Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels
Abstract Wnt pathways are important for the modulation of tissue homeostasis, and their deregulation is linked to cancer development. Canonical Wnt signaling is hyperactivated in many human colorectal cancers due to genetic alterations of the negative Wnt regulator APC. However, the expression level...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-07-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.202110874 |
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| author | Katharina Imkeller Giulia Ambrosi Nancy Klemm Ainara Claveras Cabezudo Luisa Henkel Wolfgang Huber Michael Boutros |
| author_facet | Katharina Imkeller Giulia Ambrosi Nancy Klemm Ainara Claveras Cabezudo Luisa Henkel Wolfgang Huber Michael Boutros |
| author_sort | Katharina Imkeller |
| collection | DOAJ |
| description | Abstract Wnt pathways are important for the modulation of tissue homeostasis, and their deregulation is linked to cancer development. Canonical Wnt signaling is hyperactivated in many human colorectal cancers due to genetic alterations of the negative Wnt regulator APC. However, the expression levels of Wnt‐dependent targets vary between tumors, and the mechanisms of carcinogenesis concomitant with this Wnt signaling dosage have not been understood. In this study, we integrate whole‐genome CRISPR/Cas9 screens with large‐scale multi‐omic data to delineate functional subtypes of cancer. We engineer APC loss‐of‐function mutations and thereby hyperactivate Wnt signaling in cells with low endogenous Wnt activity and find that the resulting engineered cells have an unfavorable metabolic equilibrium compared with cells which naturally acquired Wnt hyperactivation. We show that the dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and the mitochondrial phenotype of a given cell type in a context‐dependent manner. These findings illustrate the impact of context‐dependent genetic interactions on cellular phenotypes of a central cancer driver mutation and expand our understanding of quantitative modulation of oncogenic signaling in tumorigenesis. |
| format | Article |
| id | doaj-art-544ba03818a64ad99b935e09d2cfae5c |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2022-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-544ba03818a64ad99b935e09d2cfae5c2025-08-20T03:43:34ZengSpringer NatureMolecular Systems Biology1744-42922022-07-0118811810.15252/msb.202110874Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levelsKatharina Imkeller0Giulia Ambrosi1Nancy Klemm2Ainara Claveras Cabezudo3Luisa Henkel4Wolfgang Huber5Michael Boutros6German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg UniversityGerman Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg UniversityGerman Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg UniversityEuropean Molecular Biology LaboratoryGerman Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg UniversityEuropean Molecular Biology LaboratoryGerman Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg UniversityAbstract Wnt pathways are important for the modulation of tissue homeostasis, and their deregulation is linked to cancer development. Canonical Wnt signaling is hyperactivated in many human colorectal cancers due to genetic alterations of the negative Wnt regulator APC. However, the expression levels of Wnt‐dependent targets vary between tumors, and the mechanisms of carcinogenesis concomitant with this Wnt signaling dosage have not been understood. In this study, we integrate whole‐genome CRISPR/Cas9 screens with large‐scale multi‐omic data to delineate functional subtypes of cancer. We engineer APC loss‐of‐function mutations and thereby hyperactivate Wnt signaling in cells with low endogenous Wnt activity and find that the resulting engineered cells have an unfavorable metabolic equilibrium compared with cells which naturally acquired Wnt hyperactivation. We show that the dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and the mitochondrial phenotype of a given cell type in a context‐dependent manner. These findings illustrate the impact of context‐dependent genetic interactions on cellular phenotypes of a central cancer driver mutation and expand our understanding of quantitative modulation of oncogenic signaling in tumorigenesis.https://doi.org/10.15252/msb.202110874APCfunctional genomicsmulti‐omic data integrationquantitative signalingsynthetic lethality |
| spellingShingle | Katharina Imkeller Giulia Ambrosi Nancy Klemm Ainara Claveras Cabezudo Luisa Henkel Wolfgang Huber Michael Boutros Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels Molecular Systems Biology APC functional genomics multi‐omic data integration quantitative signaling synthetic lethality |
| title | Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
| title_full | Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
| title_fullStr | Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
| title_full_unstemmed | Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
| title_short | Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
| title_sort | metabolic balance in colorectal cancer is maintained by optimal wnt signaling levels |
| topic | APC functional genomics multi‐omic data integration quantitative signaling synthetic lethality |
| url | https://doi.org/10.15252/msb.202110874 |
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