The role of RAMS11 in colorectal cancer progression and treatment resistance

RAMS11 在结直肠癌进展和治疗耐药中的作用

• 批准号: 10689094
• 负责人: Ryan C Fields
• 金额: $ 56.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689094
• 关键词: Address; Adjuvant Therapy; Biological Markers; CRISPR/Cas technology; Cells; Cessation of life; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Code; Colorectal Cancer; Cytotoxic Chemotherapy; DNA topoisomerase II alpha; Data; Disease; Disease-Free Survival; Distant; Drug Screening; Epigenetic Process; Exposure to; FDA approved; Fluorouracil; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; In Vitro; Knock-out; Large-Scale Sequencing; Length; Longterm Follow-up; Meta-Analysis; Metastatic/Recurrent; Methods; Modality; Modeling; Molecular; Monitor; Mutate; Neoplasm Metastasis; Nuclear; Oncogenic; Operative Surgical Procedures; Organoids; Patients; Phenotype; Primary Neoplasm; Prognosis; Prognostic Marker; Protein Isoforms; Proteins; RNA; Regimen; Regulation; Repression; Research; Resistance; Risk; Role; Sampling; Site; Staging; Stratification; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Topoisomerase Inhibitors; Transcript; Tumor Biology; Validation; cancer therapy; chemotherapy; chromatin immunoprecipitation; clinical outcome assessment; cohort; colon cancer patients; colorectal cancer metastasis; colorectal cancer progression; differential expression; epigenetic regulation; experimental study; high risk; in vivo; insight; metastatic colorectal; molecular phenotype; patient derived xenograft model; prospective; recruit; response; side effect; therapy resistant; transcriptome sequencing; translational impact; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Although early stage colorectal cancer (CRC) is curable with surgery, there is a critical need to stratify high-risk early stage patients that would benefit from adjuvant treatment. In contrast to early stage CRC, late-stage metastatic CRC (mCRC) is usually lethal presenting a critical need to match treatment modalities to patients based on molecular phenotyping. To address these unmet clinical needs the proposed study aims to understand the molecular mechanisms enabling primary CRCs to metastasize with the longer-term goal of rationally guiding treatment decisions. While transcriptome sequencing has provided an unbiased method for discovering lncRNAs, existing large-scale sequencing projects are comprised of predominantly primary tumors without matched metastatic samples. This represents a critical barrier to studying lncRNAs involved in the progression of primary to metastatic disease. To address this gap, we conducted the first meta-analysis of normal, primary, and distant metastatic tissues across CRC patients to identify differentially expressed RNAs Associated with Metastasis (RAMS). We prioritized a previously uncharacterized nuclear localized lncRNA, RAMS11, since: (1) its expression correlated with metastatic progression, (2) its expression associated with poor disease-free survival across multiple independent patient cohorts, and (3) it promoted oncogenic phenotypes in vitro and in vivo. Further, subsequent mechanistic experiments demonstrated RAMS11- dependent recruitment of Chromobox protein 4 (CBX4) to transcriptionally activate Topoisomerase II alpha (TOP2α). This provides a strong rationale for our hypothesis that RAMS11 interacts with CBX4 to epigenetically regulate genes to promote oncogenic phenotypes and treatment resistance. This study will focus on dissecting how RAMS11 dependent CBX4 target gene regulation confers oncogenic phenotypes in vitro and in vivo. We will also assess whether RAMS11 can help identify high-risk CRC patients and its role in chemotherapy resistance. Overall, our proposal will significantly advance the lncRNA tumor biology field by providing mechanistic insight into RAMS11 epigenetic regulation to promote mCRC. Our research has translational impact by evaluating the potential role of RAMS11 to stratify CRC patients at high-risk of develop recurrent/metastatic disease that would benefit from specific adjuvant therapies.

项目摘要/摘要 尽管早期结直肠癌（CRC）可以通过手术治愈，但至关重要的需要分层高危 可以从适应治疗中受益的早期患者。与早期CRC相反，后期 转移性CRC（MCRC）通常是致命的，对患者的治疗方式匹配至关重要 基于分子表型。为了满足这些未满足的临床需求，拟议的研究旨在 了解使主要CRC能够以长期目标转移的分子机制 合理指导治疗决策。虽然转录组测序为 发现LNCRNA，现有的大规模测序项目主要是原发性肿瘤 没有匹配的转移样品。这代表了研究与 原发性转移性疾病的进展。为了解决这一差距，我们进行了第一次荟萃分析 CRC患者的正常，原发性和远处转移组织，以识别不同表达的RNA 与转移（RAMS）相关。我们优先考虑先前未表征的核局部lncRNA， RAMS11，因为：（1）其表达与转移性进程相关，（2）与 多个独立患者队列的无病生存不良，（3）促进了致癌 体外和体内表型。此外，随后的机械实验证明了RAMS11- Chromobox蛋白4（CBX4）的依赖募集到转录激活拓扑异构酶II alpha （TOP2α）。这为我们的假设提供了一个有力的理由，即RAMS11与CBX4相互作用 表观遗传调节基因以促进致癌表型和治疗耐药性。这项研究将重点 解剖RAMS11如何依赖CBX4靶基因调节在体外承认癌性表型 和体内。我们还将评估RAMS11是否可以帮助识别高风险CRC患者及其在 化学疗法抗性。总体而言，我们的建议将通过 提供对RAMS11表观遗传调节的机械洞察力，以促进MCRC。我们的研究有 通过评估RAMS11在高风险发育中对CRC患者进行分层的潜在作用来翻译影响 复发/转移性疾病将受益于特定的调整疗法。