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

项目摘要 实体瘤可以塑造它们的微环境，以最大限度地提高它们的生长和转移潜力。形成新 肿瘤内和周围的神经纤维可以改变肿瘤的行为， 微环境与口腔、前列腺、乳腺、胃、胰腺和 其他类型的癌症 .临床前和病理学研究已经描述了神经发生，即癌症发生的过程。 细胞诱导神经生长到肿瘤中，类似于新血管生成，其中癌细胞释放因子， 引发血管向肿瘤内生长然而，驱动神经浸润肿瘤的确切机制， 支持他们的成长和进步是未知的。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。 这项研究的假设是， 轴突发芽和现有神经的自主重编程是由于协调的miRNA从神经元穿梭而发生的。 癌细胞的神经元和通过激活的转录程序，建立神经元的身份和浸润 自主神经对肿瘤的抑制使肿瘤进展。神经元的表型包括 转型为 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， 神经源性炎症的发展。这些获得的能力中的每一种都可能促进肿瘤的进展和耐药性 接受治疗 这项研究是创新的，因为它将利用癌症生物学的新概念和先进的 模型系统，以深入了解肿瘤进展的机制，并确定癌症治疗的新靶点。 这 跨学科的建议将结合联合收割机的专业知识，从肿瘤学，神经发育，细胞生物学，神经生物学，癌症 遗传学，病理学和生物统计学追求三个具体目标：（1）描述发生在 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 导致正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 肿瘤相关的神经元重编程。通过使用人类来源的感觉神经元，我们将确定正常的 神经对来自癌细胞的信号的反应支持癌症进展。(3)表征感觉神经重编程及其 在口腔癌进展中的作用。使用基因工程的同基因小鼠模型，我们将阐明神经肿瘤 导致神经源性炎症和促进口腔癌进展的相互作用。我们的长期目标是阐明 相互的神经-癌症信号驱动癌症进展，以确定新的治疗靶点。一旦这些信号 诱导肿瘤神经支配是已知，靶向肿瘤生物学的这一关键组分的治疗方法可以 旨在提高生存率、治疗反应和患者的生活质量。

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.