Midde Krishna, Sun Nina, Rohena Cristina, Joosen Linda, Dhillon Harsharan, Ghosh Pradipta
Department of Medicine, University of California at San Diego, George Palade Labs, Room 232, La Jolla, CA 92093-0651, USA.
Department of Medicine, University of California at San Diego, George Palade Labs, Room 232, La Jolla, CA 92093-0651, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0651, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
iScience. 2018 Dec 21;10:53-65. doi: 10.1016/j.isci.2018.11.022. Epub 2018 Nov 15.
Molecular imaging of metastatic "potential" is an unvanquished challenge. To engineer biosensors that can detect and measure the metastatic "potential" of single living cancer cells, we carried out a comprehensive analysis of the pan-cancer phosphoproteome to search for actin remodelers required for cell migration, which are enriched in cancers but excluded in normal cells. Only one phosphoprotein emerged, tyr-phosphorylated CCDC88A (GIV/Girdin), a bona fide metastasis-related protein across a variety of solid tumors. We designed multi-modular biosensors that are partly derived from GIV, and because GIV integrates prometastatic signaling by multiple oncogenic receptors, we named them "'integrators of metastatic potential (IMP)." IMPs captured the heterogeneity of metastatic potential within primary lung and breast tumors at steady state, detected those few cells that have acquired the highest metastatic potential, and tracked their enrichment during metastasis. These findings provide proof of concept that IMPs can measure the diversity and plasticity of metastatic potential of tumor cells in a sensitive and unbiased way.
对转移性“潜能”进行分子成像仍是一项未被攻克的挑战。为了构建能够检测和测量单个活癌细胞转移性“潜能”的生物传感器，我们对泛癌磷酸化蛋白质组进行了全面分析，以寻找细胞迁移所需的肌动蛋白重塑因子，这些因子在癌症中富集但在正常细胞中不存在。仅有一种磷酸化蛋白脱颖而出，即酪氨酸磷酸化的CCDC88A（GIV/Girdin），它是多种实体瘤中真正的转移相关蛋白。我们设计了部分源自GIV的多模块生物传感器，由于GIV通过多种致癌受体整合促转移信号，我们将其命名为“转移潜能整合器（IMP）”。IMP在稳态下捕捉了原发性肺癌和乳腺癌中转移潜能的异质性，检测出那些获得最高转移潜能的少数细胞，并在转移过程中追踪它们的富集情况。这些发现提供了概念验证，即IMP能够以敏感且无偏差的方式测量肿瘤细胞转移潜能的多样性和可塑性。
