|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Hodis, 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|
|Date Published||2022 04 29|
|Keywords||Humans, Melanocytes, Melanoma, Mutation, Skin Neoplasms, Tumor Microenvironment|
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.
|Grant List||T32 GM007753 / GM / NIGMS NIH HHS / United States |
R50 CA252138 / CA / NCI NIH HHS / United States