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AP-1 和 TGFß 协同作用驱动耐药基底细胞癌中的非经典 Hedgehog 信号通路。

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

机构信息

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

Department of Developmental and Cell Biology, University of California, Irvine, USA.

出版信息

Nat Commun. 2020 Oct 8;11(1):5079. doi: 10.1038/s41467-020-18762-5.

DOI:10.1038/s41467-020-18762-5
PMID:33033234
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7546632/
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.

摘要

肿瘤异质性和对耐药细胞状态的认识不足仍然是靶向癌症治疗的障碍。基底细胞癌 (BCC) 依赖 Hedgehog (Hh)/Gli 信号通路，但可以发展出 Smoothened (SMO) 抑制剂耐药的机制。我们之前确定了一种核心肌营养素相关转录因子 (nMRTF) 耐药途径，该途径放大了非典型 Gli1 活性，但 nMRTF 细胞状态的特征和驱动因素仍不清楚。在这里，我们使用患者肿瘤的单细胞 RNA 测序来鉴定三个预后表面标志物 (LYPD3、TACSTD2 和 LY6D)，它们与 nMRTF 和 SMO 抑制剂耐药性相关。nMRTF 细胞状态类似于毛囊基质中的过渡扩增细胞，AP-1 和 TGFß 协同作用驱动 nMRTF 激活。JNK/AP-1 信号通路委托染色质可及性和 Smad3 DNA 结合，导致 RhoGEFs 的转录程序，从而促进 nMRTF 活性。重要的是，小分子 AP-1 抑制剂选择性地靶向 LYPD3+/TACSTD2+/LY6D+ nMRTF 人 BCCs 体外，为改善联合治疗开辟了途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/6c5bac2d2c2b/41467_2020_18762_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/36cc28f1a567/41467_2020_18762_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/911124f9dd2b/41467_2020_18762_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/a2f6f0737524/41467_2020_18762_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/7411acbbb476/41467_2020_18762_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/315e47764e89/41467_2020_18762_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/6c5bac2d2c2b/41467_2020_18762_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/36cc28f1a567/41467_2020_18762_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/911124f9dd2b/41467_2020_18762_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/a2f6f0737524/41467_2020_18762_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/7411acbbb476/41467_2020_18762_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/315e47764e89/41467_2020_18762_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02c2/7546632/6c5bac2d2c2b/41467_2020_18762_Fig6_HTML.jpg

相似文献

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

Nat Commun. 2020-10-8

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Single-Cell RNA Sequencing in Cancer: Lessons Learned and Emerging Challenges.

Mol Cell. 2019-7-11

[2]
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition.

Nature. 2018-10-8

[3]
TGFβ, Fibronectin and Integrin α5β1 Promote Invasion in Basal Cell Carcinoma.

J Invest Dermatol. 2018-7-14

[4]
Integrating single-cell transcriptomic data across different conditions, technologies, and species.

Nat Biotechnol. 2018-4-2

[5]
Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas.

Nat Med. 2018-2-5

[6]
Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression.

Cell Stem Cell. 2018-1-11

[7]
AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection.

Mol Cell. 2017-12-21

[8]
Stem Cell Lineage Infidelity Drives Wound Repair and Cancer.

Cell. 2017-5-4

[9]
Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Nat Genet. 2016-3-7

[10]
C4.4A as a biomarker of head and neck squamous cell carcinoma and correlated with epithelial mesenchymal transition.

Am J Cancer Res. 2015-11-15

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