Schwann Cell Reprogramming and Cancer Perineural Invasion

某些癌症在神经内、周围和沿着神经侵袭的能力称为神经周侵袭 （PNI）。PNI是与神经功能障碍的发病率相关的侵袭性疾病的指标， 复发率增加，生存率下降。癌细胞（CC）可被多种神经营养因子刺激。 促进PNI的神经释放因子。这一发现突出了神经的参与作用 微环境，使这一不利的过程。 施万细胞（SC）是PNI的关键介导者;它们插入CC之间，促进CC分散，招募CC 增强CC侵袭，最终促进PNI。有趣的是，PNI中的SC活性概括了 神经损伤后正常SC反应。在神经创伤后，静止的、有髓鞘的SC被重新编程， 到一个活跃的亚型，与祖细胞，去分化，干细胞样SC共享特征。这些"修复" SC释放神经营养因子，募集巨噬细胞，促进神经修复。以下SC重新编程 神经损伤可由c-Jun或Raf-ERK信号传导控制。 我们假设，SC支持神经在经历癌症侵袭时经历了类似于 神经损伤后的SC反应。受肿瘤侵袭影响的SC被重编程以获得表型 这使得PNI。这种SC表型包括：向能够相互作用的动态和能动细胞的转化 与其他细胞类型，神经营养配体的释放，新的细胞粘附分子的表达， 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 重编程作为对创伤的正常反应，但可能矛盾地促进PNI。我们将探讨如何 SC和癌症之间的相互作用来自一个保守的神经修复程序， 各种癌症，以促进其发展。这一跨学科的提案结合了 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，以： 1.描述PNI中SC重编程的特征，并阐明该过程的驱动因素。我们将探讨 神经损伤与PNI之间SC可塑性的关系。 2.确定重新编程的SC如何直接促进PNI。我们将确定SC c-Jun和Raf-ERK 信号传导影响PNI，并评估重编程的SC如何机械地支持PNI。 3.评估重编程的SC如何募集炎性单核细胞以间接促进PNI。我们将 确定SC介导的单核细胞募集机制，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， 确定新的治疗靶点。了解正常神经对损伤的反应如何矛盾地支持 癌症侵袭可能揭示新的机会和策略来中断这种高度不利的过程。

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.