SOX Versus XELOX for Patients With Peritoneal Metastasis of Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Neoplasm,Colorectal Neoplasms
PROVIDER: 2222653 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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2024-09-01 | E-MTAB-13741 | biostudies-arrayexpress
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Project description:Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor Sp1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.
2022-11-10 | GSE217474 | GEO
Project description:Purpose: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. Methods: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38- or oxaliplatin-resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of DNA methylation entropy to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. Results: We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences -- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy. Investigation of the representive methylome of well-established SN38 and Oxaliplatin resistant cell line models and 14 clinical colorectal metastatic samples that have developed resistance to XELOX to review the epigenetic mechnism of the drug resistance.
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Project description:10X Next GEM Single Cell 5’ Kit v2 scRNAseq of maximum 15 000 sorted CD127+ ILCs (CD45+, CD3-, CD19-, Lin- and CD127+), NK cells (CD45+, CD3-, CD19-, Lin-, CD94+/- and CD56+) and non-conventional (nc)ILCs (CD45+, CD3-, CD19-, Lin-, CD94+/-, CD56- and CD7+) per sample from 11 patients. Total of 4 paired healthy colon and colorectal cancer tumours, 2 paired healthy colon, colorectal cancer tumours and peritoneal metastasis and 5 unpaired peritoneal metastasis.
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Project description:When disseminated into the peritoneal cavity at the very early stage, cancer cells must adapt to the glucose- and oxygen-limited environment in peritoneal fluid, yet the key molecular regulators remain undefined. Here, we reveal that early disseminated OC cells are ingeniously utilize hyaluronic acid as an energy source and a signal molecule to survive in the nutrient-limited peritoneal microenvironment. Through a genome-wide CRISPR/Cas9 knockout screening in an orthotopic ovarian cancer (OC) model, we identified a series of genes involved in hyaluronic acid (HA) catabolism and glucuronic acid (GlcA) metabolism, including the HA receptor LAYN, HA catabolism enzymes (including HYAL1 and HYAL3) and key GlcA metabolic enzymes (such as AKR1A1 and XYLB). By integrating transcriptomic and metabolic analyses in multiple experimental systems, we demonstrated that HA induced the expression of key HA catabolism and GlcA pathway enzymes, which further led to the release of free GlcA from HA degradation. This GlcA is subsequently metabolized through the GlcA pathway, the pentose phosphate pathway (PPP) and glycolysis to support the maintenance and growth of disseminated OC cells. In addition, we found an atypical Rho GTPase RHOU facilitated the LAYN endosomal recycling for efficient HA uptake. Intriguingly, the rewiring of HA catabolism through GlcA pathway was regulated by its classical receptor CD44 and occurred in other peritoneal disseminating cancers such as bladder cancer and pancreatic adenocarcinoma. This signaling-metabolic axis demonstrates the dual role of HA as both a signaling molecule and an energy source supporting cancer cells survival. Importantly, pharmacological inhibition of HYAL1 with garcinol potently suppressed peritoneal disseminated metastasis in xenograft mice and synergized with cisplatin. In this study, we collectively reported a novel HA-induced metabolic reprogramming feature of the early peritoneal disseminated cancer cells, which provides new diagnostic and therapeutic strategies for the cancers prone to the potential dissemination.
2026-07-10 | MTBLS15007 | MetaboLights
Project description:This is a single arm, open-label phase II study to evaluate the efficacy and safety of Capecitabine plus oxaliplatin (XELOX) in the peri-operative treatment of patients with potentially resectable liver metastasis from colorectal cancer.
| 2079577 | ecrin-mdr-crc