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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Netrin-DCC inhibition suppresses neuroendocrine neoplasm growth in vivo
Liav Sela Peremen1, Alona Telerman2, Yuval Kahan Yossef1,2
1Gray Faculty of Medical & Health Sciences, Tel-Aviv University, Tel Aviv-Yafo, Israel.
Abstract:
DCC protein functions as a tumor suppressor and is altered in various tumors, including neuroendocrine neoplasms. Netrin (NTN)-1 serves as the primary ligand for DCC. Acting as a dependence receptor, DCC induces apoptosis in the absence of NTN and promotes cell survival when NTN is present. In certain cancers, such as small-cell lung cancer and neuroblastoma, the upregulation of NTN-3 has been observed instead of NTN-1. However, the exact role of NTNs and DCC in PNEN remains unclear. We assessed DCC and netrin expression in pancreatic neuroendocrine neoplasm (PNEN) cells (BON-1). We examined the effect of netrin on cell viability using DCC knockdown and NP137, a netrin-inhibiting antibody. In vivo, PNEN cells were injected into nude mice and treated with NP137 or PBS. Tumor RNA sequencing was performed. A population-based analysis using TCGA data evaluated the impact of DCC and NTN3 expression on survival. BON-1 cells exhibited elevated expression of DCC and NTN-3. The addition of NTN-1 augmented BON-1 viability, a response that was lessened upon NTN blockade using NP137. Furthermore, DCC siRNA negated the effect of NTN-1 on cell viability. Mice bearing PNEN BON-1 xenografts treated with NP137 exhibited markedly diminished xenograft growth. RNA sequencing revealed upregulation of small nucleolar RNAs (SNORs) in NP137-treated tumors, with enriched pathways related to RNA processing. TCGA analysis showed a negative correlation between NTN3 expression and survival. In conclusion, our data suggest that NTN-3, NTN-1, and DCC have interdependent oncogenic roles in PNENs, which can be reversed by blocking NTN binding to DCC.
Insights
Netrin-3 (NTN-3), Netrin-1 (NTN-1), and DCC protein promote pancreatic neuroendocrine tumor (PNEN) growth. Blocking NTN binding to DCC inhibits PNEN progression, offering a potential therapeutic strategy for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- DCC protein acts as a tumor suppressor, crucial in neuroendocrine neoplasms.
- DCC functions as a dependence receptor, regulating apoptosis based on Netrin (NTN) ligand presence.
- The roles of NTNs and DCC in pancreatic neuroendocrine neoplasms (PNENs) require further investigation.
Purpose of the Study:
- To investigate the expression and function of DCC and netrins in PNENs.
- To determine the effect of netrin on PNEN cell viability and tumor growth.
- To evaluate the therapeutic potential of blocking NTN-DCC interactions in PNENs.
Main Methods:
- Assessed DCC and netrin expression in PNEN BON-1 cells.
- Utilized DCC knockdown and a netrin-inhibiting antibody (NP137) to study cell viability.
- In vivo studies involved xenograft models treated with NP137, followed by RNA sequencing.
- Population-based analysis using TCGA data evaluated DCC and NTN3 expression impact on survival.
Main Results:
- PNEN BON-1 cells showed elevated DCC and NTN-3 expression.
- NTN-1 enhanced cell viability, which was reduced by NTN blockade or DCC knockdown.
- NP137 treatment significantly inhibited PNEN xenograft growth in vivo.
- TCGA data revealed a negative correlation between NTN3 expression and patient survival.
Conclusions:
- NTN-3, NTN-1, and DCC exhibit interdependent oncogenic roles in PNENs.
- Blocking NTN binding to DCC demonstrates therapeutic potential by reversing these oncogenic roles.
- Targeting the NTN-DCC pathway represents a promising strategy for PNEN treatment.
