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: 10227704
• 负责人: Richard J Wong
• 金额: $ 64.07万
• 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/10227704
• 关键词: Affect; Automobile Driving; Bacillus; 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; Oncology; 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; nerve repair; neurodevelopment; neurotrophic factor; new therapeutic target; novel; 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.

一些癌症侵入神经内部、周围和沿神经的能力被称为神经周围浸润

项目成果

The Role of Schwann Cells in Cancer.

• DOI: 10.1002/adbi.202200089
• 发表时间: 2022-09
• 期刊: ADVANCED BIOLOGY
• 影响因子: 3.7
• 作者: Deborde, Sylvie;Wong, Richard J.
• 通讯作者: Wong, Richard J.

Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion.

• DOI: 10.1158/2159-8290.cd-21-1690
• 发表时间: 2022-10-05
• 期刊: Cancer discovery
• 影响因子: 28.2

Patterns of recurrence in oral tongue cancer with perineural invasion.

• DOI: 10.1002/hed.25110
• 发表时间: 2018-06
• 期刊: Head & neck
• 作者: Cracchiolo JR;Xu B;Migliacci JC;Katabi N;Pfister DG;Lee NY;Patel SG;Ghossein RA;Wong RJ
• 通讯作者: Wong RJ