mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis

Siegel, 2019, Cancer statistics, 2019, CA Cancer J Clin, 69, 7, 10.3322/caac.21551 Jones, 2008, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science, 321, 1801, 10.1126/science.1164368 Guerra, 2007, Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice, Cancer Cell, 11, 291, 10.1016/j.ccr.2007.01.012 Eser, 2013, Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer, Cancer Cell, 23, 406, 10.1016/j.ccr.2013.01.023 Ardito, 2012, EGF receptor is required for KRAS-induced pancreatic tumorigenesis, Cancer Cell, 22, 304, 10.1016/j.ccr.2012.07.024 Heid, 2011, Early requirement of Rac1 in a mouse model of pancreatic cancer, Gastroenterology, 141, 719, 10.1053/j.gastro.2011.04.043 Wu, 2014, PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice, Gastroenterology, 147, 1405, 10.1053/j.gastro.2014.08.032 Innocenti, 2018, New insights into the formation and the function of lamellipodia and ruffles in mesenchymal cell migration, Cell Adh Migr, 12, 401 Messal, 2019, Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis, Nature, 566, 126, 10.1038/s41586-019-0891-2 Ma, 2008, SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs, Cell, 133, 303, 10.1016/j.cell.2008.02.031 Jacinto, 2004, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive, Nat Cell Biol, 6, 1122, 10.1038/ncb1183 Morrison, 2015, mTOR directs breast morphogenesis through the PKC-alpha-Rac1 Signaling Axis, PLoS Genet, 11, 10.1371/journal.pgen.1005291 Morrison Joly, 2017, Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis, Breast Cancer Res, 19, 74, 10.1186/s13058-017-0868-8 Driscoll, 2016, mTORC2 signaling drives the development and progression of pancreatic cancer, Cancer Res, 76, 6911, 10.1158/0008-5472.CAN-16-0810 Kong, 2016, A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling, Gut, 65, 647, 10.1136/gutjnl-2014-307616 van der Kammen, 2017, Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2, Development, 144, 4588 Benitz, 2019, Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis, Gut, 68, 2007, 10.1136/gutjnl-2018-317208 Cheng, 2019, Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment, Int J Cancer, 144, 2529, 10.1002/ijc.31981 Innocenti, 2004, Abi1 is essential for the formation and activation of a WAVE2 signalling complex, Nat Cell Biol, 6, 319, 10.1038/ncb1105 Bellizzi, 2010, The mTOR pathway is frequently activated in pancreatic ductal adenocarcinoma and chronic pancreatitis, Appl Immunohistochem Mol Morphol, 18, 442, 10.1097/PAI.0b013e3181de115b Petrov, 2010, Therapeutic implications of oxidative stress in acute and chronic pancreatitis, Curr Opin Clin Nutr Metab Care, 13, 562, 10.1097/MCO.0b013e32833b64b9 Chen, 2017, Salidroside suppressing LPS-induced myocardial injury by inhibiting ROS-mediated PI3K/Akt/mTOR pathway in vitro and in vivo, J Cell Mol Med, 21, 3178, 10.1111/jcmm.12871 Goley, 2006, The ARP2/3 complex: an actin nucleator comes of age, Nat Rev Mol Cell Biol, 7, 713, 10.1038/nrm2026 Benitz, 2016, Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells, Oncotarget, 7, 11424, 10.18632/oncotarget.6717 Kong, 2018, Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy, Gut, 67, 146, 10.1136/gutjnl-2015-310913 Shevchenko, 2006, In-gel digestion for mass spectrometric characterization of proteins and proteomes, Nat Protoc, 1, 2856, 10.1038/nprot.2006.468 Tyanova, 2016, The MaxQuant computational platform for mass spectrometry-based shotgun proteomics, Nat Protoc, 11, 2301, 10.1038/nprot.2016.136 Cox, 2011, Andromeda: a peptide search engine integrated into the MaxQuant environment, J Proteome Res, 10, 1794, 10.1021/pr101065j Tyanova, 2016, The Perseus computational platform for comprehensive analysis of (prote)omics data, Nat Methods, 13, 731, 10.1038/nmeth.3901 Orsulic, 2002, Induction of ovarian cancer by defined multiple genetic changes in a mouse model system, Cancer Cell, 1, 53, 10.1016/S1535-6108(01)00002-2 Leyton-Puig, 2016, PFA fixation enables artifact-free super-resolution imaging of the actin cytoskeleton and associated proteins, Biol Open, 5, 1001, 10.1242/bio.019570 Ilatovskaya, 2013, Arp2/3 complex inhibitors adversely affect actin cytoskeleton remodeling in the cultured murine kidney collecting duct M-1 cells, Cell Tissue Res, 354, 783, 10.1007/s00441-013-1710-y Utomo, 2014, mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma, Cancer Lett, 346, 309, 10.1016/j.canlet.2014.01.014 DeFeo-Jones, 2005, Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members, Mol Cancer Ther, 4, 271, 10.1158/1535-7163.271.4.2 Aiyar, 2000, Involvement of G protein-coupled receptor kinase-6 in desensitization of CGRP receptors, Eur J Pharmacol, 403, 1, 10.1016/S0014-2999(00)00419-2 Onesto, 2008, Characterization of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases, Methods Enzymol, 439, 111, 10.1016/S0076-6879(07)00409-0 Jo, 2012, Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death, Proc Natl Acad Sci U S A, 109, 10581, 10.1073/pnas.1202810109 Knudsen, 2019, Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer, Oncogene, 38, 3355, 10.1038/s41388-018-0650-0 Gafni, 2013, Derivation of novel human ground state naive pluripotent stem cells, Nature, 504, 282, 10.1038/nature12745