Dataset Information

Prognostic value of the PrP^C-ILK-IDO1 axis in the mesenchymal colorectal cancer subtype.

ABSTRACT: The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrP^C is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrP^C downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the integrin-linked kinase ILK as a proximal effector of PrP^C that mediates its control on the CMS4 phenotype. We further leveraged three independent large CRC cohorts to assess correlations in gene expression pattern with patient outcomes and found that ILK is overexpressed in CMS4 mesenchymal tumors and confers a poor prognosis, especially when combined with high expression of the PrP^C encoding gene PRNP. Of note, we discovered that the PrP^C-ILK signaling axis controls the expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase IDO1, a key player in immune tolerance. In addition, we monitored alterations in the levels of tryptophan and its metabolites of the kynurenine pathway in the plasma of metastatic CRC patients (n = 325) and we highlight their prognostic value in combination with plasma PrP^C levels. Thus, the PrP^C-ILK-IDO1 axis plays a key role in the mesenchymal subtype of CRC. PrP^C and IDO1-targeted strategies may represent new avenues for patient stratification and treatment in CRC.

SUBMITTER: Ghazi A

PROVIDER: S-EPMC8244775 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Prognostic value of the PrPC-ILK-IDO1 axis in the mesenchymal colorectal cancer subtype.

Ghazi Alexandre A Le Corre Delphine D Pilati Camilla C Taieb Julien J Aparicio Thomas T Didelot Audrey A Dedhar Shoukat S Mulot Claire C Le Malicot Karine K Djouadi Fatima F de Reynies Aurélien A Launay Jean-Marie JM Laurent-Puig Pierre P Mouillet-Richard Sophie S

Oncoimmunology 20210628 1

The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrPC is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrPC downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the ...[more]

PMID: 34249475

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Project description:Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality globally and is the third most prevalent cancer. The effective treatment of CRC is challenged by tumor drug resistance, underscoring the urgent need for novel therapeutic strategies. It is well recognized that epigenetic modifications, particularly DNA methylation, significantly contribute to the initiation and advancement of CRC. Tumors frequently exhibit hypermethylation of specific gene promoters alongside a general hypomethylation of genomic DNA. In normal tissues, gene promoters, particularly those of tumor suppressor genes, are typically unmethylated, whereas they are often hypermethylated in cancerous tissues. Previous studies have identified the methylation status of the CpG island within the SLC30A10 gene as a reliable biomarker for CRC. Notably, a hypermethylated phenotype is inversely correlated with SLC30A10 expression. However, the precise functional implications of SLC30A10 suppression in the context of CRC progression remain to be elucidated.). The investigation of molecular pathways involved in metal metabolism in CRC has not been conducted previously at the transcriptomic level. Furthermore, the relationship between the mutational characteristics of tumors—such as individual mutations, mutational burden, and microsatellite instability—and the activity of genes related to metal metabolic pathways has not been explored. This project aims to be the first to examine the antitumor potential of modulating the transport systems for manganese and zinc ions in CRC. The molecular function of SLC30A10 is to export zinc (Zn) and manganese (Mn) ions from the cell. Additionally, SLC30A10 plays a crucial role in mitigating Mn-induced cytotoxicity and facilitates Zn transport to early endosomes while promoting endosomal recirculation to avert Zn toxicity. Our findings indicate that overexpression of SLC30A10 is correlated with the knockout of its functional antagonist, SLC39A14 in the HuTu80 and HCT-15 cell lines.

Project description:PurposeIntratumor metabolic heterogeneity parameters on 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) have been proven to be predictors of the clinical prognosis of cancer patients. The study aimed to examine the correlation between 18F-FDG PET-CT-defined heterogeneity parameters and the prognostic significance in patients with colorectal cancer.MethodsThe study included 188 patients with colorectal cancer who received surgery and 18F-FDG PET/CT examinations. Preoperative 18F-FDG PET/CT conventional and metabolic heterogeneity parameters were collected, including maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), heterogeneity index-1 (HI-1) and heterogeneity index-2 (HI-2), and clinicopathological information. Correlations between these parameters and patient survival outcomes were inferred.ResultsThe associations between 18F-FDG PET/CT parameters and clinical outcomes were analyzed. Tumor thrombus (P < 0.001), tumor stage (P=0.001), MTV (P=0.003), HI-1 (P=0.032), and HI-2 (P=0.001) differed between the two groups with and without recurrence. Multivariate analysis showed that, in the radical surgery group, HI-2 (HR = 1.10, 95% CI: 1.04-1.17, P=0.001), tumor stage (HR = 20.65, 95% CI: 4.81-88.62, P < 0.001), and regional lymph nodes status (HR = 0.16, 95% CI: 0.04-0.57, P=0.005) were independent variables significantly correlated with progression-free survival (PFS) and HI-2 (HR = 1.16, 95% CI: 1.07-1.26, P < 0.001) was an independent variable affecting overall survival (OS). In the palliative surgery group, HI-2 (HR = 1.03, 95% CI: 1.01-1.06, P=0.020) was an independent variable affecting PFS, and all the parameters were not statistically significant for OS.ConclusionHI-2, tumor stage, and regional lymph nodes status might predict the outcomes of colorectal cancer more effectively than other 18F-FDG PET/CT defined parameters.

Dataset Information

Prognostic value of the PrP^C-ILK-IDO1 axis in the mesenchymal colorectal cancer subtype.

Publications

Prognostic value of the PrP<sup>C</sup>-ILK-IDO1 axis in the mesenchymal colorectal cancer subtype.

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