IGF1R signaling induces epithelial-mesenchymal plasticity via ITGAV in cutaneous carcinoma.

IF 11.4 1区医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2024-07-29 DOI:10.1186/s13046-024-03119-3

Marta Lopez-Cerda, Laura Lorenzo-Sanz, Victoria da Silva-Diz, Sandra Llop, Rosa M Penin, Josep Oriol Bermejo, Richard de Goeij-de Haas, Sander R Piersma, Thang V Pham, Connie R Jimenez, Juan Martin-Liberal, Purificación Muñoz

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引用次数: 0

Abstract

Background: Early cutaneous squamous cell carcinomas (cSCCs) generally show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits associated with tumor relapse, metastasis, and poor survival. Currently, the mechanisms involved in cSCC progression are unclear, and the established markers are suboptimal for accurately predicting the clinical course of the disease.

Methods: Using a mouse model of cSCC progression, expression microarray analysis, immunofluorescence and flow cytometry assays, we have identified a prognostic biomarker of tumor relapse, which has been evaluated in a cohort of cSCC patient samples. Phosphoproteomic analysis have revealed signaling pathways induced in epithelial plastic cancer cells that promote epithelial-mesenchymal plasticity (EMP) and tumor progression. These pathways have been validated by genetic and pharmacological inhibition assays.

Results: We show that the emergence of epithelial cancer cells expressing integrin αV (ITGAV) promotes cSCC progression to a mesenchymal state. Consistently, ITGAV expression allows the identification of patients at risk of cSCC relapse above the currently employed clinical histopathological parameters. We also demonstrate that activation of insulin-like growth factor-1 receptor (IGF1R) pathway in epithelial cancer cells is necessary to induce EMP and mesenchymal state acquisition in response to tumor microenvironment-derived factors, while promoting ITGAV expression. Likewise, ITGAV knockdown in epithelial plastic cancer cells also blocks EMP acquisition, generating epithelial tumors.

Conclusions: Our results demonstrate that ITGAV is a prognostic biomarker of relapse in cSCCs that would allow improved patient stratification. ITGAV also collaborates with IGF1R to induce EMP in epithelial cancer cells and promotes cSCC progression, revealing a potential therapeutic strategy to block the generation of advanced mesenchymal cSCCs.

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IGF1R 信号通过 ITGAV 在皮肤癌中诱导上皮-间质可塑性。

背景：早期皮肤鳞状细胞癌（cSCC）一般表现为上皮分化特征，预后良好，而晚期cSCC则表现为间质特征，与肿瘤复发、转移和生存率低有关。目前，参与 cSCC 进展的机制尚不清楚，已有的标记物也无法准确预测疾病的临床过程：方法：我们利用小鼠 cSCC 进展模型、表达微阵列分析、免疫荧光和流式细胞术检测，确定了肿瘤复发的预后生物标志物，并在一组 cSCC 患者样本中进行了评估。磷蛋白组学分析揭示了上皮可塑性癌细胞中诱导的信号通路，这些通路促进了上皮-间质可塑性（EMP）和肿瘤的进展。这些通路已通过基因和药理抑制实验得到验证：结果：我们发现，表达整合素αV（ITGAV）的上皮癌细胞的出现促进了cSCC向间充质状态的进展。同样，ITGAV 的表达可以识别有复发风险的 cSCC 患者，其风险高于目前使用的临床组织病理学参数。我们还证明，上皮癌细胞中胰岛素样生长因子-1 受体（IGF1R）通路的激活是诱导 EMP 和间质状态获得的必要条件，以应对肿瘤微环境衍生因子，同时促进 ITGAV 的表达。同样，ITGAV在上皮整形癌细胞中的敲除也会阻止EMP的获得，从而产生上皮肿瘤：我们的研究结果表明，ITGAV是cSCC复发的预后生物标志物，可改善患者分层。ITGAV还与IGF1R合作诱导上皮癌细胞中的EMP，并促进cSCC的进展，从而揭示了阻止晚期间质型cSCC生成的潜在治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.