ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer

Hashimoto Shigeru; Furukawa Shotaro; Hashimoto Ari; Tsutaho Akio; Fukao Akira; Sakamura Yurika; Parajuli Gyanu; Onodera Yasuhito; Otsuka Yutaro; Handa Haruka; Oikawa Tsukasa; Hata Soichiro; Nishikawa Yoshihiro; Mizukami Yusuke; Kodama Yuzo; Murakami Masaaki; Fujiwara Toshinobu; Hirano Satoshi; Sabe Hisataka

Title	en ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer
Creator	en Hashimoto, Shigeru en Furukawa, Shotaro en Hashimoto, Ari NRID 1000060390803 en Tsutaho, Akio en Fukao, Akira NRID 1000050733979 en Sakamura, Yurika en Parajuli, Gyanu en Onodera, Yasuhito NRID 1000090435561 en Otsuka, Yutaro en Handa, Haruka en Oikawa, Tsukasa NRID 1000020457055 en Hata, Soichiro en Nishikawa, Yoshihiro NRID 1000080802785 en Mizukami, Yusuke NRID 1000030400089 en Kodama, Yuzo en Murakami, Masaaki NRID 1000000250514 en Fujiwara, Toshinobu NRID 1000080362804 en Hirano, Satoshi NRID 1000050322813 en Sabe, Hisataka NRID 1000040187282
Accessrights	open access
Rights	https://creativecommons.org/licenses/by-nc-nd/4.0/ en Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Subject	Other en ARF6 Other en mRNA translation Other en pancreatic driver oncogenes Other en PD-L1 Other en mevalonate pathway NDC 490
Description	Abstract en Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor beta (PDGFR beta) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, elF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among elF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.
Publisher	en National Academy of Sciences.
Date	Issued2019-08-27
Language	eng
Resource Type	journal article
Version Type	VoR
Identifier	HDL http://hdl.handle.net/2115/75628
Relation	isIdenticalTo DOI https://doi.org/10.1073/pnas.1901765116 PMID 31399545
Journal	PISSN 0027-8424 en Proceedings of the National Academy of Sciences of the United States of America (PNAS) Volume Number116 Issue Number35 Page Start17450 Page End17459
File	fulltext PNAS 116(35) 17450-17459.pdf 2.7 MB (application/pdf) Issued2019-08-27
Oaidate	2023-10-07