c-FOS drives reversible basal to squamous cell carcinoma transition

被引：14

作者：

Kuonen, Francois ^{[1
,2
]}

Li, Nancy Yanzhe ^{[1
]}

Haensel, Daniel ^{[1
]}

Patel, Tiffany ^{[1
]}

Gaddam, Sadhana ^{[1
]}

Yerly, Laura ^{[2
]}

Rieger, Kerri ^{[1
]}

Aasi, Sumaira ^{[1
]}

Oro, Anthony E. ^{[1
]}

机构：

[1] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA

[2] Lausanne Univ Hosp Ctr, Hop Beaumont, Dept Dermatol & Venereol, CH-1011 Lausanne, Switzerland

来源：

CELL REPORTS | 2021年 / 37卷 / 01期

基金：

瑞士国家科学基金会;

关键词：

ADENOSQUAMOUS CARCINOMA; HEDGEHOG PATHWAY; TRANSCRIPTION FACTORS; GENE-EXPRESSION; BASOSQUAMOUS CARCINOMA; CONFERS RESISTANCE; PROMOTER ACTIVITY; GENOMIC ANALYSIS; DRUG-RESISTANCE; GROWTH;

D O I：

10.1016/j.celrep.2021.109774

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its underlying mechanism remains poorly understood. Here, using surface markers of resistant basal cell carcinomas (BCCs) and patient single-cell and bulk transcriptomic data, we uncover the dynamic roadmap of basal to squamous cell carcinoma transition (BST). Experimentally induced BST identifies activator protein 1 (AP-1) family members in regulating tumor plasticity, and we show that c-FOS plays a central role in BST by regulating the accessibility of distinct AP-1 regulatory elements. Remarkably, despite prominent changes in cell morphology and BST marker expression, we show using inducible model systems that c-FOS-mediated BST demonstrates reversibility. Blocking EGFR pathway activation after c-FOS induction partially reverts BST in vitro and prevents BST features in both mouse models and human tumors. Thus, by identifying the molecular basis of BST, our work reveals a therapeutic opportunity targeting plasticity as a mechanism of tumor resistance.

引用

页数：25

共 119 条

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