Immuno-genomic classification of colorectal cancer organoids reveals cancer cells with intrinsic immunogenic properties associated with patient survival
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171682 | GEO | 2021/07/20
REPOSITORIES: GEO
Similar Datasets
Project description:BackgroundThe intrinsic immuno-ge7nomic characteristics of colorectal cancer cells that affect tumor biology and shape the tumor immune microenvironment (TIM) are unclear.MethodsWe developed a patient-derived colorectal cancer organoid (CCO) model and performed pairwise analysis of 87 CCOs and their matched primary tumors. The TIM type of the primary tumor was classified as immuno-active, immuno-exhausted, or immuno-desert.ResultsThe gene expression profiles, signaling pathways, major oncogenic mutations, and histology of the CCOs recapitulated those of the primary tumors, but not the TIM of primary tumors. Two distinct intrinsic molecular subgroups of highly proliferative and mesenchymal phenotypes with clinical significance were identified in CCOs with various cancer signaling pathways. CCOs showed variable expression of cancer-specific immune-related genes such as those encoding HLA-I and HLA-II, and molecules involved in immune checkpoint activation/inhibition. Among these genes, the expression of HLA-II in CCOs was associated with favorable patient survival. K-means clustering analysis based on HLA-II expression in CCOs revealed a subgroup of patients, in whom cancer cells exhibited Intrinsically Immunogenic Properties (Ca-IIP), and were characterized by high expression of signatures associated with HLA-I, HLA-II, antigen presentation, and immune stimulation. Patients with the Ca-IIP phenotype had an excellent prognosis, irrespective of age, disease stage, intrinsic molecular type, or TIM status. Ca-IIP was negatively correlated with intrinsic E2F/MYC signaling. Analysis of the correlation between CCO immuno-genotype and TIM phenotype revealed that the TIM phenotype was associated with microsatellite instability, Wnt/β-catenin signaling, APC/KRAS mutations, and the unfolded protein response pathway linked to the FBXW7 mutation in cancer cells. However, Ca-IIP was not associated with the TIM phenotype.ConclusionsWe identified a Ca-IIP phenotype from a large set of CCOs. Our findings may provide an unprecedented opportunity to develop new strategies for optimal patient stratification in this era of immunotherapy.
| S-EPMC8276416 | biostudies-literature
Project description:Immuno-genomic classification of colorectal cancer organoids reveals cancer cells with intrinsic immunogenic properties associated with patient survival
| PRJNA720562 | ENA
Project description:Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. Here, using several clinically relevant colorectal cancer (CRC) gene expression signatures, we assessed the susceptibility of these signatures to the confounding effects of ITH using gene expression microarray data obtained from multiple tumour regions of a cohort of 24 patients, including central tumour, the tumour invasive front and lymph node metastasis. Sample clustering alongside correlative assessment revealed variation in the ability of each signature to cluster samples according to patient-of-origin rather than region-of-origin within the multi-region dataset. Signatures focused on cancer-cell intrinsic gene expression were found to produce more clinically useful, patient-centred classifiers, as exemplified by the CRC intrinsic signature (CRIS), which robustly clustered samples by patient-of-origin rather than region-of-origin. These findings highlight the potential of cancer-cell intrinsic signatures to reliably stratify CRC patients by minimising the confounding effects of stromal-derived ITH.
| S-EPMC5460026 | biostudies-literature
Project description:The drug 5-fluorouracil (5-Fu) is the critical composition of colorectal cancer (CRC) treatments. Prognostic and predictive molecular biomarkers for CRC patients (CRCpts) treated with 5-Fu-based chemotherapy can provide assistance for tailoring treatment approach. Here, we established a molecular biomarker of 5-Fu resistance derived from colorectal cancer organoids (CRCOs) for predicting the survival of CRCpts. Forty-one CRCO cultures were generated from 50 CRC tumor tissues after surgery (82%). The following experiments revealed a great diversity in drug sensitivity for 10 μM 5-Fu treatment tested by using organoid size change. Fourteen cases (34.1%) were 5-Fu sensitive and the other 27 (65.9%) were resistant. Then, differentially expressed genes (DEGs) associated with 5-Fu resistance were outputted by transcriptome sequencing. In particular, DEGs were generated in two comparison groups: 1) 5-Fu sensitive and resistant untreated CRCOs; 2) CRCOs before 5-Fu treatment and surviving CRCOs after 5-Fu treatment. Some molecules and most of the pathways that have been reported to be involved in 5-Fu resistance were identified in the current research. By using DEGs correlated with 5-Fu resistance and survival of CRCpts, the gene signature and drug-resistant score model (DRSM) containing five molecules were established in The Cancer Genome Atlas (TCGA)-CRC cohort by least absolute shrinkage and selection operator (LASSO) regression analysis and 5-fold cross-validation. Multivariate analysis revealed that drug-resistant score (DRS) was an independent prognostic factor for overall survival (OS) in CRCpts in TCGA-CRC cohort (P < 0.001). Further validation results from four Gene Expression Omnibus (GEO) cohorts elucidated that the DRSM based on five genes related to 5-Fu chemosensitivity and developed from patient-derived organoids can predict survival of CRCpts. Meanwhile, our model could predict the survival of CRCpts in different subgroups. Besides, the difference of molecular pathways, tumor mutational burden (TMB), immune response-related pathways, immune score, stromal score, and immune cell proportion were dissected between DRS-high and DRS-low patients in TCGA-CRC cohort.
| S-EPMC9004628 | biostudies-literature
Project description:DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms-for instance signals derived from the microenvironment-must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.
| S-EPMC8582471 | biostudies-literature
Project description:Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. Using several clinically relevant colorectal cancer (CRC) gene expression signatures, we assessed the susceptibility of these signatures to the confounding effects of ITH using gene expression microarray data obtained from multiple tumour regions of a cohort of 24 patients, including central tumour, the tumour invasive front and lymph node metastasis.
2017-05-01 | GSE95109 | GEO
Project description:BackgroundRecent studies have shown patient-derived tumor organoids can predict the drug response of patients with cancer. However, the prognostic value of patient-derived tumor organoid-based drug tests in predicting the progression-free survival of patients with stage IV colorectal cancer after surgery remains unknown.ObjectiveThis study aimed to explore the prognostic value of patient-derived tumor organoid-based drug tests in patients with stage IV colorectal cancer after surgery.DesignRetrospective cohort study.SettingsSurgical samples were obtained from patients with stage IV colorectal cancer at the Nanfang Hospital.PatientsA total of 108 patients who underwent surgery with successful patient-derived tumor organoid culture and drug testing were recruited between June 2018 and June 2019.InterventionsPatient-derived tumor organoid culture and chemotherapeutic drug testing.Main outcomes measuresProgression-free survival.ResultsAccording to the patient-derived tumor organoid-based drug test, 38 patients were drug sensitive and 76 patients were drug resistant. The median progression-free survival was 16.0 months in the drug-sensitive group and 9.0 months in the drug resistant group ( p < 0.001). Multivariate analyses showed that drug resistance (HR, 3.38; 95% CI, 1.84-6.21; p < 0.001), right-sided colon (HR, 3.50; 95% CI, 1.71-7.15; p < 0.001), mucinous adenocarcinoma (HR, 2.47; 95% CI, 1.34-4.55; p = 0.004), and non-R0 resection (HR, 2.70; 95% CI, 1.61-4.54; p < 0.001) were independent predictors of progression-free survival. The new patient-derived tumor organoid-based drug test model, which includes the patient-derived tumor organoid-based drug test, primary tumor location, histological type, and R0 resection, was more accurate than the traditional clinicopathological model in predicting progression-free survival ( p = 0.001).LimitationsA single-center cohort study.ConclusionsPatient-derived tumor organoids can predict progression-free survival in patients with stage IV colorectal cancer after surgery. Patient-derived tumor organoid drug resistance is associated with shorter progression-free survival, and the addition of patient-derived tumor organoid drug tests to existing clinicopathological models improves the ability to predict progression-free survival.
| S-EPMC10072204 | biostudies-literature
Project description:Immunotherapy using chimeric antigen receptor (CAR)-engineered lymphocytes has shown impressive results in leukemia. However, for solid tumors such as colorectal cancer (CRC), new preclinical models are needed that allow to test CAR-mediated cytotoxicity in a tissue-like environment. Here, we developed a platform to study CAR cell cytotoxicity against 3-dimensional (3D) patient-derived colon organoids. Luciferase-based measurement served as a quantitative read-out for target cell viability. Additionally, we set up a confocal live imaging protocol to monitor effector cell recruitment and cytolytic activity at a single organoid level. As proof of principle, we demonstrated efficient targeting in diverse organoid models using CAR-engineered NK-92 cells directed toward a ubiquitous epithelial antigen (EPCAM). Tumor antigen-specific cytotoxicity was studied with CAR-NK-92 cells targeting organoids expressing EGFRvIII, a neoantigen found in several cancers. Finally, we tested a novel CAR strategy targeting FRIZZLED receptors that show increased expression in a subgroup of CRC tumors. Here, comparative killing assays with normal organoids failed to show tumor-specific activity. Taken together, we report a sensitive in vitro platform to evaluate CAR efficacy and tumor specificity in a personalized manner.
| S-EPMC6576164 | biostudies-literature
Project description: Not available
| S-EPMC7803352 | biostudies-literature
Project description:Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies. This was observed in tumorigenic as well as in normal organoids. Moreover, dual inhibition of the EGFR-MEK-ERK pathway in RAS mutant organoids induced a transient cell-cycle arrest rather than cell death. In vivo drug response of xenotransplanted RAS mutant organoids confirmed this growth arrest upon pan-HER/MEK combination therapy. Altogether, our studies demonstrate the potential of patient-derived CRC organoid libraries in evaluating inhibitors and drug combinations in a preclinical setting.
| S-EPMC5127645 | biostudies-literature