研究人员依次将多达五个基因的突变引入健康的人类黑色素细胞，这些基因横跨六条常见的黑色素瘤途径，形成了九个遗传上不同的黑色素瘤细胞模型。研究人员将突变的黑色素细胞基因型与体外和体内的恶性细胞表达程序、复制永生性、恶性程度、肿瘤快速生长、色素沉着、转移和组织病理学相联系。恶性细胞的突变也影响了肿瘤微环境的组成和细胞状态。
这个黑色素瘤模型与患者的黑色素瘤共享基因型相关的表达程序，一个深度学习模型显示，这些模型也部分再现了基因型相关的组织病理学特征。因此，一系列渐进式基因组编辑的人类癌症模型，可以将携带多个突变的基因型与表型进行因果联系。
据了解，在人类癌症的基因改变和恶性肿瘤的特定表型之间建立因果关系仍然是一个挑战。
附：英文原文
Title: Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment
Author: Eran Hodis, Elena Torlai Triglia, John Y. H. Kwon, Tommaso Biancalani, Labib R. Zakka, Saurabh Parkar, Jan-Christian Hütter, Lorenzo Buffoni, Toni M. Delorey, Devan Phillips, Danielle Dionne, Lan T. Nguyen, Denis Schapiro, Zoltan Maliga, Connor A. Jacobson, Ayal Hendel, Orit Rozenblatt-Rosen, Martin C. Mihm Jr., Levi A. Garraway, Aviv Regev
Issue&Volume: 2022-04-29
Abstract: Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis, and histopathology. Mutations in malignant cells also affected tumor microenvironment composition and cell states. Our melanoma models shared genotype-associated expression programs with patient melanomas, and a deep learning model showed that these models partially recapitulated genotype-associated histopathological features as well. Thus, a progressive series of genome-edited human cancer models can causally connect genotypes carrying multiple mutations to phenotype.
DOI: abi8175
Source: https://www.science.org/doi/10.1126/science.abi8175