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.

项目总结