Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
Nat Commun. 2020 Oct 12;11(1):5126. doi: 10.1038/s41467-020-18919-2.
Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment. Genomic alterations in these cells remain a point of contention. We report that CAFs from skin squamous cell carcinomas (SCCs) display chromosomal alterations, with heterogeneous NOTCH1 gene amplification and overexpression that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 amplification is expanded by chronic UVA exposure, to which CAFs are resistant. The advantage conferred by NOTCH1 amplification and overexpression can be explained by NOTCH1 ability to block the DNA damage response (DDR) and ensuing growth arrest through suppression of ATM-FOXO3a association and downstream signaling cascade. In an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer/stromal cells expansion. Here we show that NOTCH1 gene amplification and increased expression in CAFs are an attractive target for stroma-focused anti-cancer intervention.
癌症相关成纤维细胞（CAFs）是肿瘤微环境的关键组成部分。这些细胞的基因组改变仍然存在争议。我们报告称，来自皮肤鳞状细胞癌（SCC）的 CAFs 显示染色体改变，NOTCH1 基因扩增和过表达具有异质性，并且在明显未受影响的皮肤真皮成纤维细胞中也以较小的程度发生。后者细胞中携带 NOTCH1 扩增的部分通过慢性 UVA 暴露而扩大，而 CAFs 对此具有抗性。NOTCH1 扩增和过表达赋予的优势可以通过 NOTCH1 阻断 DNA 损伤反应（DDR）并通过抑制 ATM-FOXO3a 结合和下游信号级联来阻止生长停滞来解释。在皮肤 SCC 的原位模型中，NOTCH1 活性的遗传或药理学抑制可抑制癌症/基质细胞的扩增。在这里，我们表明 CAFs 中的 NOTCH1 基因扩增和表达增加是针对基质的抗癌干预的有吸引力的靶标。
