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Science DOI:10.1126/science.abi8175

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

Publication TypeJournal Article
Year of Publication2022
AuthorsHodis, E, Triglia, ETorlai, Kwon, JYH, Biancalani, T, Zakka, LR, Parkar, S, Hütter, J-C, Buffoni, L, Delorey, TM, Phillips, D, Dionne, D, Nguyen, LT, Schapiro, D, Maliga, Z, Jacobson, CA, Hendel, A, Rozenblatt-Rosen, O, Mihm, MC, Garraway, LA, Regev, A
JournalScience
Volume376
Issue6592
Pageseabi8175
Date Published2022 04 29
ISSN1095-9203
KeywordsHumans, Melanocytes, Melanoma, Mutation, Skin Neoplasms, Tumor Microenvironment
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.

DOI10.1126/science.abi8175
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35482859?dopt=Abstract

Alternate JournalScience
PubMed ID35482859
Grant ListT32 GM007753 / GM / NIGMS NIH HHS / United States
R50 CA252138 / CA / NCI NIH HHS / United States