scholarly journals The role of PDGFRA as a therapeutic target in young colorectal cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tae Won Kim ◽  
Hye Kyung Hong ◽  
Chung Lee ◽  
Sunmin Kim ◽  
Woo Yong Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Age Groups ◽  
Young Patients ◽  
Growth Factor Receptor ◽  
Predictive Biomarker ◽  
Molecular Characteristics ◽  
Novel Therapeutic Strategies ◽  
Consensus Molecular Subtype

Abstract Background Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear. Methods We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation. Results Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients. Conclusions Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.

scholarly journals Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093608
Author(s):  
Giulia Martini ◽  
Rodrigo Dienstmann ◽  
Javier Ros ◽  
Iosune Baraibar ◽  
Jose Luis Cuadra-Urteaga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Clonal Selection ◽  
Selection Process ◽  
Growth Factor Receptor ◽  
Genomic Analysis ◽  
Molecular Profile ◽  
Molecular Alterations ◽  
Molecular Tests ◽  
Consensus Molecular Subtype

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.

scholarly journals Integrated Multi-Omics Analysis of Colorectal Cancer Reveals Mir-20a as a Regulator of Fatty Acid Metabolism in Consensus Molecular Subtype 3

2021 ◽  
Author(s):  
Kai Song ◽  
Chao Liu ◽  
Jiashuai Zhang ◽  
Yang Yao ◽  
Huiting Xiao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acid ◽  
Molecular Subtype ◽  
Mirna Gene ◽  
In Vitro Assays ◽  
Bioinformatics Analyses ◽  
Proliferation And Metastasis ◽  
And Migration ◽  
Consensus Molecular Subtype

Abstract BackgroundmicroRNAs (miRNAs) serve important roles in metabolism. The consensus molecular subtype (CMS) 3 of colorectal cancer (CRC) is characterized by activated fatty acid (FA) metabolism. We aimed to identify essential miRNAs of CMS3-CRC and analyze the regulatory role in the FA metabolism. MethodsThe RobustRankAggreg method by integrating multi-omics data including genome, epigenome, transcriptome and interactome, was applied to filter out functional genes (Fgenes). The backward derivation approach based on Fgenes and miRNA-gene interactions was further applied to identify functional miRNAs (Fmirs). Nine human CRC cell lines with different CMSs were investigated. RT-qPCR, western blotting and immunofluorescence were performed to examine the effect of miR-20a on FA synthesis and Wnt/β-catenin signaling. The effect of miR-20a on cell proliferation and metastasis were studied by clone-formation, EdU assay, wound healing and transwell assay.ResultsWe identified 12 Fmirs by integrating multi-omics features in CMS3-CRC. These Fmirs exhibited significantly enriched CRC driver miRNAs and significant impacts on CMS3-CRC cell growth. Beyond the findings, miR-20a was significantly correlated with Wnt/β-catenin signaling and participated in FA metabolism subpathway. In vitro assays combined with bioinformatics analyses demonstrated that elevated miR-20a up-regulated FA synthesis enzymes FASN, ACAC and ACLY via Wnt/β-catenin signaling, and finally promoted proliferative and migration of CMS3-CRC cells. ConclusionsOverall, our study revealed that miR-20a promoted progression of CMS3-CRC by regulating FA metabolism and served as a potential target for preventing tumor metastasis.

scholarly journals The roles and prognostic significance of ABI1-TSV-11 expression in patients with left-sided colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Zhang ◽  
Zhaohui Zhong ◽  
Mei Li ◽  
Jingyi Chen ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
The Cancer Genome Atlas ◽  
Actin Dynamics ◽  
Elevated Expression ◽  
Sw480 Cells ◽  
And Migration

AbstractAbnormally expressed and/or phosphorylated Abelson interactor 1 (ABI1) participates in the metastasis and progression of colorectal cancer (CRC). ABI1 presents as at least 12 transcript variants (TSVs) by mRNA alternative splicing, but it is unknown which of them is involved in CRC metastasis and prognosis. Here, we firstly identified ABI1-TSV-11 as a key TSV affecting the metastasis and prognosis of left-sided colorectal cancer (LsCC) and its elevated expression is related to lymph node metastasis and shorter overall survival (OS) in LsCC by analyzing data from The Cancer Genome Atlas and TSVdb. Secondly, ABI1-TSV-11 overexpression promoted LoVo and SW480 cells adhesion and migration in vitro, and accelerated LoVo and SW480 cells lung metastasis in vivo. Finally, mechanism investigations revealed that ABI1-isoform-11 interacted with epidermal growth factor receptor pathway substrate 8 (ESP8) and regulated actin dynamics to affect LoVo and SW480 cells biological behaviors. Taken together, our data demonstrated that ABI1-TSV-11 plays an oncogenic role in LsCC, it is an independent risk factor of prognosis and may be a potential molecular marker and therapeutic target in LsCC.

scholarly journals Circulating tumor cell-related transcripts in blood as prognostic biomarkers of early recurrence after liver resection for colorectal metastases

2019 ◽  
Vol 34 (3) ◽  
pp. 269-275
Author(s):  
Felice Giuliante ◽  
Elena Panettieri ◽  
Francesco Ardito ◽  
Agostino De Rose ◽  
Krizia Pocino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Resection ◽  
Tumor Cell ◽  
Carcinoembryonic Antigen ◽  
Growth Factor Receptor ◽  
Predictive Biomarker ◽  
Circulating Tumor Cell ◽  
Early Recurrence ◽  
Colorectal Metastases

Background: Several prognostic factors were proposed to improve early detection of recurrence after liver resection of metastases of colorectal cancer. Circulating tumor cell-related transcripts were evaluated in colorectal cancer patients with conflicting results. The aim of this study was to investigate usefulness of carcinoembryonic antigen CAM5, epidermal growth factor receptor, and ERCC1 transcripts in the bloodstream as predictive factors of recurrence in patients who underwent liver resection for metastases of colorectal cancer. Methods: Peripheral blood was collected from 29 patients at the time of the colorectal cancer liver metastasis resection, and from 25 normal controls. Follow-up draws (FUDs) were also performed at 30 days, and 3 and 12 months since surgery. On each sample, carcinoembryonic antigen CAM5, ERCC1, and GAPDH mRNAs were examined by quantitative reverse transcription (qRT). Results: Carcinoembryonic antigen transcript levels were linearly correlated to the number of spiked cells (qRT analytical limit = five cells). Among 29 patients (20 M/9 F; mean age 63 years (range 32–79), highly significant levels of carcinoembryonic antigen, if compared to the baseline, were detected in those relapsing after surgery ( P <0.05). The main differences were between the 1st- and 12th-month FUDs. Significantly higher levels of carcinoembryonic antigen were also detected in patients who died from disease progression during the follow-up (as evaluated at 30 days and 90 days FUDs). Conclusions: Blood carcinoembryonic antigen-mRNA absolute copy number overtime variation can represent a valid early predictor of relapse after liver resection in colorectal liver metastases patients. Prospective studies, in the context of large clinical trials, will provide further data to also qualify ERCC1 as a predictive biomarker for decisions on therapeutic strategies.

scholarly journals BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Carla Azzurra Amoreo ◽  
Isabella Sperduti ◽  
Sara Donzelli ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Promoter ◽  
Predictive Biomarker ◽  
Open Chromatin ◽  
Therapeutic Success ◽  
Rna Pol Ii ◽  
Pten Loss ◽  
Braf Inhibition ◽  
Dependent Mechanism

Abstract Inflammation might substantially contribute to the limited therapeutic success of current systemic therapies in colorectal cancer (CRC). Amongst cytokines involved in CRC biology, the proinflammatory chemokine IL-8 has recently emerged as a potential prognostic/predictive biomarker. Here, we show that BRAF mutations and PTEN-loss are associated with high IL-8 levels in CRC models in vitro and that BRAF/MEK/ERK, but not PI3K/mTOR, targeting controls its production in different genetic contexts. In particular, we identified a BRAF/ERK2/CHOP axis affecting IL-8 transcription, through regulation of CHOP subcellular localization, and response to targeted inhibitors. Moreover, RNA Pol II and an open chromatin status in the CHOP-binding region of the IL-8 gene promoter cooperate towards increased IL-8 expression, after a selective BRAF inhibition. Overall, our data show that IL-8 production is finely and differentially regulated depending on the tumor genetic context and might be targeted for therapeutic purposes in molecularly defined subgroups of CRC patients.

scholarly journals Human Colorectal Cancer from the Perspective of Mouse Models

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 788 ◽  
Author(s):  
Monika Stastna ◽  
Lucie Janeckova ◽  
Dusan Hrckulak ◽  
Vitezslav Kriz ◽  
Vladimir Korinek
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Mouse Models ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Molecular Subtype ◽  
Transforming Growth Factor Β ◽  
Dna Mismatch ◽  
Individual Mouse ◽  
Consensus Molecular Subtype

Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.

scholarly journals Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers

2021 ◽  
Vol 9 (12) ◽  
pp. e003414
Author(s):  
Jung Ho Kim ◽  
Mi-Kyoung Seo ◽  
Ji Ae Lee ◽  
Seung-Yeon Yoo ◽  
Hyeon Jeong Oh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microsatellite Instability ◽  
Molecular Subtype ◽  
Colorectal Cancers ◽  
Molecular Characteristics ◽  
Immune Parameters ◽  
Whole Exome ◽  
Tumor Mutational Burden ◽  
Consensus Molecular Subtype

BackgroundColorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.MethodsWe conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.ResultsWe found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.ConclusionsMSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.

scholarly journals Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (24) ◽  
pp. 36632-36644 ◽  
Author(s):  
Philip D. Dunne ◽  
Paul G. O’Reilly ◽  
Helen G. Coleman ◽  
Ronan T. Gray ◽  
Daniel B. Longley ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Marker ◽  
Molecular Subtype ◽  
Consensus Molecular Subtype ◽  
Stratified Analysis

scholarly journals Bi-clustering based biological and clinical characterization of colorectal cancer in complementary to CMS classification

2018 ◽  
Author(s):  
Sha Cao ◽  
Wennan Chang ◽  
Changlin Wan ◽  
Yong Zhang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Large Scale ◽  
Molecular Subtype ◽  
Resistance Mechanisms ◽  
Low Rank ◽  
Data Sets ◽  
Alternative Drug ◽  
Transcriptomics Data ◽  
Consensus Molecular Subtype

In light of the marked differences in the intrinsic biological underpinnings and prognostic outcomes among different subtypes, Consensus Molecular Subtype (CMS) classification provides a new taxonomy of colorectal cancer (CRC) solely based on transcriptomics data and has been accepted as a standard rule for CRC stratification. Even though CMS was built on highly cancer relevant features, it suffers from limitations in capturing the promiscuous mechanisms in a clinical setting. There are at least two facts about using transcriptomic data for prognosis prediction: the engagement of genes or pathways that execute the clinical response pathway are highly dynamic and interactive with others; and a predefined patient stratification not only largely decrease the statistical analysis power, but also excludes the fact that clusters of patients that confer similar clinical outcomes may or may not overlap with a pre-defined subgrouping. To enable a flexible and prospective stratified exploration, we here present a novel computational framework based on bi-clustering aiming to identify gene regulatory mechanisms associated with various biological, clinical and drug-resistance features, with full recognition of the transiency of transcriptional regulation and complicacies of patients subgrouping with regards to different biological and clinical settings. Our analysis on multiple large scale CRC transcriptomics data sets using a bi-clustering based formulation suggests that the detected local low rank modules can not only generate new biological understanding coherent to CMS stratification, but also identify predictive markers for prognosis that are general to CRC or CMS dependent, as well as novel alternative drug resistance mechanisms. Our key results include: (1) a comprehensive annotation of the local low rank module landscape of CRC; (2) a mechanistic relationship between different clinical subtypes and outcomes, as well as their characteristic biological underpinnings, visible through a novel consensus map; and (3) a few (novel) resistance mechanisms of Oxaliplatin, 5-Fluorouracil, and the FOLFOX therapy are revealed, some of which are validated on independent datasets.

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