Multi-omics, organoid-based modeling reveals an SRC/mTOR-dependent fetal-like stem cell trajectory in colorectal cancer
Rattachement africain : de, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Background Single-cell atlases have described diverse stem cell states in colorectal cancer (CRC), however, the overarching trajectories of those states and the underlying functional mechanisms, including their relevance for drug sensitivity, need better understanding. Methods We established 64 patient-derived organoids from microsatellite-stable colorectal cancers, characterized their transcriptomes and genomes, and performed drug screening with 62-140 clinically approved substances. We analyzed additional published transcriptome data from patient-derived organoids (72 patients from three independent datasets), TCGA-CRC data (466 patients), and single-cell transcriptomes of tumor biopsies (123,000 cells from six independent cohorts) to establish a functional and molecular landscape of CRC stem cells. We performed mechanistic follow-up analyses by mass-spectrometry-based proteomics, large-scale kinase inhibition assays and immunofluorescence analyses. Results We find a continuous landscape of CRC stem cells that is characterized by distinct developmental programs: adult stem cell-to fetal-like regenerative states and transition between differentiation programs. By large-scale drug perturbations and multi-omics modeling, we identify a regenerative/fetal-like stem cell trajectory characterized by PI3K/mTOR dependency. We find the identified developmental axes conserved in organoid, clinical, as well as single-cell data, and the fetal-like PI3K/mTOR-dependent state to be associated with poor clinical prognosis. Mechanistically, PI3K/mTOR vulnerability is linked to a lack of adaptive capability due to suppressed mRNA translation and associated with an upregulated SRC signaling network. Conclusions Our work moves beyond a molecular CRC landscape by combined functional perturbation analyses in organoids. This enables mechanistic modeling of stem cell state regulation and identifies an SRC/mTOR-dependent regenerative state in CRC, which might allow improved therapeutic targeting in the future.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Multi-omics, organoid-based modeling reveals an SRC/mTOR-dependent fetal-like stem cell trajectory in colorectal cancer
- Date Crossref
- 03/07/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
German Cancer Research Center Division of Molecular Genome Analysis pays non établi dans la noticeStructure de recherche
-
Heidelberg University pays non établi dans la noticeUniversité ou école supérieure
-
University Hospital Heidelberg pays non établi dans la noticeÉtablissement de santé
-
University Medical Center Department of Medicine II pays non établi dans la noticeÉtablissement de santé
-
University Medical Centre Mannheim pays non établi dans la noticeOrganisme public
-
Deutsches Konsortium für Translationale Krebsforschung pays non établi dans la noticeStructure de recherche
-
Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models pays non établi dans la noticeÉtablissement de santé
-
MMPU Microbiota Drug Metabolism and Cancer Therapy pays non établi dans la noticeInstitution
-
Medical Faculty Heidelberg Department of Molecular Human Genetics pays non établi dans la noticeUniversité ou école supérieure
-
German Cancer Consortium (DKTK) pays non établi dans la noticeInstitution
-
Mannheim Cancer Center pays non établi dans la noticeInstitution
Division of Molecular Genome Analysis — German Cancer Research Center, Heidelberg University et University Hospital Heidelberg, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.