Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment

• Published in: Science (American Association for the Advancement of Science) 2022-04, Vol.376 (6592), p.eabi8175-eabi8175
• Main Authors: Hodis, Eran, Torlai Triglia, Elena, Kwon, John Y H, Biancalani, Tommaso, Zakka, Labib R, Parkar, Saurabh, Hütter, Jan-Christian, Buffoni, Lorenzo, Delorey, Toni M, Phillips, Devan, Dionne, Danielle, Nguyen, Lan T, Schapiro, Denis, Maliga, Zoltan, Jacobson, Connor A, Hendel, Ayal, Rozenblatt-Rosen, Orit, Mihm, Jr, Martin C, Garraway, Levi A, Regev, Aviv
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenomatous polyposis coli; AKT protein; Algorithms; Animal models; Cancer; Cell culture; Cell differentiation; Colorectal cancer; Colorectal carcinoma; Combinatorial analysis; Computer applications; Design of experiments; Editing; Epistasis; Experimental design; Gene expression; Gene sequencing; Genes; Genetic modification; Genetics; Genome editing; Genomes; Genomics; Genotype & phenotype; Genotypes; Histology; Histopathology; Humans; Machine learning; Malignancy; MAP kinase; Melanocytes; Melanocytes - metabolism; Melanoma; Melanoma - pathology; Metastases; Microenvironments; Mutation; Pathogenesis; Phenotypes; Pigmentation; Research Design; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Stem cells; Telomerase; Tumor Microenvironment - genetics; Tumors; Xenografts; Xenotransplantation
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abi8175

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.