Cancers adapt to their mutational load by buffering protein misfolding stress
In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging co...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/87301 |
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| author | Susanne Tilk Judith Frydman Christina Curtis Dmitri A Petrov |
| author_facet | Susanne Tilk Judith Frydman Christina Curtis Dmitri A Petrov |
| author_sort | Susanne Tilk |
| collection | DOAJ |
| description | In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities. |
| format | Article |
| id | doaj-art-fdb8cd79eb9c48c1b55d351cb94b5f02 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-fdb8cd79eb9c48c1b55d351cb94b5f022024-11-25T17:20:55ZengeLife Sciences Publications LtdeLife2050-084X2024-11-011210.7554/eLife.87301Cancers adapt to their mutational load by buffering protein misfolding stressSusanne Tilk0https://orcid.org/0000-0002-9156-9360Judith Frydman1https://orcid.org/0000-0003-2302-6943Christina Curtis2https://orcid.org/0000-0003-0166-3802Dmitri A Petrov3https://orcid.org/0000-0002-3664-9130Department of Biology, Stanford University, Stanford, United StatesDepartment of Biology, Stanford University, Stanford, United StatesDepartment of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, United States; Department of Genetics, Stanford University School of Medicine, Stanford, United States; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, United StatesDepartment of Biology, Stanford University, Stanford, United States; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, United StatesIn asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.https://elifesciences.org/articles/87301cancersomatic evolutionproteostasismutational load |
| spellingShingle | Susanne Tilk Judith Frydman Christina Curtis Dmitri A Petrov Cancers adapt to their mutational load by buffering protein misfolding stress eLife cancer somatic evolution proteostasis mutational load |
| title | Cancers adapt to their mutational load by buffering protein misfolding stress |
| title_full | Cancers adapt to their mutational load by buffering protein misfolding stress |
| title_fullStr | Cancers adapt to their mutational load by buffering protein misfolding stress |
| title_full_unstemmed | Cancers adapt to their mutational load by buffering protein misfolding stress |
| title_short | Cancers adapt to their mutational load by buffering protein misfolding stress |
| title_sort | cancers adapt to their mutational load by buffering protein misfolding stress |
| topic | cancer somatic evolution proteostasis mutational load |
| url | https://elifesciences.org/articles/87301 |
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