小柯机器人

比利时布鲁塞尔自由大学Cédric Blanpain等研究人员合作发现，药理靶向netrin-1可抑制癌症的EMT。2023年8月2日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现在一个表现出自发上皮细胞向间质转化（EMT）的原发性皮肤鳞状细胞癌（SCC）小鼠模型中，netrin-1上调。NP137是一种阻断netrin-1的单克隆抗体，目前正用于人类癌症的临床试验（ClinicalTrials.gov编号NCT02977195），通过服用NP137对netrin-1进行药理抑制，可以降低皮肤鳞状细胞癌中EMT肿瘤细胞的比例、减少转移数量并提高肿瘤细胞对化疗的敏感性。单细胞RNA测序显示，对照组SCC存在不同的EMT状态，包括上皮、早期和晚期混合EMT以及完全EMT状态。

相比之下，服用NP137可阻止癌细胞向晚期EMT状态发展，并维持肿瘤上皮状态。短发夹RNA敲除EPCAM⁺肿瘤细胞中的netrin-1及其受体UNC5B可在没有基质细胞的情况下抑制体外EMT，并调节促进肿瘤上皮状态和限制EMT的共同基因特征。为了评估这些发现与人类癌症的相关性，研究人员用NP137处理移植了A549人类癌细胞系的小鼠。netrin-1抑制剂可减少这些移植的A549细胞的EMT。总之，这些研究结果确定了一种靶向癌症EMT的药理学策略，为抗癌疗法开辟了新的治疗途径。

据了解，EMT调控着肿瘤的发生、发展、转移和对抗癌疗法的耐药性。尽管人们在了解EMT及其在癌症中的调控机制方面取得了很大进展，但目前还没有发现针对EMT的药物治疗策略。

附：英文原文

Title: Pharmacological targeting of netrin-1 inhibits EMT in cancer

Author: Lengrand, Justine, Pastushenko, Ievgenia, Vanuytven, Sebastiaan, Song, Yura, Venet, David, Sarate, Rahul M., Bellina, Melanie, Moers, Virginie, Boinet, Alice, Sifrim, Alejandro, Rama, Nicolas, Ducarouge, Benjamin, Van Herck, Jens, Dubois, Christine, Scozzaro, Samuel, Lemaire, Sophie, Gieskes, Sarah, Bonni, Sophie, Collin, Amandine, Braissand, Nicolas, Allard, Justine, Zindy, Egor, Decaestecker, Christine, Sotiriou, Christos, Salmon, Isabelle, Mehlen, Patrick, Voet, Thierry, Bernet, Agns, Blanpain, Cdric

Issue&Volume: 2023-08-02

Abstract: Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy1,2,3,4,5,6,7. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line—which undergoes EMT following TGFβ1 administration8,9—with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.

DOI: 10.1038/s41586-023-06372-2

Source: https://www.nature.com/articles/s41586-023-06372-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html