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

Author

Listed:
  • 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
    University of California)

  • Kavita Y. Sarin

    (Stanford University School of Medicine)

  • Ramon J. Whitson

    (Stanford University School of Medicine
    Genomics Institute of the Novartis Research Foundation)

  • Siegen McKellar

    (Stanford University School of Medicine
    University of Washington School of Medicine)

  • Gautam Shankar

    (Stanford University School of Medicine
    Johns Hopkins 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)

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.

Suggested Citation

  • 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 & Anthony E. , 2020. "AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18762-5
    DOI: 10.1038/s41467-020-18762-5
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    Cited by:

    1. Daniel Haensel & Sadhana Gaddam & Nancy Y. Li & Fernanda Gonzalez & Tiffany Patel & Jeffrey M. Cloutier & Kavita Y. Sarin & Jean Y. Tang & Kerri E. Rieger & Sumaira Z. Aasi & Anthony E. Oro, 2022. "LY6D marks pre-existing resistant basosquamous tumor subpopulations," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Daniel Haensel & Bence Daniel & Sadhana Gaddam & Cory Pan & Tania Fabo & Jeremy Bjelajac & Anna R. Jussila & Fernanda Gonzalez & Nancy Yanzhe Li & Yun Chen & JinChao Hou & Tiffany Patel & Sumaira Aasi, 2023. "Skin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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