Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability
Abstract Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyze...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55574-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850076596959969280 |
|---|---|
| author | Arezo Torang Aleksandar B. Kirov Veerle Lammers Kate Cameron Valérie M. Wouters Rene F. Jackstadt Tamsin R. M. Lannagan Joan H. de Jong Jan Koster Owen Sansom Jan Paul Medema |
| author_facet | Arezo Torang Aleksandar B. Kirov Veerle Lammers Kate Cameron Valérie M. Wouters Rene F. Jackstadt Tamsin R. M. Lannagan Joan H. de Jong Jan Koster Owen Sansom Jan Paul Medema |
| author_sort | Arezo Torang |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition. |
| format | Article |
| id | doaj-art-d30874535a2f4405a197ebf7d3ce5dd4 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d30874535a2f4405a197ebf7d3ce5dd42025-08-20T02:46:00ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-55574-3Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerabilityArezo Torang0Aleksandar B. Kirov1Veerle Lammers2Kate Cameron3Valérie M. Wouters4Rene F. Jackstadt5Tamsin R. M. Lannagan6Joan H. de Jong7Jan Koster8Owen Sansom9Jan Paul Medema10Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamHeidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)Cancer Research UK Scotland Institute, Garscube EstateLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamCancer Research UK Scotland Institute, Garscube EstateLaboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of AmsterdamAbstract Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition.https://doi.org/10.1038/s41467-024-55574-3 |
| spellingShingle | Arezo Torang Aleksandar B. Kirov Veerle Lammers Kate Cameron Valérie M. Wouters Rene F. Jackstadt Tamsin R. M. Lannagan Joan H. de Jong Jan Koster Owen Sansom Jan Paul Medema Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability Nature Communications |
| title | Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability |
| title_full | Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability |
| title_fullStr | Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability |
| title_full_unstemmed | Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability |
| title_short | Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability |
| title_sort | enterocyte like differentiation defines metabolic gene signatures of cms3 colorectal cancers and provides therapeutic vulnerability |
| url | https://doi.org/10.1038/s41467-024-55574-3 |
| work_keys_str_mv | AT arezotorang enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT aleksandarbkirov enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT veerlelammers enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT katecameron enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT valeriemwouters enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT renefjackstadt enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT tamsinrmlannagan enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT joanhdejong enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT jankoster enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT owensansom enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability AT janpaulmedema enterocytelikedifferentiationdefinesmetabolicgenesignaturesofcms3colorectalcancersandprovidestherapeuticvulnerability |