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

定义肿瘤中性串扰在头颈癌进展和治疗耐药中的作用

• 批准号: 10381327
• 负责人: Moran Amit
• 金额: $ 11.19万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-10-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381327
• 关键词: Adrenergic Agents; Afferent Neurons; Biological Models; Biometry; Blood Vessels; Breast; Cancer Biology; Cells; Cellular biology; Clinical; Development; Event; Genetic Engineering; Goals; Growth; Head and Neck Cancer; Human; Infiltration; Lead; Malignant Neoplasms; MicroRNAs; Neoplasms; Nerve; Nerve Fibers; Neurobiology; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Neurogenic Inflammation; Neurons; Oncology; Oral; Outcome; Pancreas; Pathologic; Pathology; Patients; Peripheral Nervous System; Pharmacology; Phenotype; Play; Process; Prostate; Quality of life; RNA; Research; Resistance; Role; Shapes; Signal Transduction; Solid Neoplasm; Stomach; Supporting Cell; TP53 gene; Therapeutic; Transcriptional Activation; Tumor Biology; afferent nerve; axonal sprouting; cancer cell; cancer genetics; cancer therapy; cancer type; cell type; density; genetic approach; improved; innovation; insight; malignant mouth neoplasm; mouse model; nerve supply; neurodevelopment; new therapeutic target; pre-clinical; programs; release factor; response; targeted cancer therapy; therapy resistant; treatment response; tumor; tumor behavior; tumor microenvironment; tumor progression; tumorigenesis

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.

项目摘要 实体瘤可以塑造其微环境，以最大程度地发挥其生长和转移潜力。这 肿瘤内外的新神经纤维的形成会改变肿瘤行为，而神经的密度更高 肿瘤微环境中的纤维与口服，前列腺患者的临床结局差有关 乳腺癌，胃，胰腺和其他类型的癌症。临床前和病理研究描述了 Neoneurogenoferation，癌细胞诱导神经生长到肿瘤中的过程，类似于 新血管生成，其中癌细胞释放引起血管生长到肿瘤中的因子。 但是，驱动神经浸润肿瘤并支持其生长和进展的确切机制 是未知的。初步研究表明，癌细胞通过穿梭p53-与神经元“通信”。 依赖性RNA物种，进一步诱导肿瘤神经。这项研究的假设是轴突 精心策划的miRNA穿梭导致现有神经的发芽和自主性重编程 从癌细胞到神经元，以及通过建立神经元身份的转录程序的激活 自主神经毒剂对肿瘤的浸润可以使肿瘤进展。新生工具的表型 包括转换为发芽的单元格可以浸润并与其他单元类型相互作用， 肾上腺神经活性分子和神经源性注射的发展。这些都获得了 能力可以促进肿瘤的进展和对治疗的抵抗力。拟议的研究是创新的 因为它将利用癌症生物学和高级模型系统中的新概念，以产生洞察力 肿瘤进展的机制并确定了癌症治疗的新靶标。这个跨学科 提案将结合肿瘤学，神经发育，细胞生物学，神经生物学，癌症遗传学的专业知识， 病理学和生物统计学以购买三个具体目的：（1）描述发生的信号事件 肿瘤发生过程中的癌细胞和神经元，使用药物和遗传学方法来理解 癌细胞通常会导致通常静止的神经元重编程并连续发芽以维持肿瘤 生长。 （2）阐明肿瘤相关神经元重编程的驱动因素。通过使用人类衍生的感觉 神经元，我们将确定正常的神经对癌细胞信号的神经反应如何支持癌症 进展。 （3）表征感觉神经重编程及其在口腔癌进展中的作用。使用 基因设计的合成小鼠模型，我们将阐明导致的神经肿瘤相互作用 神经源性炎症并促进口腔癌的进展。我们的长期目标是阐明倒数 神经癌信号驱动癌症进展以识别新的治疗靶标。一旦信号表明 诱导肿瘤神经是已知的，靶向肿瘤生物学关键成分的治疗方法 可以开发以改善生存，治疗反应和患者的生活质量。