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

Catherine D Yao1, Daniel Haensel1, Sadhana Gaddam1

  • 1Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.

Nature Communications
|October 9, 2020
PubMed

Insights

Researchers identified new markers (LYPD3, TACSTD2, LY6D) for resistant basal cell carcinoma (BCC) cell states. Targeting the AP-1 pathway with inhibitors shows promise for treating these resistant BCC tumors.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • Tumor heterogeneity and resistance mechanisms hinder effective cancer therapies.
  • Basal cell carcinomas (BCCs) often develop resistance to Smoothened (SMO) inhibitors via pathways like nuclear myocardin-related transcription factor (nMRTF).
  • The specific characteristics and drivers of the nMRTF resistant cell state in BCCs are not well understood.

Purpose of the Study:

  • To identify prognostic surface markers associated with the nMRTF resistant cell state in BCCs.
  • To elucidate the molecular drivers and cellular characteristics of nMRTF-mediated SMO inhibitor resistance.
  • To evaluate the therapeutic potential of targeting the identified resistance pathways in BCC.

Main Methods:

  • Single-cell RNA sequencing (scRNA-seq) of patient-derived BCC tumors.
  • Correlation analysis of surface marker expression with nMRTF pathway activation and SMO inhibitor resistance.
  • Investigation of signaling pathways (AP-1, TGFß, JNK) involved in nMRTF activation.
  • Ex vivo drug sensitivity assays using small molecule AP-1 inhibitors.

Main Results:

  • Three prognostic surface markers, LYPD3, TACSTD2, and LY6D, were identified and correlated with the nMRTF cell state and SMO inhibitor resistance.
  • The nMRTF cell state shares similarities with hair follicle matrix transit-amplifying cells.
  • AP-1 and TGFß signaling cooperativity drives nMRTF activation, involving JNK/AP-1 mediated chromatin accessibility and Smad3 binding.
  • Small molecule AP-1 inhibitors demonstrated selective targeting of LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo.

Conclusions:

  • LYPD3, TACSTD2, and LY6D are key prognostic markers for a specific resistant BCC cell state.
  • The nMRTF cell state is driven by a cooperative signaling network involving AP-1 and TGFß.
  • Targeting the AP-1 pathway with small molecule inhibitors offers a promising therapeutic strategy for overcoming SMO inhibitor resistance in BCC.

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