Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment
Name
nihms-1829473.pdf
Description
Accepted version
Size
3.51 MB
Format
Adobe PDF
Checksum (MD5)
341a04ad06fd48d670bbdc346d6b0ed6
Author(s)
Hodis, Eran
Triglia, Elena Torlai
Kwon, John YH
Biancalani, Tommaso
Zakka, Labib R
Parkar, Saurabh
Hütter, Jan-Christian
Buffoni, Lorenzo
Delorey, Toni M
Phillips, Devan
Date Issued
2022
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Hodis, Eran, Triglia, Elena Torlai, Kwon, John YH, Biancalani, Tommaso, Zakka, Labib R et al. 2022. "Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment." Science, 376 (6592).
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCIENCE.ABI8175
