Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Department of Animal Science, McGill University, Sainte-Anne-de-Bellevue, QC, Canada.
Nat Commun. 2021 May 24;12(1):3055. doi: 10.1038/s41467-021-23316-4.
Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.
三阴性乳腺癌（TNBC）患者的生存预后较差，且缺乏有效的靶向治疗方法。本研究采用无偏倚的体内全基因组 CRISPR 筛选技术，探究了 TNBC 的肿瘤易感性，并鉴定了致癌和肿瘤抑制途径之间的相互作用。该研究揭示了 mTOR 和 Hippo 通路中关键组成部分在 TNBC 中的肿瘤调控功能。通过体外药物矩阵协同模型和体内患者来源的异种移植模型，进一步证实了我们研究结果的治疗相关性，并表明 mTORC1/2 和癌蛋白 YAP 的药理学抑制可有效抑制 TNBC 的肿瘤发生。在分子水平上，我们发现，虽然 verteporfin 诱导的 YAP 抑制导致细胞凋亡，但 torin1 介导的 mTORC1/2 抑制促进巨胞饮作用。torin1 诱导的巨胞饮作用进一步促进了 verteporfin 的摄取，从而大大增强了其在癌细胞中的促凋亡作用。总的来说，本研究强调了体内 CRISPR 全基因组筛选在鉴定癌症中具有临床相关性和创新性治疗方式方面的强大功能和稳健性。
