Smoothened (SMO) inhibitors through both genetic and epigenetic tumor mechanisms, providing a unique opportunity to study human tumor and tumor environmental 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 demonstrating the wide applicability of our studies. We have developed patient tumor-derived organoids to perform "clinic trials in a dish" with candidate therapeutics to add to our treatment armamentarium. 

Read Nature Comm Paper on Skin Cancer Associated Myeloid Cells Read Nature Comm Paper on Tumor Evolution Markers
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Basal-to-Inflammatory Transition (BIT): Paradoxical Tumor Resistance from Too Much Inflammation

Cancer-associated inflammation is a double-edged sword possessing both pro-and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialize inflammatory microenvironment.

Read the Nature Comm Paper on the BIT resistance mechanism
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Atypical Protein Kinase C and Other Chromatin Kinases in Transcriptional Regulation

Local control of chromatin-associated kinases have powerful transcriptional effects that lead to developmental and cancer resistance phenotypes. 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 on Intranuclear Trafficking of Transcription Factors Read the Nature paper on the aPKC chromatin kinase

Human Tissue Replacement Therapy from Genetically-corrected Pluripotent Cells 

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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 Nature Comm paper on Skin Tissue Replacement Manufacturing
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    Developmental Chromatin Dynamic Maps Predict Human Tissues States and Disease Trajectories

    Using single-cell and spatial transcriptomics and chromatin accessibility we have created chromatin dynamic maps that link cell state specific enhancer-promoter connections to tissue and disease states. We have demonstrated this for both human hair follicle and developing surface ectoderm / Ectodermal dysplasias including skin abnormalities and cleft lip/palate result from improper surface ectoderm (SE) patterning. Our studies elucidate the logic underlying SE commitment and deepen our understanding of human oligogenic disease pathogenesis.

    Read Nature Genetics paper on Human Hair Follicle Chromatin Map Read iScience Paper on Surface Ectoderm Chromatin Dynamics Map
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    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.

    Read Developmental Cell Paper on Machine Learning approaches to Tissue Replacement Manufacturing
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