CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
Ligue Nationale Contre le Cancer, Cartes d'Identité des Tumeurs Program, 75013 Paris, France.
Sci Transl Med. 2014 Jul 9;6(244):244ra91. doi: 10.1126/scitranslmed.3008970.
Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.
肌层浸润性膀胱癌（MIBC）是一组预后较差的异质性肿瘤。MIBC 的分子分层可能确定具有临床相关性的肿瘤亚群，并有助于提供有效的靶向治疗。从七组大规模转录组数据（383 个肿瘤）中，我们鉴定出占 MIBC 23.5%的 MIBC 亚组，其与较短的生存时间和基底样表型相关，这表现在上皮基底细胞标志物的表达上。基底样肿瘤表现出表皮生长因子受体（EGFR）通路的激活，这与 EGFR 频繁获得和 EGFR 自分泌环的激活有关。我们使用源自人类肿瘤的 40 个基因表达分类器来鉴定人类膀胱癌细胞系和化学诱导的小鼠膀胱癌模型，该模型对应于人类基底样膀胱癌。我们在这两种模型中都表明，肿瘤细胞对 EGFR 抑制剂治疗敏感。我们的研究结果提供了临床前概念验证，表明 EGFR 抑制剂治疗可用于靶向表达基底细胞标志物的侵袭性较强的 MIBC 肿瘤亚群，并提供了用于鉴定这些肿瘤的诊断工具。
