{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T17:44:11Z","timestamp":1776015851799,"version":"3.50.1"},"posted":{"date-parts":[[2025,5,23]]},"group-title":"Cancer Biology","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Genomic alterations driving tumorigenesis in sinonasal malignancies remain largely unexplored. Here, we perform an\n                  <jats:italic>in vivo<\/jats:italic>\n                  loss-of-function screen using a pooled custom single-guide library delivered to the sinonasal cavity by adeno-associated virus vector to identify cancer driver genes across diverse sinonasal malignancies. This approach yielded sinonasal malignancies with diverse histologies, including sinonasal squamous cell carcinoma, adenocarcinoma, poorly differentiated sinonasal carcinoma, and sinonasal neuroendocrine tumors characteristic of olfactory neuroblastoma. Surprisingly, rather than observing distinct sgRNA profiles across sinonasal tumor subtypes, common recurrent mutations were identified in\n                  <jats:italic>Nf1<\/jats:italic>\n                  (79%),\n                  <jats:italic>Rasa1<\/jats:italic>\n                  (74%), and\n                  <jats:italic>Trp53<\/jats:italic>\n                  (68%) across malignancies with distinct histologies. Utilizing an orthogonal approach, we confirmed that\n                  <jats:italic>Nf1\/Trp53<\/jats:italic>\n                  were required for sinonasal tumorigenesis. Given that loss-of-function in\n                  <jats:italic>NF1<\/jats:italic>\n                  and\n                  <jats:italic>RASA1<\/jats:italic>\n                  may lead to increased Ras activity and downstream MEK signaling, we tested small molecule targeting of the RAS-MAPK pathway in sinonasal malignancies. Indeed, both tumor cell lines derived from our loss-of-function approach as well as from human sinonasal malignancies displayed significant sensitivity to MEK inhibition in standard\n                  <jats:italic>in vitro<\/jats:italic>\n                  culture and organoid models. These findings demonstrate that loss of NF1 and RASA1-mediated Ras-GAP activity leads to Ras activation and downstream MEK signaling which is a potential common target throughout major sinonasal tumor subtypes.\n                <\/jats:p>","DOI":"10.1101\/2025.05.19.654661","type":"posted-content","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:45:31Z","timestamp":1748047531000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>In vivo<\/i>\n                  CRISPR screening identifies\n                  <i>NF1\/RASA1\/TP53<\/i>\n                  co-mutations and downstream MEK signaling as a common key mechanism of sinonasal tumorigenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9396-1120","authenticated-orcid":false,"given":"Kenny","family":"Vu","sequence":"first","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sreenivasulu","family":"Gunti","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramya","family":"Viswanathan","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjali","family":"Nandal","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riley","family":"Larkin","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"},{"name":"Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center; Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sungwoo","family":"Cho","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Zou","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shivani","family":"Ramolia","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin T.K.","family":"Hoke","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"},{"name":"Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center; Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siani M.","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Sinonasal and Skull Base Tumor Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary L.","family":"Gallia","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; Baltimore, MD, USA"},{"name":"Department of Neurosurgery, Johns Hopkins University School of Medicine; Baltimore, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa M.","family":"Rooper","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charalampos S.","family":"Floudas","sequence":"additional","affiliation":[{"name":"Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Cheng","sequence":"additional","affiliation":[{"name":"National Institute of Deafness and Other Communication Disorders, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine N.","family":"Miller","sequence":"additional","affiliation":[{"name":"Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research; Frederick, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary R.","family":"Guest","sequence":"additional","affiliation":[{"name":"Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research; Frederick, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Notaro","sequence":"additional","affiliation":[{"name":"enGene Statistics GmbH, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arati","family":"Raziuddin","sequence":"additional","affiliation":[{"name":"Genomics Technology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonghe","family":"Sun","sequence":"additional","affiliation":[{"name":"Genomics Technology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolin","family":"Wu","sequence":"additional","affiliation":[{"name":"Genomics Technology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farhoud","family":"Faraji","sequence":"additional","affiliation":[{"name":"Division of Surgery, Division of Otolaryngology \u2013 Head and Neck Surgery, University of California San Diego Health; La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt","family":"Lechner","sequence":"additional","affiliation":[{"name":"Division of Surgery and Interventional Science, University College London; London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Comoglio","sequence":"additional","affiliation":[{"name":"enGene Statistics GmbH, Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elijah F.","family":"Edmondson","sequence":"additional","affiliation":[{"name":"Molecular Histopathology Core, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research; 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