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摘要 食管癌是全球第六大死亡原因，5年生存率低于 20％。类似于其他胸膜内恶性肿瘤，例如肺癌，化学放疗治疗（CRT）是 治疗食管腺癌（EAC）的有效工具。但是，CRT导致完成 EAC仅在大约25％的患者中。那是表征发生的细胞和分子变化的 在CRT期间的肿瘤和肿瘤微环境中，可以提供高度准确的预测工具来识别 EAC患者将产生对治疗的耐药性。 CRT诱导细胞死亡途径铁凋亡 在癌细胞中，以及铁腐病是获得放射疗法耐药性的关键调节剂的假设是 获得了对治疗和铁（ARTI）中心的抵抗力的中心主题。项目3将有助于 通过在项目1和项目1和 临床EAC肿瘤活检的项目2，在基线（治疗前）和中间收集 CRT方案。这些EAC肿瘤活检将进行单细胞转录组分析以识别表达 与铁吞作用相关的基因，并提供对肿瘤之间复杂通信的理解 肿瘤微环境的细胞和细胞可能会驱动和/或调节铁铁作用（AIM 1）。鉴别 直接或间接与铁凋亡有关的转录组可能有助于证明EAC患者 可能会或可能不会回应CRT。进一步的空间细胞映射和解密差异的关系 表达的具有铁凋亡的基因将提供证据证明肿瘤在 辐照。 AIM 2将专注于确定是否由于选择了对治疗的适应性抗药性 罕见但已有预先存在的肿瘤细胞，或者是由于直接或间接相关的基因改变的从头获取而引起的 进行铁凋亡信号通路。 AIM 3将重点阐明肿瘤微环境机制 5月会议会议对CRT的氟化性抗性，例如成纤维细胞，已证明可以调节胱氨酸 促进抗铁氧作用的转运蛋白SCL7A11。此外，肿瘤浸润的免疫小球与 将分析低氧特征与CRT抗铁毒性抗性的关联。在EAC肿瘤中 对CRT的抗性，观察到髓样细胞的扩张，以及髓样细胞的表型和激活状态 将使用原始移植的患者衍生的EAC肿瘤评估。进一步应用 来自ARTI中心的分子成像核心的创新正电子发射断层扫描示踪剂评估 肿瘤的氧化潜力与在抗性肿瘤中观察到的髓样细胞膨胀有关将有助于 发现与铁凋亡有关的分子和细胞途径。项目3会迭代地加强和支持 基础科学/机械项目1和2，以及项目3将对ARTI中心的目标做出重大贡献 确定患有最大风险的患者发展获得获得的辐射抗性。