Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment
<jats:p>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 n...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science (AAAS)
2023
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| Online Access: | https://hdl.handle.net/1721.1/147070 |
| _version_ | 1826198484131250176 |
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| author | 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 Dionne, Danielle Nguyen, Lan T Schapiro, Denis Maliga, Zoltan Jacobson, Connor A Hendel, Ayal Rozenblatt-Rosen, Orit Mihm, Martin C Garraway, Levi A Regev, Aviv |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 Dionne, Danielle Nguyen, Lan T Schapiro, Denis Maliga, Zoltan Jacobson, Connor A Hendel, Ayal Rozenblatt-Rosen, Orit Mihm, Martin C Garraway, Levi A Regev, Aviv |
| author_sort | Hodis, Eran |
| collection | MIT |
| description | <jats:p>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.</jats:p> |
| first_indexed | 2024-09-23T11:05:40Z |
| format | Article |
| id | mit-1721.1/147070 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:05:40Z |
| publishDate | 2023 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1470702023-01-12T03:31:49Z Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment 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 Dionne, Danielle Nguyen, Lan T Schapiro, Denis Maliga, Zoltan Jacobson, Connor A Hendel, Ayal Rozenblatt-Rosen, Orit Mihm, Martin C Garraway, Levi A Regev, Aviv Massachusetts Institute of Technology. Department of Biology <jats:p>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.</jats:p> 2023-01-11T18:29:56Z 2023-01-11T18:29:56Z 2022 2023-01-11T18:06:11Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147070 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). en 10.1126/SCIENCE.ABI8175 Science Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | 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 Dionne, Danielle Nguyen, Lan T Schapiro, Denis Maliga, Zoltan Jacobson, Connor A Hendel, Ayal Rozenblatt-Rosen, Orit Mihm, Martin C Garraway, Levi A Regev, Aviv Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment |
| title | Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment |
| title_full | Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment |
| title_fullStr | Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment |
| title_full_unstemmed | Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment |
| title_short | Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment |
| title_sort | stepwise edited human melanoma models reveal mutations effect on tumor and microenvironment |
| url | https://hdl.handle.net/1721.1/147070 |
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