Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2013 Aug;123(8):3525-38. doi: 10.1172/JCI68899. Epub 2013 Jul 8.
Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common and lethal human cancer, and relatively little progress has been made in improving outcomes for SCC due to a poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression of the p53-related transcription factor p63. We developed an in vivo murine tumor model to investigate the function and key transcriptional programs of p63 in SCC. Here, we show that established SCCs are exquisitely dependent on p63, as acute genetic ablation of p63 in advanced, invasive SCC induced rapid and dramatic apoptosis and tumor regression. In vivo genome-wide gene expression analysis identified a tumor-survival program involving p63-regulated FGFR2 signaling that was activated by ligand emanating from abundant tumor-associated stroma. Correspondingly, we demonstrate the therapeutic efficacy of extinguishing this signaling axis in endogenous SCCs using the clinical FGFR2 inhibitor AZD4547. Collectively, these results reveal an unanticipated role for p63-driven paracrine FGFR2 signaling as an addicting pathway in human cancer and suggest a new approach for the treatment of SCC.
致癌转录因子驱动着许多人类癌症，但识别和治疗由此导致的失调途径一直很困难。鳞状细胞癌（SCC）是一种常见且致命的人类癌症，由于对其潜在分子发病机制的理解有限，因此在改善 SCC 的预后方面进展甚微。虽然 SCC 通常缺乏体细胞致癌基因激活突变，但它们表现出 p53 相关转录因子 p63 的频繁过表达。我们开发了一种体内小鼠肿瘤模型来研究 p63 在 SCC 中的功能和关键转录程序。在这里，我们表明已建立的 SCC 对 p63 具有极高的依赖性，因为在晚期侵袭性 SCC 中急性遗传消融 p63 会诱导快速而显著的细胞凋亡和肿瘤消退。体内全基因组基因表达分析确定了一个涉及 p63 调节的 FGFR2 信号的肿瘤存活程序，该程序被来自丰富的肿瘤相关基质的配体激活。相应地，我们使用临床 FGFR2 抑制剂 AZD4547 证明了在体内 SCC 中消除这种信号轴的治疗效果。总之，这些结果揭示了 p63 驱动的旁分泌 FGFR2 信号作为人类癌症成瘾途径的预期作用，并为 SCC 的治疗提供了一种新方法。
