AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma

Catherine D. Yao, Daniel Haensel, Sadhana Gaddam, Tiffany Patel, Scott X. Atwood, Kavita Y. Sarin, Ramon J. Whitson, Siegen McKellar, Gautam Shankar, Sumaira Aasi, Kerri Rieger and Anthony E. Oro ()
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Catherine D. Yao: Stanford University School of Medicine
Daniel Haensel: Stanford University School of Medicine
Sadhana Gaddam: Stanford University School of Medicine
Tiffany Patel: Stanford University School of Medicine
Scott X. Atwood: Stanford University School of Medicine
Kavita Y. Sarin: Stanford University School of Medicine
Ramon J. Whitson: Stanford University School of Medicine
Siegen McKellar: Stanford University School of Medicine
Gautam Shankar: Stanford University School of Medicine
Sumaira Aasi: Stanford University School of Medicine
Kerri Rieger: Stanford University School of Medicine
Anthony E. Oro: Stanford University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.

Date: 2020
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DOI: 10.1038/s41467-020-18762-5

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