Colon Cancer Patient-Derived Spheroids and their Stem Cell-Intrinsic mRNA Expression Yield Novel Prognostic Signatures
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216724 | GEO | 2025/10/27
REPOSITORIES: GEO
Similar Datasets
Project description:Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.
2025-03-17 | PXD056331 | Pride
Project description:Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 159 CRC cell lines to CMS. By integrating results from large scale drug screens, we discovered that CMS1 cancer is highly vulnerable to the survivin suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrate a 100-fold higher sensitivity of CMS1 lines. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 cancer, low concentrations of YM155 induced apoptosis and expression signatures associated with NFkappaB and ER stress mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we discovered a novel role of genes involved in LDL-receptor recycling as modulators of YM155 response in CMS1 CRC. Our work shows that combining drug response data with CMS classification in cell lines can reveal specific vulnerabilities and propose YM155 as novel CMS1 specific drug. We performed expression profiling experiments in order to validate molecular subtypes for selected cell lines
2018-07-03 | GSE116528 | GEO
Project description:Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer death globally. The molecular mechanisms underlying CRC have been investigated using different omics technologies including genomics, proteomics, and metabolomics. Resulting molecular signatures can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease recurrence are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at stage II or III. We identified microsatellite instability and tumor stage as the two main clinical traits statistically linked to the risk of relapse. Integrating proteomics and transcriptomics data, we classified the tumors into four consensus molecular subtypes, and found that stage III tumors showed higher epithelial-to-mesenchymal transition signature than stage II. As the mesenchymal-like subtype is the one with most invasive and metastatic phenotype, we focused on proteins over-expressed in this subtype and evaluated their potential as relapse-free survival markers. Specifically, we studied on the role of CAVIN1 in the formation and progression of colorectal cancer in a 3D in vitro model. Finally, using hybrid-DIA phosphoproteomics profiling we identified an mTOR kinase activity footprint that was specific to patients that suffered post-surgery relapse. Compared to previous omics analysis of CRC, our multi-omics classification provided deeper insights into the mesenchymal-like subtypes with stronger correlations with risk of relapse.
2025-03-26 | PXD044246 | Pride
Project description:Locally advanced head and neck squamous cell carcinomas (HNSCC) are commonly treated with chemoradiotherapy (CRT) or induction chemotherapy followed by radiotherapy/CRT or surgery. The purpose of our study was to identify expression signatures and molecular markers able to anticipate tumor response to therapy and clinical outcome. We performed a study with 63 pre-treatment tumor biopsies from locally advanced HNSCC treated with either of the two standard treatments. Cluster analysis identified three tumor subtypes associated with significant differences in local recurrence-free survival (LRFS) and overall survival (OS). Tumor subtype 1, associated with low LRFS and OS, showed features of epithelial-mesenchymal transition and undifferentiation. It also overexpressed genes related to cell adhesion, NF-κB and integrin signalling pathways. Tumor subtype 3, associated with a high LRFS and OS, showed a high degree of differentiation and overexpressed genes located in chromosome regions 19q13 and 1q21. Tumor subtype 2, with a LRFS that was similar to subtype 3 and an OS similar to subtype 1, overexpressed genes involved in branching morphogenesis. ROC analysis identified genes associated with local recurrence and survival. Using qRT-PCR we confirmed the association of RAB25, DUOX1 and THBS1 expression with LRFS and OS. Patients whose tumors displayed high RAB25 or DUOX1 mRNA levels had longer LRFS and OS than patients with low mRNA levels. In contrast, patients bearing tumors with high THBS1 levels had a shorter OS than patients with low THBS1 levels. RAB25, DUOX1 and THBS1 could be good molecular markers to identify patients who would benefit from genotoxic treatment. Sixty three pretreatment HNSCC biopsies and five normal mucosas were assayed using the Affymetrix HG-U133A2.0 array.
2011-05-31 | E-GEOD-23036 | biostudies-arrayexpress
Project description:High-throughput genomic studies have identified thousands of genetic alterations in colorectal cancer (CRC). Distinguishing driver from passenger mutations is critical for developing rational therapeutic strategies. Because only a few transcriptional subtypes exist in previously studied tumor types, we hypothesize that highly heterogeneous genomic alterations may converge to a limited number of distinct mechanisms that drive unique gene expression patterns in different transcriptional subtypes. In this study, we defined transcriptional subtypes for CRC and identified driver networks/pathways for each subtype, respectively. Applying consensus clustering to a patient cohort with 1173 samples identified three transcriptional subtypes, which were validated in an independent cohort with 485 samples. The three subtypes were characterized by different transcriptional programs related to normal adult colon, early colon embryonic development, and epithelial mesenchymal transition, respectively. They also showed statistically different clinical outcomes. For each subtype, we mapped somatic mutation and copy number variation data onto an integrated signaling network and identified subtype-specific driver networks using a random walk-based strategy. We found that genomic alterations in the Wnt signaling pathway were common among all three subtypes; however, unique combinations of pathway alterations including Wnt, VEGF, Notch and TGF-beta drove distinct molecular and clinical phenotypes in different CRC subtypes. Our results provide a coherent and integrated picture of human CRC that links genomic alterations to molecular and clinical consequences, and which provides insights for the development of personalized therapeutic strategies for different CRC subtypes. To characterize the embryonic development of colon, we conducted a time course microarray study using the inbred C57BL/6 (Jackson Laboratories, Bar Harbor, ME) mice. Seven samples corresponding to the mouse colonic development from E13.5 to E18.5 and adult (eight week post-natal) were collected. RNA samples were submitted to the Vanderbilt Functional Genomics Shared Resource (FSGR, http://array.mc.vanderbilt.edu), where RNA was hybridized to the Affymetrix Mouse Genome 430 2.0 GeneChip Expression Arrays (Santa Clara, CA) according to manufacturer’s instructions. The RMA algorithm was used for data normalization. Mouse gene symbols were mapped to human gene symbols by the Human and Mouse Orthology list available from the Mouse Genome Informatics (http://www.informatics.jax.org/).
2013-12-22 | E-GEOD-38831 | biostudies-arrayexpress
Project description:Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 159 CRC cell lines to CMS. By integrating results from large scale drug screens, we discovered that CMS1 cancer is highly vulnerable to the survivin suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrate a 100-fold higher sensitivity of CMS1 lines. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 cancer, low concentrations of YM155 induced apoptosis and expression signatures associated with NFkappaB and ER stress mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we discovered a novel role of genes involved in LDL-receptor recycling as modulators of YM155 response in CMS1 CRC. Our work shows that combining drug response data with CMS classification in cell lines can reveal specific vulnerabilities and propose YM155 as novel CMS1 specific drug.
2018-07-03 | GSE116529 | GEO
Project description:The purpose of our study was to identify expression signatures and molecular markers associated with tumor recurrence and survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). We studied the expression profile of 63 pre-treatment tumor biopsies obtained from locally advanced HNSCCs treated with standard treatments. Cluster analysis identified three tumor subtypes associated with significant differences in local recurrence-free survival (LRFS), progression free-survival (PFS) and overall survival (OS). Tumor subtype 1, associated with short LRFS, PFS and OS, showed features of epithelial-mesenchymal transition and undifferentiation. It also overexpressed genes involved in cell adhesion, NF-κB and integrin signalling. Tumor subtype 3, associated with longer LRFS, PFS and OS, showed a high degree of differentiation and overexpressed genes located in chromosomal regions 19q13 and 1q21. Tumor subtype 2, which had a clinical outcome intermediate between subtype 1 and subtype 3, overexpressed genes involved in branching morphogenesis. Receiver Operating Characteristic (ROC) analysis identified a subset of genes associated with local recurrence and survival. We validated the association between gene cluster classification and patient survival using two HNSCC data sets obtained from two independent patient cohorts. Finally, using the gene expression profile of the pre-treatment tumor biopsy, we generated a gene expression signature that could predict survival in locally advanced patients.
2011-05-31 | GSE23036 | GEO
Project description:Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of >10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients, as well as transcriptomes of 145 cell lines and 89 patients defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,000 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data to the community to e.g. facilitate the design of innovative prospective clinical trials.
2017-12-12 | PXD005354 | Pride
Project description:Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of >10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients, as well as transcriptomes of 145 cell lines and 89 patients defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,000 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data to the community to e.g. facilitate the design of innovative prospective clinical trials.
2017-12-12 | PXD005355 | Pride
Project description:Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of >10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients, as well as transcriptomes of 145 cell lines and 89 patients defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,000 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data to the community to e.g. facilitate the design of innovative prospective clinical trials.
2017-12-13 | PXD005353 | Pride