Defining the Role of Tumor-Neural Crosstalk in head and Neck Cancer Progression and Treatment Resistance

定义肿瘤神经串扰在头颈癌进展和治疗抵抗中的作用

基本信息

批准号：
10634541
负责人：
Moran Amit
金额：
$ 44.85万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634541
关键词：
Ablation Address Adrenergic Agents Afferent Neurons Attention Axon Biological Models Biometry Blood Vessels Breast Cancer Biology Cell Communication Cells Cellular Structures Cellular biology Clinical Complement Complex Cues Data Development Epithelium Event Genes Genetic Engineering Genetic Transcription Genetically Engineered Mouse Goals Growth Head and Neck Cancer Human Infiltration Inflammation Knowledge Light Malignant Neoplasms Mediating Mediator MicroRNAs Molecular Neoplasms Nerve Nerve Fibers Neurobiology Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neurogenic Inflammation Neurons Oncology Oral Outcome Pancreas Pathologic Pathology Patients Peripheral Nervous System Persons Phenotype Play Positioning Attribute Pre-Clinical Model Process Prostate Quality of life RNA Research Resistance Role Shapes Signal Induction Signal Repression Signal Transduction Small RNA Solid Neoplasm Stomach Supporting Cell TP53 gene Testing Therapeutic Time Transcriptional Activation Tumor Biology Tumor Cell Invasion Tumor Promotion Tumor-Derived Work afferent nerve angiogenesis axonal sprouting cancer cell cancer genetics cancer therapy cancer type candidate identification cell type exosome genetic approach improved innovation insight malignant mouth neoplasm mouse model mouth squamous cell carcinoma neoplastic cell nerve supply neural neurodevelopment neuronal tumor neurotransmission new therapeutic target novel strategies novel therapeutic intervention oral cavity epithelium perineural pharmacologic pre-clinical prevent programs recruit release factor response success targeted cancer therapy therapy development therapy resistant treatment response tumor tumor behavior tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Solid tumors can shape their microenvironments to maximize their growth and metastatic potential. The formation of new nerve fibers within and around tumors can alter tumor behavior, and higher densities of nerve fibers in the tumor microenvironment are associated with poor clinical outcomes in patients with oral, prostate, breast, gastric, pancreatic and other types of cancer . Preclinical and pathological studies have described neoneurogenesis, the process by which cancer cells induce the growth of nerves into tumors, as analogous to neoangiogenesis, in which cancer cells release factors that elicit the growth of blood vessels into the tumor. However, the exact mechanisms that drive nerves to infiltrate tumors and support their growth and progression is unknown. Preliminary research shows that cancer cells `communicate' with neurons through shuttling of p53-dependent RNA species that further induce tumor innervation. The hypothesis of this study is that axonal sprouting and autonomic reprogramming of existing nerves occur as a result of orchestrated miRNA shuttling from cancer cells to neurons and via activation of the transcriptional programs that establish neuronal identity and that infiltration of tumors by autonomic neonerves enables tumor progression. The neonerve's phenotype includes transformation into a sprouting cell able to infiltrate and interact with other cell types, the release of adrenergic neuroactive molecules, and the development of neurogenic inflammation. Each of these acquired capabilities may promote tumor progression and resistance to therapy. The proposed research is innovative because it will capitalize on new concepts in cancer biology and advanced model systems to yield insights into the mechanisms of tumor progression and identify new targets for cancer therapy. This cross-disciplinary proposal will combine expertise from oncology, neurodevelopment, cell biology, neurobiology, cancer genetics, pathology, and biostatistics to pursue three specific aims: (1) Delineate the signaling events that occur between cancer cells and neurons during tumorigenesis, using pharmacologic and genetic approaches to understand how cancer cells cause normally quiescent neurons to reprogram and continually sprout to sustain neoplastic growth. (2) Elucidate the drivers of tumor-associated neuronal reprogramming. By using human-derived sensory neurons, we will determine how the normal nerve response to signals from cancer cells supports cancer progression. (3) Characterize sensory nerve reprogramming and its role in oral cancer progression. Using a genetically engineered syngeneic mouse model, we will elucidate the neural-tumor interactions that lead to neurogenic inflammation and promote oral cancer progression. Our long-term goal is to elucidate the reciprocal nerve-cancer signals that drive cancer progression to identify novel targets for therapy. Once the signals that induce tumor innervation are known, therapeutic approaches to target this critical component of tumor biology can be developed to improve survival, treatment responses, and patients' quality of life.

项目概要实体瘤可以塑造其微环境，以最大限度地发挥其生长和转移潜力。新的形成肿瘤内部和周围的神经纤维可以改变肿瘤的行为，并且肿瘤中神经纤维的密度更高微环境与口腔、前列腺、乳腺癌、胃、胰腺和癌症患者的不良临床结果相关其他类型的癌症。临床前和病理学研究已经描述了新神经发生，即癌症发生的过程。细胞诱导神经生长成肿瘤，类似于新血管生成，其中癌细胞释放因子引起血管生长进入肿瘤。然而，驱动神经浸润肿瘤的确切机制和支持他们的成长和进步尚不清楚。初步研究表明癌细胞与神经元“交流” 通过 p53 依赖性 RNA 种类的穿梭进一步诱导肿瘤神经支配。本研究的假设是现有神经的轴突萌芽和自主神经重新编程是精心策划的 miRNA 穿梭的结果癌细胞到神经元，并通过激活建立神经元身份和渗透的转录程序自主神经神经对肿瘤的抑制使肿瘤进展。新生神经的表型包括转变为发芽细胞能够渗透并与其他细胞类型相互作用，释放肾上腺素能神经活性分子，以及神经源性炎症的发展。这些获得的能力中的每一个都可能促进肿瘤进展和抵抗来治疗。拟议的研究具有创新性，因为它将利用癌症生物学和先进的新概念模型系统，以深入了解肿瘤进展机制并确定癌症治疗的新靶点。这跨学科提案将结合肿瘤学、神经发育、细胞生物学、神经生物学、癌症的专业知识遗传学、病理学和生物统计学以追求三个特定目标：（1）描述之间发生的信号事件肿瘤发生过程中的癌细胞和神经元，使用药理学和遗传学方法来了解癌细胞如何导致通常静止的神经元重新编程并不断发芽以维持肿瘤生长。 (2) 阐明驱动因素肿瘤相关神经元重编程。通过使用人类来源的感觉神经元，我们将确定正常的感觉神经元如何神经对癌细胞信号的反应支持癌症进展。 (3) 感觉神经重编程及其特征在口腔癌进展中的作用。使用基因工程同基因小鼠模型，我们将阐明神经肿瘤导致神经源性炎症并促进口腔癌进展的相互作用。我们的长期目标是阐明驱动癌症进展的相互神经癌症信号以确定新的治疗靶点。一旦发出信号表明诱导肿瘤神经支配是已知的，针对肿瘤生物学这一关键组成部分的治疗方法可以是旨在提高生存率、治疗反应和患者的生活质量。