{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:21:39Z","timestamp":1783606899056,"version":"3.55.0"},"reference-count":37,"publisher":"Bioscientifica","issue":"11","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1530\/erc-25-0226","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:45:59Z","timestamp":1761043559000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Netrin\u2013DCC inhibition suppresses neuroendocrine neoplasm growth\n                    <i>in vivo<\/i>"],"prefix":"10.1530","volume":"32","author":[{"given":"Liav","family":"Sela Peremen","sequence":"first","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alona","family":"Telerman","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuval","family":"Kahan 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