Enteric Glia is New Biological Target to Block Drug Resistance in Colon Cancer

肠胶质细胞是阻断结肠癌耐药性的新生物靶点

基本信息

批准号：
10659846
负责人：
Laurianne Chantal Van Landeghem
金额：
$ 34.03万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659846
关键词：
3-Dimensional ATM Signaling Pathway Apoptosis Automobile Driving Biological Cell Line Cells Chemoprotection Chemoprotective Agent Chemoresistance Chemotherapy-Oncologic Procedure Coculture Techniques Colon Colon Adenocarcinoma Colon Carcinoma Colonic Neoplasms Complex Cues Cytoprotection DNA Damage DNA Repair Development Dinoprostone Drug resistance Drug usage Embryo Engraftment Enteral Enteric Nervous System Fluorouracil Follistatin Gene Targeting Genetic Glial Fibrillary Acidic Protein Growth Human Immunodeficient Mouse In Vitro Induction of Apoptosis Infiltration Knockout Mice Ligands Light Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Molecular Molecular Profiling Neuroglia Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Probability Production Prognosis Proliferating Rattus Resistance Signal Transduction Solid Neoplasm Survival Rate Testing Therapeutic Therapeutic Intervention Time Tissues Transgenic Mice Treatment Efficacy Tumor Stem Cells WFDC2 gene ataxia telangiectasia mutated protein cancer cell cancer stem cell cancer therapy carcinogenicity chemotherapy colon carcinogenesis design glial activation healing improved in vivo mouse model neoplastic cell new therapeutic target novel novel therapeutics oxaliplatin paracrine pharmacologic protective effect public health relevance resistance factors response sensor single-cell RNA sequencing stem cell survival targeted treatment therapeutic target tumor tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Resistance to anti-cancer therapies largely explains the abysmal 5-year survival rate of patients with advanced colon cancer. Traditional chemotherapy regimens have been designed to efficiently stop proliferation and initiate apoptosis in cancer cells, but have failed to appreciate the pro-chemoresistance signals emanating from cells surrounding the tumor. We have identified a novel cellular component of the tumor microenvironment: the enteric glial cells (EGC). We and others have shown over the last 15 years that EGC are potent inducers of barrier function and healing in a healthy colon. Recently we have demonstrated that the EGC network substantially infiltrates human colon adenocarcinomas and promotes cancer stem cell tumor-forming abilities via a paracrine PGE2-EP4 pathway. Nevertheless, whether EGC impact colon cancer resistance to chemotherapy remains unknown. Our preliminary studies indicate that EGC protect cancer stem cells against apoptosis induced by chemotherapeutic drugs, allowing for enhanced tumor formation and growth despite the chemotherapy treatment. We also have evidence that this is (1) dependent on activation of the MRN-ATM pathway - a central player in DNA repair- in cancer cells and (2) exacerbated by EGC activation with chemotherapy. Using mass spectrometry analyses, we have identified FSTL3 as a novel EGC-derived factor and generated preliminary results implicating FSTL3 in EGC chemoprotective effects. Therefore, we propose to test the hypothesis that “in response to chemotherapeutic drugs, EGC release larger amounts of FSTL3 in the tumor microenvironment, which enhances cancer stem cell chemoresistance and allows for tumor formation and growth by promoting DNA repair driven by the MRN-ATM pathway”. Specific Aim 1 will determine whether EGC promote cancer stem cell resistance to chemotherapies via the release of FSTL3. Specific Aim 2 will test whether EGC protective effects are mediated by increased DNA repair as a result of activation of the MRN-ATM pathway. Specific Aim 3 will determine whether blocking FSTL3 production in EGC sensitizes colon tumors to chemotherapies in vivo. Studies will use translationally relevant primary cultures of human EGC and cancer cells, 3D co-culture platforms, orthotopic co-engraftment in immunodeficient mice, murine models of colon carcinogenesis, transgenic mice allowing for chemogenetic activation of EGC (GFAP-hM3Dq) and inducible gene targeting in EGC (GFAP- CreERT2), in addition to cutting-edge molecular profiling using single cell RNA seq and mass spectrometry studies to identify the pro-chemoresistance factor(s) (and in particular FSTL3) and pathway(s) involved. These studies will not only improve our understanding of the cellular and molecular mechanisms driving colon cancer chemoresistance but will also demonstrate the therapeutic potential of developing strategies combining targeted therapies against EGC-derived FSTL3 and traditional chemotherapy regimens.

项目摘要/摘要对抗癌疗法的抵抗力在很大程度上解释了晚期患者的糟糕率5年生存率结肠癌。传统的化学疗法方案旨在有效停止增殖并开始癌细胞中的凋亡，但未能理解细胞发出的促耐药信号围绕肿瘤。我们已经确定了肿瘤微环境的新型细胞成分：Enter 神经胶质细胞（EGC）。在过去的15年中，我们和其他人表明，EGC是潜在的障碍影响者健康结肠的功能和愈合。最近，我们证明了EGC网络基本上浸润人类结肠腺癌并通过旁分泌促进癌症干细胞形成肿瘤的能力 PGE2-EP4途径。然而，EGC是否会影响结肠癌对化学疗法的抗性性未知。我们的初步研究表明，EGC保护癌症干细胞免受诱导的凋亡化学治疗药物，允许增强的肿瘤形成和生长目的地化学疗法治疗。我们还有证据表明这是（1）取决于MRN -ATM途径的激活 - 中央癌细胞中DNA修复的参与者，（2）通过化学疗法激活EGC激活。使用质量光谱分析，我们已经将FSTL3识别为一种新型EGC衍生因子，并产生了初步结果隐含在EGC化学保护作用中的FSTL3。因此，我们建议检验以下假设：对化学治疗药物的反应，EGC在肿瘤微环境中释放了更多的FSTL3，这增强了癌症干细胞的化学抗性，并通过促进DNA允许形成肿瘤和生长由MRN-ATM途径驱动的维修”。具体目标1将决定EGC是否促进癌症干细胞通过FSTL3的释放对化学疗法的抗性。特定目标2将测试EGC保护效果是否由于MRN-ATM途径的激活，通过增加的DNA修复介导。具体的目标3将确定EGC中的FSTL3产生是否会在体内感知结肠肿瘤对化学疗法。研究将使用人类EGC和癌细胞，3D共培养平台的翻译相关的原发性培养物，免疫缺陷小鼠的原位共晶，结肠癌的鼠模型，转基因小鼠模型允许EGC（GFAP-HM3DQ）和诱导基因靶向EGC（GFAP-- Creert2），除了使用单细胞RNA SEQ和质谱法的尖端分子分析外研究涉及促氧化因子（尤其是FSTL3）和途径的研究。这些研究不仅会提高我们对驱动结肠癌的细胞和分子机制的理解化学耐药性，但也将证明制定策略结合目标的策略的治疗潜力针对EGC衍生的FSTL3和传统化学疗法方案的疗法。