NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress
Yi Xu, Michael H. Nipper, Angel A. Dominguez, Chenhui He, Francis E. Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang
Yi Xu, Michael H. Nipper, Angel A. Dominguez, Chenhui He, Francis E. Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang
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Research Article Gastroenterology Genetics Oncology

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

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.

Authors

Yi Xu, Michael H. Nipper, Angel A. Dominguez, Chenhui He, Francis E. Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang

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Figure 2

Loss of NF2 facilitates aggressive progression of acinar-derived human PDAC.

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Loss of NF2 facilitates aggressive progression of acinar-derived human P...
(A) Kaplan-Meier plots of TCGA PDAC patients (all 149 patients, 84 classical PDAC patients, 65 basal PDAC patients, respectively) separated by median NF2 expression level. (B) Western blot of NF2 expression in KPT and KPTN organoids derived from 4 independent cultures. (C) Representative images of xenograft tumors harvested from NSG mice transplanted with KPT or KPTN organoids derived from 4 independent cultures. The numbers of tumor formed and the total number of transplantations are indicated. Quantification of tumor size. Data represent the SD. *P < 0.05, **P < 0.01, and ***P < 0.001, between 2 genotypes, by 2-tailed Student’s t test. (D) Representative H&E-stained and Alcian blue staining of tumor tissues as shown in C (n = 13 KPT tumors, n = 21 KPTN tumors). Scale bars: 100 μm and 25 μm (inset). (E) Representative immunofluorescence staining of the indicated proteins from tumor tissues as shown in C (n = 13 KPT tumors, n = 21 KPTN tumors). Cell nuclei were counterstained with DAPI. Scale bars: 50 μm.