Hiba Haidar


Deciphering the mechanisms of nerve-tumour interactions: the role of Netrin-1/DCC axonal guidance signalling

Nerve-tumor interactions are receiving increasing attention due to the recently identified role of the nervous system in regulating cancer initiation and progression. In pancreatic ductal adenocarcinoma (PDAC), sympathetic nerve fibers grow and branch around (pre)cancerous pancreatic lesions, exerting an anti-tumorigenic activity. The molecular mechanisms responsible for the structural changes in sympathetic innervation induced by cancer are unknown. Axon guidance molecules (AGMs), which are involved in neural circuit formation during embryogenesis, are potential candidates. Indeed, AGMs are frequently re-expressed in cancers, where they play important roles in cancer cell survival and invasion, angiogenesis and immune cell regulation. However, the currently known functions of AGMs in cancer are not linked to their developmental role in axonal guidance, and their involvement in cancer-associated neuroplasticity remains to be demonstrated.


The aim of my PhD research was to explore the role of AGMs in axonal remodeling induced by PDAC. To do so, I first used a mouse model of chronic pancreatitis, a well-known risk factor for developing PDAC, which generates metaplastic lesions highly innervated by the sympathetic nervous system. I analyzed the expression of AGMs, showing the presence of Netrin-1 in macrophages and metaplastic pancreatic cells, while the Netrin-1 receptor DCC was re-expressed by sympathetic axons. Selective genetic deletion of Dcc in sympathetic neurons inhibited their innervation of metaplastic lesions. In addition, conditional deletion of Ntn1 in either macrophages or pancreatic cells revealed that pancreatic metaplastic cells were the major source of axonal growth signal. Next, to test the implication of this signaling pathway in early cancer development, I used an anti-Netrin-1 antibody (NET-H-mab) to block its function in the KIC transgenic mouse model of PDAC. This significantly inhibited the remodeling of sympathetic axons around precancerous lesions, leading to a faster progression to higher-grade lesions.


In conclusion, my results demonstrate the involvement of the Netrin-1/DCC signaling pathway in neural plasticity during the early stages of PDAC development. Furthermore, this study highlights the importance of axon-related functions of AGMs in carcinogenesis.