AP-1 and TGFß Cooperativity Drives Non-Canonical Hedgehog Signaling in Resistant Basal Cell Carcinoma

    October 2020 in “ Nature Communications ”
    Catherine Yao, Daniel Haensel, Sadhana Gaddam, Tiffany Patel, Scott X. Atwood, Kavita Y. Sarin, Ramon J. Whitson, Siegen A. McKellar, Gautam Shankar, Sumaira Z. Aasi, Kerri E. Rieger, Anthony E. Oro
    TLDR AP-1 and TGFß work together to drive resistance in basal cell carcinoma, suggesting new treatment options.
    This study investigated resistance mechanisms in basal cell carcinomas (BCCs) that rely on Hedgehog (Hh)/Gli signaling and can develop resistance to Smoothened (SMO) inhibitors. Researchers used single cell RNA-sequencing on patient tumors to identify three surface markers (LYPD3, TACSTD2, and LY6D) associated with a nuclear myocardin-related transcription factor (nMRTF) resistance pathway. This pathway was driven by AP-1 and TGFß cooperativity, resembling transit-amplifying cells of the hair follicle matrix. The study found that JNK/AP-1 signaling facilitated chromatin accessibility and Smad3 DNA binding, promoting nMRTF activity. Notably, small molecule AP-1 inhibitors selectively targeted the resistant nMRTF cell state, suggesting potential for improved combinatorial therapies in treating BCCs.
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