Uncovering the role of netrins and DCC (deleted in colorectal cancer) in pancreatic neuroendocrine neoplasms (PNEN) tumorigenesis (B06)

Introduction: DCC functions as a tumor suppressor and is altered in various tumors, including
neuroendocrine neoplasms. Netrin (NTN)-1 serves as the primary ligand for DCC. Operating as a
dependence receptor, DCC induces apoptosis without NTN and promotes cell survival in its presence. In
some cancers like small cell lung cancer and neuroblastoma, upregulation of NTN-3 rather than NTN-1
has been observed. However, the precise involvement of NTNs and DCC in PNEN remains unclear.

Aim(s): Our research aims to elucidate the roles of DCC and NTNs in PNEN tumorigenesis and explore
their potential for targeted treatment.

Materials and methods: In vitro experiments utilized the PNEN cell line BON1. Evaluation of DCC, NTN-1, and NTN-3 expression levels was performed using QPCR, western blotting, and ELISA. Cell viability and proliferation studies were conducted after manipulating DCC expression via DCC siRNA, utilizing varied NTN-1 concentrations, and employing an NTN scavenger antibody (NP137- NETRIS Pharma). In vivo experiments entailed monitoring the growth of BON1 xenografts in nude mice treated with NP137 or PBS.

Results: BON-1 cells exhibited elevated expression of DCC and NTN-3. The addition of NTN-1 augmented BON1 viability, a response lessened upon NTN blockade using NP137. Furthermore, DCC siRNA negated the effect of NTN-1 on cell viability. Mice bearing BON1 tumors and treated with NP137 exhibited markedly diminished xenograft growth.
Moreover, analysis of Pan-cancer TCGA data suggested a higher likelihood of survival linked to lower
DCC and NTN-3 expression.

Conclusion: Our data suggests that NTN-3, NTN-1, and DCC play codependent oncogenic role in PNENs, that are reversible by inhibiting NTN binding to DCC. NTN inhibition merits further investigation as a potential therapeutic target.

Keywords: neuroendocrine, netrin, pancreatic neuroendocrine tumor, dcc