NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.
NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.
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DOI：
10.1016/j.celrep.2022.111623
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发表时间：
2022-11-08
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
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. Ramakrishnan et al. show that genetic inactivation of NF1 can substitute for oncogenic Kras in driving PDAC pathogenesis and progression. As such, this finding unveils a long-sought-after mechanism leading to fatal PDAC in the substantial fraction of patients with normal KRAS.
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影响因子：
64.5
作者：
Burd CE;Sorrentino JA;Clark KS;Darr DB;Krishnamurthy J;Deal AM;Bardeesy N;Castrillon DH;Beach DH;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
影响因子：
3.7
作者：
Leung L;Radulovich N;Zhu CQ;Wang D;To C;Ibrahimov E;Tsao MS
通讯作者：
Tsao MS
影响因子：
64.5
作者：
Korbel, Jan O.;Campbell, Peter J.
通讯作者：
Campbell, Peter J.