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Dissection of prognostic traits in colorectal cancer using multi-dimensional proteomics

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

DISEASE(S): Colorectal Cancer

SUBMITTER: Ana Martinez-Val

LAB HEAD: Jesper V. Olsen

PROVIDER: PXD044246 | Pride | 2025-03-26

REPOSITORIES: Pride

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			Action	DRS
	20191009_EXP1_Evo1_DBJ_DIAprot_15k2s_CV-45_PAC_COLON_sample-165_02.raw	Raw
	20191009_EXP1_Evo1_DBJ_DIAprot_15k2s_CV-45_PAC_COLON_sample-166_02.raw	Raw
	20191009_EXP1_Evo1_DBJ_DIAprot_15k2s_CV-45_PAC_COLON_sample-167_02.raw	Raw
	20191009_EXP1_Evo1_DBJ_DIAprot_15k2s_CV-45_PAC_COLON_sample-168_02.raw	Raw
	20191009_EXP1_Evo1_DBJ_DIAprot_15k2s_CV-45_PAC_COLON_sample-169_02.raw	Raw

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Project description:Background: Colorectal cancer (CRC) is one of the major causes of cancer-related death worldwide. Although commercial biomarkers of CRC are currently available, they are still lacking in terms of sensitivity and specificity; thus, searching for reliable blood-based biomarkers are important for the primary screening of CRC. Methods: Plasma samples of patients with non-metastatic (NM) and metastatic (M) CRC and healthy controls were fractionated using MARS-14 immunoaffinity chromatography. The flow-through and elute fractions representing low- and high-abundant proteins, respectively, were analyzed by label-free quantitative proteomics mass spectrometry. The functional analysis of the proteins with greater than 1.5-fold differential expression level between the CRC and the healthy control groups were analyzed for their biological processes and molecular functions. In addition, the levels of plasma proteins showing large alterations in CRC patients were confirmed by immunoblotting using two independent cohorts. Moreover, receiver operating characteristic (ROC) curve analysis was performed for individual and combinations of biomarker candidates so as to evaluate the diagnostic performance of biomarker candidates. Results: From 163 refined identifications, five proteins were up-regulated and two proteins were down-regulated in NM-CRC while eight proteins were up-regulated and three proteins were down-regulated in M-CRC, respectively. Altered plasma proteins in NM-CRC were mainly involved in complement activation, while those in M-CRC were clustered in acute-phase response, complement activation, and inflammatory response. Results from the study- and validation-cohorts indicate that the levels of LRG, C9, AGP1, and A1AT were statistically increased, while FN level was statistically decreased in CRC patients compared to healthy controls, with most alterations found in a metastatic stage-dependent manner. ROC analysis revealed that FN exhibited the best diagnostic performance to discriminate CRC patients and healthy controls while AGP1 showed the best discrimination between the disease stages in both cohorts. The combined biomarker candidates, FN+A1AT+AGP1, exhibited perfect discriminatory power to discriminate between the CRC population and healthy controls whereas LRG+A1AT+AGP1 was likely to be the best panel to discriminate the metastatic stages in both cohorts. Conclusions: This study identified and quantified distinct plasma proteome profiles of CRC patients. Selected CRC biomarker candidates including FN, LRG, C9, A1AT, and AGP1 may be further applied for screening larger cohorts.

Project description:Background an Aim: Epigenetics are thought to play a major role in the carcinogenesis of patients that develop multiple colorectal cancers (CRC) in the non-hereditary setting. Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the underlying epigenetic signature that differentiates multiple from solitary colorectal cancer tumors using a genome-scale DNA methylation profiling. Patients and Methods: We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 age- sex- and tumor location-paired solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significantly hypermethylated CpG sites results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP) using the Infinium DNA methylation data; KRAS and BRAF mutations; microsatellite instability; and immunohistochemistry for MLH1/MSH2/MSH6/PMS2. Functional annotation clustering of differentially methylated genes between multiple and solitary CRCs was performed. Results: We identified 102 CpG sites that showed significant DNA hypermethylation in multiple versus solitary tumors (difference in M-NM-2 value >0.1 and p<0.05). Methylight assays validated the array results for 4 selected significantly hypermethylated genes (MAP1B, HTRA1, ALOX15, TIMP3) identified in the profiling (p=0.0002). Based on the Infinium data, 8/12 (66.6%) of multiple tumors were classified as CIMP-high, as compared to 5/29 (17%) solitary tumors (p=0.004). CIMP-high tumors displayed significant hypermethylation in 301 CpG sites (difference in M-NM-2 value >0.1; p value <0.05). Interestingly, 76/102 (74.5%) of the hypermethylated CpG sites found in multiple vs. solitary tumors were also seen to be hypermethylated in CIMP-H tumors. Functional analysis of hypermethylated genes found in multiple vs. solitary tumors showed the presence and enrichment of genes involved in different tumorigenic functions. Conclusions: Multiple colorectal cancers are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity in the non-hereditary scenario, and provide novel potential biomarkers for identifying high-risk patients and tailoring surveillance strategies. We used a population-based cohort (EPICOLON II) of 12 patients with synchronous CRC and 29 solitary CRC patients. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay.

Project description:Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.

Project description:Colorectal cancer (CRC) is one of the major causes of cancer-related death worldwide, for which diagnosis and prognosis are still inadequate mainly due to local recurrence and metastasis, although medical and surgical treatment in cancer therapy advanced. Diagnosis is frequently late, the high capacity of CRC to infiltrate and develop metastasis has the consequence that 40% of patients with CRC have metastasis in liver already at the time of diagnosis. The prognosis of CRC is closely related to the stage, but classification of patients is affected by a great variability in response to therapy and clinical outcome. The localization of the tumor determines a huge inter-tumoral heterogeneity and the intra-tumoral heterogeneity connected to the tumor microenvironment increases the complexity. The heterogeneity typical of CRC is also associated to the several oncogenic signaling pathways, among them the glucose-related pathways, indeed, the glucose metabolic reprogramming of cancer cells appears to be implicated in the malignant progression of CRC. This metabolic alteration seems to be associated to the epithelial-mesenchymal transition (EMT), which is considered the main event promoting the invasion and migration of CRC cells. However, the comprehensive understanding of the molecular mechanisms associated to EMT in CRC is still a challenge and despite decades of research, the process of tumor dissemination is insufficiently understood. Therefore, it is necessary to identify novel biomarkers associated with the prevention, diagnosis and treatment of CRC, as well as potential therapeutic targets. In this context, we performed a large-scale shotgun proteomic investigation on CRC with the aim of discover novel potential protein hallmarks able to distinguish with high specificity and sensitivity tumoral tissue from the health one, and to classify the superficial and the internal deep tumoral tissues. The EMT process is driven by the deep tumoral cells in CRC, therefore, to find significant differences at proteomic levels with respect to the peripheric tumoral tissue and to the healthy mucosa, and to identify specific classifying factors can be useful to individuate potential biomarkers of CRC invasiveness and potential therapy targets. Moreover, the functional enrichment analysis of proteomic data can provide information on biological processes implicated and associated to the variations of the protein profiles, and thus, help to understand the molecular mechanism associated to the CRC progression and malignance. Our approaches coupling high-throughput proteomic strategy with highly accurate statistical and enrichments analysis highlighted not only confirmation on potential biomarkers already proposed in other studies but also novel biomarkers able to distinguish with high sensitivity and specificity the deep tumor from the superficial one and to the healthy mucosa. Our investigation suggested a strong contribution of proteins implicated in metabolic pathways as catalytic and regulatory activities, some of them with high classifying power and potentially useful as biomarker and therapeutic target.

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Dissection of prognostic traits in colorectal cancer using multi-dimensional proteomics

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