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In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (\n                    <jats:italic>NF2<\/jats:italic>\n                    ) emerging as the top target. Functional validation confirmed that loss of\n                    <jats:italic>NF2<\/jats:italic>\n                    promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation.\n                    <jats:italic>NF2<\/jats:italic>\n                    inactivation was found to enhance PDAC cell fitness under nutrient starvation. This adaptation not only reinforced the oncogenic state but also conferred therapeutic resistance. Additionally, we found that\n                    <jats:italic>NF2<\/jats:italic>\n                    loss was associated with fibroblast heterogeneity and cancer-stroma communication in tumor evolution. These findings establish\n                    <jats:italic>NF2<\/jats:italic>\n                    as a critical tumor suppressor in PDAC and uncover its role in mediating nutrient adaptation and drug resistance. Importantly, this study provides additional insights into drug resistance mechanisms and potential therapeutic targets in PDAC.\n                  <\/jats:p>","DOI":"10.1172\/jci194395","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T19:01:04Z","timestamp":1767294064000},"source":"Crossref","is-referenced-by-count":6,"title":["NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress"],"prefix":"10.1172","volume":"136","author":[{"given":"Yi","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Cell Systems and Anatomy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Nipper","sequence":"additional","affiliation":[{"name":"Department of Cell Systems and Anatomy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel A.","family":"Dominguez","sequence":"additional","affiliation":[{"name":"Department of Cell Systems and 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