Defining the Role of Tumor-Neutral 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。的 肿瘤内和周围新神经纤维的形成可以改变肿瘤行为，并增加神经密度 肿瘤微环境中的纤维与口腔，前列腺， 乳腺癌、胃癌、胰腺癌和其他类型的癌症。临床前和病理学研究已经描述了 神经发生是癌细胞诱导神经生长成肿瘤的过程，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。 然而，驱动神经浸润肿瘤并支持其生长和进展的确切机制 不明初步研究表明，癌细胞通过p53- 依赖的RNA种类进一步诱导肿瘤神经支配。这项研究的假设是， 现有神经的发芽和自主重编程是由于协调的miRNA穿梭 从癌细胞到神经元，以及通过激活建立神经元身份的转录程序， 并且自主神经对肿瘤的浸润使肿瘤进展。神经细胞表型 包括转化成能够渗透并与其它细胞类型相互作用的发芽细胞， 肾上腺素能神经活性分子和神经源性炎症的发展。每一个获得 能力可能促进肿瘤进展和对治疗的抵抗。建议的研究是创新的 因为它将利用癌症生物学的新概念和先进的模型系统， 肿瘤进展的机制，并确定癌症治疗的新靶点。这种跨学科 该提案将联合收割机肿瘤学、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 癌细胞如何导致正常静止的神经元重新编程并持续发芽以维持肿瘤 增长(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官 神经元，我们将确定正常神经对癌细胞信号的反应如何支持癌症 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 基因工程同基因小鼠模型，我们将阐明神经肿瘤的相互作用，导致 神经源性炎症和促进口腔癌进展。我们的长期目标是阐明 神经癌信号驱动癌症进展，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的，靶向肿瘤生物学的这一关键组分的治疗方法 可以提高生存率、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.