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

• 批准号: 10339165
• 负责人: Karin Marie Hardiman
• 金额: $ 41.47万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/10339165
• 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; Clone Cells; Data; Development; Enzymes; Future; Genetic Transcription; Glycoproteins; Golgi Apparatus; Human; Immunohistochemistry; Individual; Lead; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Mediator of activation protein; 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 - Cell Movement; Structure; TNFRSF1A gene; Testing; Therapeutic; Tissues; base; beta-site APP cleaving enzyme 1; cancer cell; cell type; chemoradiation; extracellular vesicles; functional gain; gastrointestinal; glycosylation; glycosyltransferase; inhibitor; inorganic phosphate; knock-down; neoplastic cell; 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

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.

联合放化疗用于治疗多种胃肠道（GI）癌症，包括