A novel, transferable sialylation-mediated mechanism of chemoradioresistance in GI cancer

胃肠道癌症中一种新型的、可转移的唾液酸化介导的放化疗耐药机制

基本信息

批准号：
10556396
负责人：
Karin Marie Hardiman
金额：
$ 37.88万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556396
关键词：
Adenocarcinoma Affect Aftercare Apoptosis Apoptotic Cancer Etiology Cancer Model Cancer cell line Cell Separation Cell Survival Cell surface Cells Cessation of life Charge Data Development Enzymes Future Genetic Transcription Glycoproteins Golgi Apparatus Human Immunohistochemistry Individual Inhibition of Apoptosis Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediating Mediator Membrane Lipids Messenger RNA Modeling Neoplasm Metastasis Organoids Patients Persons Primary Neoplasm Proteins Public Health RNA Rectal Cancer Rectal Neoplasms Recurrence Regulation Research Resistance Risk Role Sampling Sialic Acids Sorting Structure TNFRSF1A gene Testing Therapeutic Tissues Tumor Promotion beta-site APP cleaving enzyme 1 cancer cell cell type chemoradiation extracellular vesicles functional gain gastrointestinal glycosylation glycosyltransferase inhibitor inorganic phosphate knock-down novel novel therapeutics overexpression particle patient response protein function radiation resistance receptor resistance mechanism response sialylation single cell sequencing small hairpin RNA standard of care sugar therapy resistant trafficking treatment response tumor vector

项目摘要

ABSTRACT — Combination chemoradiation is utilized to treat multiple gastrointestinal (GI) cancers including rectal cancer. Rectal cancer affects 40,000 people per year in the US. Approximately 85% of patients have an incomplete or poor response to treatment increasing their risk of recurrence. We have found that poor responders harbor sub-clones that are more resistant to treatment, and that the enzyme ST6Gal-1 is enriched in these sub- clones. ST6Gal-1 is a Golgi glycosyltransferase that adds the negatively-charged sugar, sialic acid (SA), to specific proteins destined for the cell surface. SA can have profound effects on the structure and function of proteins. ST6Gal-1 is one of the most pervasively upregulated glycosyltransferases in cancer cells. ST6Gal-1 has been shown to specifically promote tumor cell survival and resistance via sialylation. In addition, ST6Gal-1 has been found in extracellular vesicles (ECVs) made by cancer cells. ECVs are particles with a lipid membrane that contains RNA and protein cargo; thus, they are potential mediators of transferable resistance between cancer sub-clones. The role of ST6Gal-1 and ECVs in resistance to chemoradiation has not been investigated. The overall objective of this application is to ascertain the role of ST6Gal-1 in innate and transferable resistance to chemoradiotherapy in rectal cancer. Based on our preliminary data, we hypothesize that ST6Gal-1 mediates resistance to chemoradiation in individual sub-clones in rectal cancer, that this resistance is transferred to other sub-clones via ECVs spreading resistance, and that this resistance is regulated by ST6Gal-1 cleavage by BACE1. We have found that ST6Gal-1 is increased in rectal cancer models after treatment with chemoradiation. We will investigate our hypothesis with 3 aims: AIM 1 — Determine the role of ST6Gal-1 in chemoradiation resistance in human rectal cancer. We hypothesize that ST6Gal-1 causes treatment resistance after chemoradiation by inhibiting apoptosis. We will employ cell sorting, sequencing, and shRNA approaches. We will also conduct studies to investigate its function in patient samples. AIM 2 — Determine if ECVs carrying ST6Gal-1 transfer resistance to chemoradiation between sub-clones in rectal cancer. We hypothesize that ECVs act as vectors that impart resistance to chemoradiotherapy from sub-clone to sub-clone by trafficking ST6Gal-1, and thus, glycoprotein sialylation, in rectal cancer causing decreased apoptosis in the recipient sub-clones. AIM 3 — Determine if BACE1 promotes chemoradiosensitivity in rectal cancer due, in part, to ST6Gal-1 cleavage. We show that BACE1 mRNA is increased in tumors from patients who completely respond to chemoradiotherapy. BACE1 is known to cleave ST6Gal-1, and we found through inhibitor studies that BACE1 appear to regulate SA due to cleavage of ST6Gal-1 by BACE1. This research will evaluate a previously unknown mechanism of resistance to chemoradiotherapy in rectal cancer, with future potential for development of novel therapeutics that could target multiple resistant sub-clones across multiple GI adenocarcinomas, where the standard of care is pre-operative chemoradiation treatment.

摘要 — 联合放化疗用于治疗多种胃肠道 (GI) 癌症，包括直肠癌在美国每年影响 40,000 人，其中约 85% 的患者患有直肠癌。我们发现，治疗反应不完全或反应不佳会增加复发的风险。含有对治疗更有抵抗力的亚克隆，并且酶 ST6Gal-1 在这些亚克隆中富集 ST6Gal-1 是一种高尔基体糖基转移酶，可将带负电荷的糖唾液酸 (SA) 添加到 SA 的特定蛋白质可以对细胞表面的结构和功能产生深远的影响。 ST6Gal-1 是癌细胞中最普遍上调的糖基转移酶之一。已被证明可以通过唾液酸化特异性促进肿瘤细胞存活和抵抗。在癌细胞产生的细胞外囊泡 (ECV) 中发现了 ECV 是具有脂质膜的颗粒。含有RNA和蛋白质货物；因此，它们是可转移耐药性的潜在介体； ST6Gal-1 和 ECV 在抗放化疗中的作用尚未得到研究。本申请的总体目标是确定 ST6Gal-1 在先天性和转移性耐药中的作用根据我们的初步数据，我们认为 ST6Gal-1 介导直肠癌放化疗。直肠癌个体亚克隆对放化疗的耐药性，这种耐药性会转移通过 ECV 传播耐药性到其他亚克隆，并且这种耐药性由 ST6Gal-1 调节我们发现直肠癌模型中 ST6Gal-1 在接受 BACE1 治疗后会增加。我们将通过 3 个目标来研究我们的假设： AIM 1 — 确定 ST6Gal-1 在放化疗中的作用。我们认为 ST6Gal-1 可以治疗直肠癌的化疗耐药性。我们将采用细胞分选、测序和 shRNA 来抑制放化疗后的耐药性。我们还将进行研究以调查其在患者样本中的功能 - 确定是否。携带 ST6Gal-1 的 ECV 在直肠癌亚克隆之间转移对放化疗的耐药性。培养出 ECV 作为载体，在亚克隆与亚克隆之间传递对放化疗的抗性通过在直肠癌中运输 ST6Gal-1，从而糖蛋白唾液酸化，导致细胞凋亡减少受体亚克隆 AIM 3 — 确定 BACE1 是否会促进直肠癌的放化疗敏感性，我们发现，在患有以下疾病的患者的肿瘤中，BACE1 mRNA 增加。已知 BACE1 可裂解 ST6Gal-1，我们通过抑制剂发现。研究表明，BACE1 似乎可以通过 BACE1 切割 ST6Gal-1 来调节 SA。本研究将进行评估。直肠癌放化疗耐药的一种以前未知的机制，未来有潜力开发可以针对多个胃肠道中的多个耐药亚克隆的治疗小说腺癌，其护理标准是术前放化疗。