Role of genomic and microenvironment factors in conferring acquired resistance to ferroptosis to chemoradiation in esophageal adenocarcinoma

基因组和微环境因素在食管腺癌放化疗获得性铁死亡抗性中的作用

• 批准号: 10707135
• 负责人: Steven Hsesheng Lin
• 金额: $ 28.45万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707135
• 关键词: Basic Science; Biopsy; Biopsy Specimen; Cancer cell line; Cause of Death; Cell Death Induction; Cell Differentiation process; Cells; Chemotherapy and/or radiation; Chromosome abnormality; Clinical; Communication; Complex; Cystine; DNA copy number; DNA sequencing; Data; Disease; Drops; Esophageal Adenocarcinoma; Excision; Fibroblasts; Fluorescent in Situ Hybridization; Future; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Healthcare; Heterogeneity; Hypoxia; Image; Immune; In complete remission; Iron; KRAS2 gene; Link; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Maps; Mediating; Molecular; Morbidity - disease rate; Myeloid Cells; Neutrophil Infiltration; Nonmetastatic; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Positron-Emission Tomography; Pre-Clinical Model; Preclinical Testing; Radiation therapy; Refractory; Regimen; Resistance; Resolution; Risk; Role; Sampling; Selection for Treatments; Signal Pathway; Societies; Solid Neoplasm; Stromal Cells; Survival Rate; Technology; Testing; Time; Tracer; Transplant Recipients; Treatment outcome; Treatment-related toxicity; Tumor-infiltrating immune cells; base; cancer cell; cancer therapy; care burden; chemoradiation; curative treatments; cytokine; data integration; determinants of treatment resistance; differential expression; humanized mouse; improved; innovation; insight; irradiation; molecular imaging; mortality; mouse model; neoplastic cell; neutrophil; predicting response; predictive tools; radiation resistance; response; single-cell RNA sequencing; therapy development; therapy resistant; tissue mapping; tool; trait; transcriptome; transcriptomic profiling; treatment response; tumor; tumor microenvironment

Project 3 Summary Esophageal cancer is the sixth most common cause of deaths worldwide with a 5-year survival rate of less than 20%. Similar to other intrathoracic malignancies, such as lung cancer, chemoradiation therapy (CRT) is an effective tool for treating esophageal adenocarcinoma (EAC). However, CRT leads to complete responses in EAC in only approximately 25% of patients. Thus, characterizing the cellular and molecular changes that occur in the tumor and tumor microenvironment during CRT can provide highly accurate predictive tools to identify which EAC patients will develop acquired resistance to therapy. CRT induces the cell death pathway ferroptosis in cancer cells, and the hypothesis that ferroptosis is a key regulator in acquired radiation therapy resistance is a central theme of the Acquired Resistance to Therapy and Iron (ARTI) Center. Project 3 will contribute to this central theme by bridging the basic science mechanisms in preclinical models discovered in Project 1 and Project 2 with clinical EAC tumor biopsies, collected at baseline (before treatment) and during the middle of the CRT regimen. These EAC tumor biopsies will undergo single cell transcriptome profiling to identify expression of ferroptosis-related genes and to provide an understanding of the complex communications between tumor cells and cells of the tumor microenvironment that may drive and/or regulate ferroptosis (Aim 1). Identification of transcriptomes that are directly or indirectly related to ferroptosis may help to prognose EAC patients who may or may not respond to CRT. Further spatial cellular mapping and deciphering the relationship of differentially expressed genes with ferroptosis will provide evidence for the tumor’s ability to evade ferroptosis upon irradiation. Aim 2 will focus on determining whether adaptive resistance to therapy occurs due to selection of rare, but pre-existing tumor cells, or due to de novo acquisition of alterations in genes directly or indirectly related to ferroptosis signaling pathways. Aim 3 will focus on elucidating the tumor microenvironment mechanisms that may confer ferroptosis resistance to CRT, such as fibroblasts, which have been shown to regulate the cystine transporter SCL7A11 that promotes ferroptosis resistance. In addition, tumor-infiltrated immune cells with hypoxic signatures will be analyzed for their association with ferroptosis resistance to CRT. In EAC tumors resistant to CRT, myeloid cell expansion was observed, and the phenotype and activation status of myeloid cells will be assessed using orthotopically transplanted patient derived EAC tumors. Further application of an innovative positron emission tomography tracer from the Molecular Imaging Core of the ARTI Center to assess oxidative potential of tumors as related to the myeloid cell expansion observed in resistant tumors will help discover molecular and cellular pathways related to ferroptosis. Project 3 will iteratively strengthen and support the basic science/mechanistic Projects 1 and 2, and Project 3 will significantly contribute to the ARTI Center goal of identifying patients who are at greatest risk to develop acquired radiation resistance.

项目3总结 食管癌是全球第六大常见死因，5年生存率低于 20% 与肺癌等其他胸腔内恶性肿瘤类似，放化疗 (CRT) 是一种治疗方法。 治疗食管腺癌 (EAC) 的有效工具 然而，CRT 可实现完全缓解。 EAC 仅在大约 25% 的患者中出现，因此可以表征发生的细胞和分子变化。 CRT 期间的肿瘤和肿瘤微环境中的数据可以提供高度准确的预测工具来识别 EAC 患者会对 CRT 治疗产生获得性耐药性，从而诱导细胞死亡途径铁死亡。 在癌细胞中，铁死亡是获得性放射治疗耐药性的关键调节因子的假设是 获得性治疗抵抗和铁 (ARTI) 中心项目 3 的一个中心主题将有助于： 通过连接项目 1 和项目 1 中发现的临床前模型中的基础科学机制来实现这一中心主题 项目 2 包含临床 EAC 肿瘤活检，在基线（治疗前）和治疗中期收集 CRT 方案将对这些 EAC 肿瘤活检进行单细胞转录组分析以鉴定表达。 铁死亡相关基因的研究并提供对肿瘤之间复杂通讯的理解 可能驱动和/或调节铁死亡的细胞和肿瘤微环境的细胞（目标 1）。 与铁死亡直接或间接相关的转录组可能有助于预测 EAC 患者 可能会也可能不会对 CRT 进行进一步的空间细胞映射并破译差异关系。 具有铁死亡的表达基因将为肿瘤逃避铁死亡的能力提供证据 目标 2 将重点确定适应性是否因选择而发生治疗耐药。 罕见但预先存在的肿瘤细胞，或由于从头获得直接或间接相关的基因改变 目标 3 将重点阐明肿瘤微环境机制。 可能会赋予 CRT 铁死亡抗性，例如成纤维细胞，已被证明可以调节胱氨酸 转运蛋白 SCL7A11 促进铁死亡抵抗此外，肿瘤浸润的免疫细胞具有 将分析 EAC 肿瘤中缺氧特征与铁死亡的相关性。 对CRT耐药，观察髓系细胞扩增，并观察髓系细胞的表型和活化状态 将使用原位移植的患者来源的 EAC 肿瘤进行评估。 来自 ARTI 中心分子成像核心的创新正电子发射断层扫描示踪剂用于评估 与耐药肿瘤中观察到的骨髓细胞扩张相关的肿瘤氧化潜力将有助于 发现与铁死亡相关的分子和细胞途径，项目 3 将迭代加强和支持。 基础科学/机械项目 1 和 2 以及项目 3 将为 ARTI 中心的目标做出重大贡献 那些最有可能产生获得性辐射耐受性的患者。