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AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma
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-r...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546632/ https://www.ncbi.nlm.nih.gov/pubmed/33033234 http://dx.doi.org/10.1038/s41467-020-18762-5 |
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author | Yao, Catherine D. Haensel, Daniel Gaddam, Sadhana Patel, Tiffany Atwood, Scott X. Sarin, Kavita Y. Whitson, Ramon J. McKellar, Siegen Shankar, Gautam Aasi, Sumaira Rieger, Kerri Oro, Anthony E. |
author_facet | Yao, Catherine D. Haensel, Daniel Gaddam, Sadhana Patel, Tiffany Atwood, Scott X. Sarin, Kavita Y. Whitson, Ramon J. McKellar, Siegen Shankar, Gautam Aasi, Sumaira Rieger, Kerri Oro, Anthony E. |
author_sort | Yao, Catherine D. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7546632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75466322020-10-19 AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma Yao, Catherine D. Haensel, Daniel Gaddam, Sadhana Patel, Tiffany Atwood, Scott X. Sarin, Kavita Y. Whitson, Ramon J. McKellar, Siegen Shankar, Gautam Aasi, Sumaira Rieger, Kerri Oro, Anthony E. Nat Commun Article 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. Nature Publishing Group UK 2020-10-08 /pmc/articles/PMC7546632/ /pubmed/33033234 http://dx.doi.org/10.1038/s41467-020-18762-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Yao, Catherine D. Haensel, Daniel Gaddam, Sadhana Patel, Tiffany Atwood, Scott X. Sarin, Kavita Y. Whitson, Ramon J. McKellar, Siegen Shankar, Gautam Aasi, Sumaira Rieger, Kerri Oro, Anthony E. AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma |
title | AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma |
title_full | AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma |
title_fullStr | AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma |
title_full_unstemmed | AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma |
title_short | AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma |
title_sort | ap-1 and tgfß cooperativity drives non-canonical hedgehog signaling in resistant basal cell carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546632/ https://www.ncbi.nlm.nih.gov/pubmed/33033234 http://dx.doi.org/10.1038/s41467-020-18762-5 |
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