Schwann Cell Reprogramming and Cancer Perineural Invasion

雪旺细胞重编程和癌症神经周围浸润

• 批准号: 9752257
• 负责人: Richard J Wong
• 金额: $ 59.73万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752257
• 关键词: Affect; Automobile Driving; Bacillus (bacterium); Biological Assay; Biometry; CCL2 gene; Cell Adhesion Molecules; Cell Culture Techniques; Cell physiology; Cellular biology; Characteristics; Chemotaxis; Clinical Data; Coculture Techniques; Complement; Disease; Functional disorder; Impairment; Infection; Inflammatory; Intercalated Cell; Interruption; Invaded; JUN gene; Laboratories; Leprosy; Ligands; London; Malignant Neoplasms; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Morbidity - disease rate; Mus; Myelin; Nerve; Neuraxis; Neurons; Operative Surgical Procedures; Pathogenicity; Pathology; Pathway interactions; Phenotype; Physiological; Play; Positioning Attribute; Process; Recurrence; Resources; Role; Schwann Cells; Signal Transduction; Site; Specimen; Supporting Cell; System; Transgenic Organisms; Trauma; Universities; axon regeneration; cancer cell; cell dedifferentiation; cell motility; cell type; clinically significant; college; experience; glial cell-line derived neurotrophic factor; injury and repair; macrophage; monocyte; mouse model; myelination; nerve injury; neurodevelopment; neurotrophic factor; new therapeutic target; novel; oncology; perineural; progenitor; programs; recruit; release factor; repaired; response; response to injury; sciatic nerve; stem; trafficking

The ability of some cancers to invade in, around, and along nerves is a process termed perineural invasion (PNI). PNI is an indicator of aggressive disease that is associated with morbidity from nerve dysfunction, increased recurrence, and worse survival. Cancer cells (CC) may be stimulated by a variety of neurotrophic factors released by nerves to facilitate PNI. This finding highlights the participatory role of the nerve microenvironment in enabling this adverse process. Schwann cells (SC) are key mediators of PNI; they intercalate between CC, facilitate CC dispersion, recruit CC to nerves, enhance CC invasion, and ultimately promote PNI. Interestingly, SC activity in PNI recapitulates the normal SC response following nerve injury. After nerve trauma, quiescent, myelinating SC are reprogrammed to an active subtype that shares characteristics with progenitor, dedifferentiated, stem-like SC. These “repair” SC release neurotrophic factors, recruit macrophages, and promote nerve repair. SC reprogramming following nerve injury may be controlled by c-Jun or Raf-ERK signaling. We hypothesize that the SC supporting nerves undergoing cancer invasion experience a transition similar to SC response following nerve injury. SC affected by cancer invasion are reprogrammed to acquire a phenotype that enables PNI. This SC phenotype includes: a transformation to a dynamic and motile cell able to interact with other cell types, the release of neurotrophic ligands, the expression of new cell adhesion molecules, and the ability to recruit macrophages to sites of PNI. Each of these acquired capabilities recapitulates similar SC reprogramming as a normal response to trauma, but may paradoxically promote PNI. We will explore how the interactions between SC and cancer are derived from a conserved nerve-repair program that is exploited by various cancers to facilitate their progression. This cross-disciplinary proposal combines expertise from oncology, neurodevelopment, cell biology, macrophage trafficking, pathology, and biostatistics to: 1. Characterize SC reprogramming in PNI and elucidate the drivers of this process. We will explore parallels in SC plasticity between nerve injury and PNI. 2. Determine how reprogrammed SC directly promote PNI. We will determine how SC c-Jun and Raf-ERK signaling impact PNI, and assess how reprogrammed SC mechanistically support PNI. 3. Assess how reprogrammed SC recruit inflammatory monocytes to indirectly promote PNI. We will determine mechanisms of SC-mediated monocyte recruitment and define how macrophages promote PNI. Our overall objective is to elucidate the relationships between cancer PNI and SC nerve-repair mechanisms to identify novel targets for therapy. Understanding how normal nerve response to injury paradoxically supports cancer invasion may reveal novel opportunities and strategies to interrupt this highly adverse process.

某些癌症侵袭神经、周围和沿神经的能力称为神经周围侵袭。 (PNI)。PNI是侵袭性疾病的指标，与神经功能障碍的发病率有关， 复发增加，存活率更差。多种神经营养因子可刺激癌细胞(CC) 神经释放的促进PNI的因子。这一发现突出了神经的参与作用。 使这一不利过程成为可能的微环境。 雪旺细胞(Schwann cell，SC)是PNI的关键介质，它们介于CC之间，促进CC扩散，募集CC 神经，增强CC侵袭，最终促进PNI。有趣的是，PNI中的SC活动概括了 神经损伤后SC反应正常。神经损伤后，静止的髓鞘干细胞被重新编程 到一个活跃的亚型，该亚型与祖细胞、去分化、茎状SC具有相同的特征。这些“修理” SC释放神经营养因子，招募巨噬细胞，促进神经修复。SC重新编程如下 神经损伤可能由c-jun或Raf-ERK信号控制。 我们假设，支持癌症侵袭的SC神经经历了类似于 神经损伤后SC反应。受癌症侵袭影响的SC被重新编程以获得表型 这使得PNI成为可能。这种SC表型包括：向能够相互作用的动态和活动细胞的转变 对于其他类型的细胞，神经营养配体的释放，新的细胞黏附分子的表达，以及 将巨噬细胞募集到PNI部位的能力。这些获得的能力中的每一个都概括了类似的SC 重新编程是对创伤的正常反应，但可能会矛盾地促进PNI。我们将探讨 干细胞与癌症之间的相互作用源于一种保守的神经修复程序，该程序由 各种癌症促进了它们的发展。这项跨学科的建议结合了以下方面的专业知识 肿瘤学、神经发育、细胞生物学、巨噬细胞运输、病理学和生物统计学： 1.描述了PNI中SC重编程的特征，并阐明了这一过程的驱动因素。我们将探索Parallels 在神经损伤和PNI之间的SC可塑性。 2.确定重新编程的SC如何直接促进PNI。我们将决定SC c-jun和Raf-erk 信令影响PNI，并评估重新编程的SC如何机械地支持PNI。 3.评估重新编程的SC如何募集炎性单核细胞间接促进PNI。我们会 确定SC介导的单核细胞募集的机制，并确定巨噬细胞如何促进PNI。 我们的总体目标是阐明癌症PNI和SC神经修复机制之间的关系，以 确定新的治疗靶点。理解对损伤的正常神经反应如何矛盾地支持 癌症的侵袭可能会揭示新的机会和策略来中断这一非常不利的过程。