School of Medicine Publications and Presentations
Document Type
Article
Publication Date
11-8-2022
Abstract
A long-standing question in the pancreatic ductal adenocarcinoma (PDAC) field has been whether alternative genetic alterations could substitute for oncogenic KRAS mutations in initiating malignancy. Here, we report that Neurofibromin1 (NF1) inactivation can bypass the requirement of mutant KRAS for PDAC pathogenesis. An in-depth analysis of PDAC databases reveals various genetic alterations in the NF1 locus, including nonsense mutations, which occur predominantly in tumors with wild-type KRAS. Genetic experiments demonstrate that NF1 ablation culminates in acinar-to-ductal metaplasia, an early step in PDAC. Furthermore, NF1 haploinsufficiency results in a dramatic acceleration of KrasG12D-driven PDAC. Finally, we show an association between NF1 and p53 that is orchestrated by PML, and mosaic analysis with double markers demonstrates that concomitant inactivation of NF1 and Trp53 is sufficient to trigger full-blown PDAC. Together, these findings open up an exploratory framework for apprehending the mechanistic paradigms of PDAC with normal KRAS, for which no effective therapy is available.
Recommended Citation
Ramakrishnan, G., Parajuli, P., Singh, P., Friend, C., Hurwitz, E., Prunier, C., Razzaque, M. S., Xu, K., & Atfi, A. (2022). NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma. Cell reports, 41(6), 111623. https://doi.org/10.1016/j.celrep.2022.111623
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Publication Title
Cell Reports
DOI
https://doi.org/10.1016/j.celrep.2022.111623
Academic Level
faculty
Mentor/PI Department
Medical Education
Comments
Copyright 2022 The Author(s).This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).