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.

项目总结/摘要 虽然早期结直肠癌（CRC）可以通过手术治愈，但仍迫切需要对高风险患者进行分层。 早期患者将受益于辅助治疗。与早期CRC相比，晚期CRC 转移性结直肠癌（mCRC）通常是致命的，因此迫切需要将治疗方式与患者相匹配 基于分子表型为了解决这些未满足的临床需求，拟议的研究旨在 了解使原发性CRC转移的分子机制，长期目标是 合理指导治疗决策。虽然转录组测序提供了一种无偏倚的方法， 发现lncRNA，现有的大规模测序项目主要包括原发性肿瘤 没有匹配的转移样本这代表了研究lncRNA参与的一个关键障碍， 原发性疾病进展为转移性疾病。为了解决这一差距，我们进行了第一次荟萃分析， 在CRC患者的正常、原发和远处转移组织中鉴定差异表达的RNA 与转移相关（RAMS）。我们优先考虑了一种以前未鉴定的核定位lncRNA， RAMS 11，因为：（1）其表达与转移进展相关，（2）其表达与 在多个独立的患者队列中，无病生存率较差，（3）它促进了致癌性 表型在体外和体内。此外，随后的机理实验证明了RAMS 11- 依赖性募集染色体盒蛋白4（CBX 4）转录激活拓扑异构酶II α (TOP2α）。这为我们的假设提供了强有力的理由，即RAMS 11与CBX 4相互作用， 表观遗传学调节基因以促进致癌表型和治疗抗性。本研究将重点 在解剖RAMS 11依赖性CBX 4靶基因调控如何在体外赋予致癌表型 和体内。我们还将评估RAMS 11是否可以帮助识别高风险CRC患者，以及其在治疗中的作用。 化疗耐药性总的来说，我们的建议将大大推进lncRNA肿瘤生物学领域， 为RAMS 11表观遗传调控促进mCRC提供了机制性见解。我们的研究 通过评估RAMS 11对处于高发展风险的CRC患者进行分层的潜在作用， 复发性/转移性疾病，将受益于特定的辅助治疗。