NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress

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Abstract
Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. 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 ( NF2 ) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 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 NF2 loss was associated with fibroblast heterogeneity and cancer-stroma communication in tumor evolution. These findings establish NF2 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.
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Funding Information
  • Cancer Prevention and Research Institute of Texas (R1219)
  • Instituto Nacional de Cancerología (R21 CA218968)
  • Instituto Nacional de Cancerología (R01 CA237159)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK110361)
  • William and Ella Owens Medical Research Foundation (N.A.)

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