@article{d70aae2052fc45e6b1f8976ee8b0ba48,
title = "Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein",
abstract = "KRAS is the most frequently mutated oncogene in human neoplasia. Despite a large investment to understand the effects of KRAS mutation in cancer cells, the direct effects of the oncogenetic KRAS activation on immune cells remain elusive. Here, we report that extracellular KRASG12D is essential for pancreatic tumor-associated macrophage polarization. Oxidative stress induces KRASG12D protein release from cancer cells succumbing to autophagy-dependent ferroptosis. Extracellular KRASG12D packaged into exosomes then is taken up by macrophages through an AGER-dependent mechanism. KRASG12D causes macrophages to switch to an M2-like pro-tumor phenotype via STAT3-dependent fatty acid oxidation. Consequently, the disruption of KRASG12D release and uptake can abolish the macrophage-mediated stimulation of pancreatic adenocarcinomas in mouse models. Importantly, the level of KRASG12D expression in macrophages correlates with poor survival in pancreatic cancer patients. These findings not only identify extracellular KRASG12D as a key mediator of cancer cell-macrophage communication, but also provide a novel KRAS-targeted anticancer strategy. Abbreviations: DAMP, damage-associated molecular pattern; PBMCMs, peripheral blood mononuclear cell-derived macrophages; PDAC, pancreatic ductal adenocarcinoma; s.c., subcutaneously; TAMs, tumor-associated macrophages; TME, tumor microenvironment.",
keywords = "DAMP, KRAS, autophagy, exosomes, ferroptosis, macrophage",
author = "Enyong Dai and Leng Han and Jiao Liu and Yangchun Xie and Guido Kroemer and Klionsky, {Daniel J.} and Zeh, {Herbert J.} and Rui Kang and Jing Wang and Daolin Tang",
note = "Funding Information: We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. D.T. is supported by a grant from the American Cancer Society (research scholar grant RSG-16-014-01-CDD). R.K. is supported by a grant from the U.S. National Institutes of Health (R01CA211070). D.J.K. is supported by a grant from the U.S. National Institutes of Health (R35GM131919). G.K. is supported by the Ligue contre le Cancer ({\'e}quipe labellis{\'e}e); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Canc{\'e}rop{\^o}le Ile-de-France; Chancelerie des universit{\'e}s de Paris (Legs Poix), Fondation pour la Recherche M{\'e}dicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; LabEx Immuno-Oncology; the RHU Torino Lumi{\`e}re; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). J.L. is supported by grants from the National Natural Science Foundation of China (31671435, 81400132, and 81772508). Y.X. is supported by a grant from the National Natural Science Foundation of China (81802476). J.W., L.H., and E.D. are supported by grants from the National Natural Science Foundation of China (30870355 and 81370497), Natural Science Foundation of Jilin Province in China (20160101062JC), and the Health Foundation of the Finance Department of Jilin Province in China (SCZSY201516). Publisher Copyright: {\textcopyright} 2020 Informa UK Limited, trading as Taylor & Francis Group.",
year = "2020",
month = nov,
day = "1",
doi = "10.1080/15548627.2020.1714209",
language = "English (US)",
volume = "16",
pages = "2069--2083",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "11",
}