Title: Peripheral Nerves and Cancer
Funder: Cancer Research UK

Abstract: Background: Schwann cells (SCs), the major glial cell of the PNS, organise the complex multicellular process required for the regeneration of peripheral nerve. During this process, mature SCs are efficiently reprogrammed to progenitor-like SCs that orchestrate the repair process. Consistent with this capability, SCs are considered the cell-of-origin of many nerve-derived tumours, in particular in patients with the common genetic disorder Neurofibromatosis Type-1 (NF1), and the development and spread of these tumours is reminiscent of an unrepaired wound. The SC microenvironment, including the axonal niche, controls the differentiation state of SCs and the development of SC-derived tumours, with tumours only developing once the niche is disrupted by injury. The control of the homeostatic state, how SCs are reprogrammed and the role of the microenvironment in these processes remain poorly understood with increased understanding key for new strategies to prevent and treat these tumours. The main goal of nerve regeneration is to guide re-growing axons back to their targets. We have shown that progenitor-like SCs migrate as cords to carry re-growing axons across the injury-site directed by a polarised vasculature that forms in response to hypoxic macrophages that initiate the regenerative process. Other tumour cells such as melanoma and glioma migrate along the outside of blood vessels but this remains poorly understood. Moreover, vascularisation and innervation of tumours likely represents a co-opting of these regenerative processes. A better understanding should lead to new approaches to prevent the initiation and spread of tumours. Aims: Determine how the nerve microenvironment controls SC homeostasis and reprogramming, contributes to NF1-tumourigenesis and confers sensitivity to chemotherapy-induced neuropathies. Establish the mechanisms underlying the repair-associated migration of SCs and the links of these processes to tumour cell migration and tumour innervation. Methods: Using a combination of powerful primary in vitro, ex-vivo and in vivo rodent models, we will take a multidisciplinary approach to address these aims and determine the relevance of our findings in human tumours. This approach includes 3D-imaging across scales, tissue biology, proteomic and genomic approaches and the mechanics of cell migration. This research will be used to identify novel approaches for the prevention, development and spread of tumours, in particular those associated with NF1 but with implications for a broad range of tumour-types. Also, the innervation of tumours presents a novel target. Chemotherapy-induced neuropathies limit treatment. Our studies should identify the biology underlying this toxicity with potential for limiting this debilitating side-effect of current therapies.

Lay abstract: Background: Schwann cells (SCs), the major glial cell of the PNS, organise the complex multicellular process required for the regeneration of peripheral nerve. During this process, mature SCs are efficiently reprogrammed to progenitor-like SCs that orchestrate the repair process. Consistent with this capability, SCs are considered the cell-of-origin of many nerve-derived tumours, in particular in patients with the common genetic disorder Neurofibromatosis Type-1 (NF1), and the development and spread of these tumours is reminiscent of an unrepaired wound. The SC microenvironment, including the axonal niche, controls the differentiation state of SCs and the development of SC-derived tumours, with tumours only developing once the niche is disrupted by injury. The control of the homeostatic state, how SCs are reprogrammed and the role of the microenvironment in these processes remain poorly understood with increased understanding key for new strategies to prevent and treat these tumours. The main goal of nerve regeneration is to guide re-growing axons back to their targets. We have shown that progenitor-like SCs migrate as cords to carry re-growing axons across the injury-site directed by a polarised vasculature that forms in response to hypoxic macrophages that initiate the regenerative process. Other tumour cells such as melanoma and glioma migrate along the outside of blood vessels but this remains poorly understood. Moreover, vascularisation and innervation of tumours likely represents a co-opting of these regenerative processes. A better understanding should lead to new approaches to prevent the initiation and spread of tumours. Aims: Determine how the nerve microenvironment controls SC homeostasis and reprogramming, contributes to NF1-tumourigenesis and confers sensitivity to chemotherapy-induced neuropathies. Establish the mechanisms underlying the repair-associated migration of SCs and the links of these processes to tumour cell migration and tumour innervation. Methods: Using a combination of powerful primary in vitro, ex-vivo and in vivo rodent models, we will take a multidisciplinary approach to address these aims and determine the relevance of our findings in human tumours. This approach includes 3D-imaging across scales, tissue biology, proteomic and genomic approaches and the mechanics of cell migration. This research will be used to identify novel approaches for the prevention, development and spread of tumours, in particular those associated with NF1 but with implications for a broad range of tumour-types. Also, the innervation of tumours presents a novel target. Chemotherapy-induced neuropathies limit treatment. Our studies should identify the biology underlying this toxicity with potential for limiting this debilitating side-effect of current therapies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS