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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| Autor*in: |
Imkeller, Katharina [verfasserIn] Ambrosi, Giulia [verfasserIn] Klemm, Nancy [verfasserIn] Claveras Cabezudo, Ainara [verfasserIn] Henkel, Luisa [verfasserIn] Huber, Wolfgang [verfasserIn] Boutros, Michael [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2022 |
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| Übergeordnetes Werk: |
Enthalten in: Molecular Systems Biology - Nature Publishing Group UK, 2023, 18(2022), 8 vom: 29. Juli |
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| Übergeordnetes Werk: |
volume:18 ; year:2022 ; number:8 ; day:29 ; month:07 |
| Links: |
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| DOI / URN: |
10.15252/msb.202110874 |
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| Katalog-ID: |
SPR058140492 |
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| 100 | 1 | |a Imkeller, Katharina |e verfasserin |0 (orcid)0000-0002-5177-0852 |4 aut | |
| 245 | 1 | 0 | |a Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
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| 520 | |a 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. | ||
| 520 | |a Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. | ||
| 520 | |a Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. | ||
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| 700 | 1 | |a Ambrosi, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Klemm, Nancy |e verfasserin |4 aut | |
| 700 | 1 | |a Claveras Cabezudo, Ainara |e verfasserin |0 (orcid)0000-0003-1400-4929 |4 aut | |
| 700 | 1 | |a Henkel, Luisa |e verfasserin |4 aut | |
| 700 | 1 | |a Huber, Wolfgang |e verfasserin |0 (orcid)0000-0002-0474-2218 |4 aut | |
| 700 | 1 | |a Boutros, Michael |e verfasserin |0 (orcid)0000-0002-9458-817X |4 aut | |
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10.15252/msb.202110874 doi (DE-627)SPR058140492 (SPR)msb.202110874-e DE-627 ger DE-627 rakwb eng Imkeller, Katharina verfasserin (orcid)0000-0002-5177-0852 aut Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. APC (dpeaa)DE-He213 functional genomics (dpeaa)DE-He213 multi‐omic data integration (dpeaa)DE-He213 quantitative signaling (dpeaa)DE-He213 synthetic lethality (dpeaa)DE-He213 Ambrosi, Giulia verfasserin aut Klemm, Nancy verfasserin aut Claveras Cabezudo, Ainara verfasserin (orcid)0000-0003-1400-4929 aut Henkel, Luisa verfasserin aut Huber, Wolfgang verfasserin (orcid)0000-0002-0474-2218 aut Boutros, Michael verfasserin (orcid)0000-0002-9458-817X aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 18(2022), 8 vom: 29. Juli (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:18 year:2022 number:8 day:29 month:07 https://dx.doi.org/10.15252/msb.202110874 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 18 2022 8 29 07 |
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10.15252/msb.202110874 doi (DE-627)SPR058140492 (SPR)msb.202110874-e DE-627 ger DE-627 rakwb eng Imkeller, Katharina verfasserin (orcid)0000-0002-5177-0852 aut Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. APC (dpeaa)DE-He213 functional genomics (dpeaa)DE-He213 multi‐omic data integration (dpeaa)DE-He213 quantitative signaling (dpeaa)DE-He213 synthetic lethality (dpeaa)DE-He213 Ambrosi, Giulia verfasserin aut Klemm, Nancy verfasserin aut Claveras Cabezudo, Ainara verfasserin (orcid)0000-0003-1400-4929 aut Henkel, Luisa verfasserin aut Huber, Wolfgang verfasserin (orcid)0000-0002-0474-2218 aut Boutros, Michael verfasserin (orcid)0000-0002-9458-817X aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 18(2022), 8 vom: 29. Juli (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:18 year:2022 number:8 day:29 month:07 https://dx.doi.org/10.15252/msb.202110874 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 18 2022 8 29 07 |
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10.15252/msb.202110874 doi (DE-627)SPR058140492 (SPR)msb.202110874-e DE-627 ger DE-627 rakwb eng Imkeller, Katharina verfasserin (orcid)0000-0002-5177-0852 aut Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. APC (dpeaa)DE-He213 functional genomics (dpeaa)DE-He213 multi‐omic data integration (dpeaa)DE-He213 quantitative signaling (dpeaa)DE-He213 synthetic lethality (dpeaa)DE-He213 Ambrosi, Giulia verfasserin aut Klemm, Nancy verfasserin aut Claveras Cabezudo, Ainara verfasserin (orcid)0000-0003-1400-4929 aut Henkel, Luisa verfasserin aut Huber, Wolfgang verfasserin (orcid)0000-0002-0474-2218 aut Boutros, Michael verfasserin (orcid)0000-0002-9458-817X aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 18(2022), 8 vom: 29. Juli (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:18 year:2022 number:8 day:29 month:07 https://dx.doi.org/10.15252/msb.202110874 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 18 2022 8 29 07 |
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10.15252/msb.202110874 doi (DE-627)SPR058140492 (SPR)msb.202110874-e DE-627 ger DE-627 rakwb eng Imkeller, Katharina verfasserin (orcid)0000-0002-5177-0852 aut Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. APC (dpeaa)DE-He213 functional genomics (dpeaa)DE-He213 multi‐omic data integration (dpeaa)DE-He213 quantitative signaling (dpeaa)DE-He213 synthetic lethality (dpeaa)DE-He213 Ambrosi, Giulia verfasserin aut Klemm, Nancy verfasserin aut Claveras Cabezudo, Ainara verfasserin (orcid)0000-0003-1400-4929 aut Henkel, Luisa verfasserin aut Huber, Wolfgang verfasserin (orcid)0000-0002-0474-2218 aut Boutros, Michael verfasserin (orcid)0000-0002-9458-817X aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 18(2022), 8 vom: 29. Juli (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:18 year:2022 number:8 day:29 month:07 https://dx.doi.org/10.15252/msb.202110874 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 18 2022 8 29 07 |
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10.15252/msb.202110874 doi (DE-627)SPR058140492 (SPR)msb.202110874-e DE-627 ger DE-627 rakwb eng Imkeller, Katharina verfasserin (orcid)0000-0002-5177-0852 aut Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. APC (dpeaa)DE-He213 functional genomics (dpeaa)DE-He213 multi‐omic data integration (dpeaa)DE-He213 quantitative signaling (dpeaa)DE-He213 synthetic lethality (dpeaa)DE-He213 Ambrosi, Giulia verfasserin aut Klemm, Nancy verfasserin aut Claveras Cabezudo, Ainara verfasserin (orcid)0000-0003-1400-4929 aut Henkel, Luisa verfasserin aut Huber, Wolfgang verfasserin (orcid)0000-0002-0474-2218 aut Boutros, Michael verfasserin (orcid)0000-0002-9458-817X aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 18(2022), 8 vom: 29. Juli (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:18 year:2022 number:8 day:29 month:07 https://dx.doi.org/10.15252/msb.202110874 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 18 2022 8 29 07 |
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Enthalten in Molecular Systems Biology 18(2022), 8 vom: 29. Juli volume:18 year:2022 number:8 day:29 month:07 |
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Imkeller, Katharina @@aut@@ Ambrosi, Giulia @@aut@@ Klemm, Nancy @@aut@@ Claveras Cabezudo, Ainara @@aut@@ Henkel, Luisa @@aut@@ Huber, Wolfgang @@aut@@ Boutros, Michael @@aut@@ |
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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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">APC</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">functional genomics</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">multi‐omic data integration</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">quantitative signaling</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">synthetic lethality</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Ambrosi, Giulia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Klemm, Nancy</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Claveras Cabezudo, Ainara</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-1400-4929</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Henkel, Luisa</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huber, Wolfgang</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-0474-2218</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Boutros, Michael</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-9458-817X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Molecular Systems Biology</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">18(2022), 8 vom: 29. 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Imkeller, Katharina |
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Imkeller, Katharina misc APC misc functional genomics misc multi‐omic data integration misc quantitative signaling misc synthetic lethality Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
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Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels APC (dpeaa)DE-He213 functional genomics (dpeaa)DE-He213 multi‐omic data integration (dpeaa)DE-He213 quantitative signaling (dpeaa)DE-He213 synthetic lethality (dpeaa)DE-He213 |
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Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
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Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
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metabolic balance in colorectal cancer is maintained by optimal wnt signaling levels |
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Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
| abstract |
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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. © The Author(s) 2022 |
| abstractGer |
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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. © The Author(s) 2022 |
| abstract_unstemmed |
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. Synopsis Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. Genome‐engineering of APC mutations leads to Wnt‐hyperactivation in CRC cell lines with low endogenous Wnt signaling activity.The dosage level of oncogenic Wnt hyperactivation impacts the metabolic equilibrium and mitochondrial phenotypes of tumors.These findings suggest context‐dependent genetic interactions and quantitative modulation of oncogenic signaling during tumorigenesis. Graphical Abstract Whole‐genome CRISPR screens in genome‐engineered colorectal cancer (CRC) cell lines combined with large‐scale multi‐omic data integration reveal the role of diverging patterns of Wnt hyperactivation during the development of distinct CRC subtypes. © The Author(s) 2022 |
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Metabolic balance in colorectal cancer is maintained by optimal Wnt signaling levels |
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https://dx.doi.org/10.15252/msb.202110874 |
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Ambrosi, Giulia Klemm, Nancy Claveras Cabezudo, Ainara Henkel, Luisa Huber, Wolfgang Boutros, Michael |
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10.15252/msb.202110874 |
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2024-10-28T07:08:37.971Z |
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| score |
7.4026785 |