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CANCERDISCOVERY CONTENTS
ii | CANCER DISCOVERY�AUGUST 2016 www.aacrjournals.org
AUGUST 2016 ≠ VOLUME 6 ≠ NUMBER 8
M.P. De Macedo, J.L. Austin-Breneman, H. Jiang, Q. Chang, S.M. Reddy, W.-S. Chen, M.T. Tetzlaff, R.J. Broaddus, M.A. Davies, J.E. Gershenwald, L. Haydu, A.J. Lazar, S.P. Patel, P. Hwu, W.-J. Hwu, A. Diab, I.C. Glitza, S.E. Woodman, L.M. Vence, I.I. Wistuba, R.N. Amaria , L.N. Kwong, V. Prieto, R.E. Davis, W. Ma, W.W. Overwijk, A.H. Sharpe, J. Hu, P.A. Futreal, J. Blando, P. Sharma, J.P. Allison, L. Chin, and J.A. Wargo
Précis: Adaptive immune profi les in
early on-treatment tumor biopsies are
predictive of response and identify
potential mechanisms of resistance to
CTLA4/PD-1 blockade.
See commentary, p. 818
High-Level Clonal FGFR Amplifi cation and Response to FGFR Inhibition in a Translational Clinical Trial . . . . . . . . . 838
A. Pearson, E. Smyth, I.S. Babina, M.T. Herrera-Abreu, N. Tarazona, C. Peckitt, E. Kilgour, N.R. Smith, C. Geh, C. Rooney, R. Cutts, J. Campbell, J. Ning, K. Fenwick, A. Swain, G. Brown, S. Chua, A. Thomas,S.R.D. Johnston, M. Ajaz, K. Sumpter, A. Gillbanks, D. Watkins, I. Chau, S. Popat, D. Cunningham, and N.C. Turner
Précis: Tumors with high copy-number
FGFR2 amplifi cation exhibit oncogene
addiction with dependence on FGFR-
mediated PI3K–AKT signaling, creating
sensitivity to FGFR inhibition.
Obesity-Induced Infl ammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy . . . . . . . . . . . . . . .852
J. Incio, H. Liu, P. Suboj, S.M. Chin, I.X. Chen, M. Pinter, M.R. Ng, H.T. Nia, J. Grahovac, S. Kao, S. Babykutty, Y. Huang, K. Jung, N.N. Rahbari, X. Han, V.P. Chauhan, J.D. Martin, J. Kahn, P. Huang, V. Desphande, J. Michaelson, T.P. Michelakos, C.R. Ferrone, R. Soares, Y. Boucher, D. Fukumura, and R.K. Jain
Précis: Obesity promotes PDAC growth and
chemoresistance via a proinfl ammatory,
profi brotic mechanism that may be reversed
by angiotensin-II type-1 receptor blockade.
See commentary, p. 821
RESEARCHARTICLES
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 803
Important news stories affecting the community . . . . . . . . . . 808
Reconstituting the Human Immune System . . . . . . . . . . . . . . . . 812
Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . . 813
For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
In The Spotlight
Checkpoint Immunotherapy: Picking a Winner . . . . . . . . . . . . . . . 818
M.W.L. Teng, R. Khanna, and M.J. Smyth
See article, p. 827
Adipocytes and Neutrophils Give a Helping Hand to Pancreatic Cancers . . . . . . . . . . . . 821
V. Bronte and G. Tortora
See article, p. 852
Genomic Amplifi cations Cause False Positives in CRISPR Screens . . . . 824
A. Sheel and W. Xue
See article, p. 900
See article, p. 914
Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade . . . . . . . . . . 827
P.-L. Chen, W. Roh, A. Reuben, Z.A. Cooper,C.N. Spencer, P.A. Prieto, J.P. Miller, R.L. Bassett, V. Gopalakrishnan, K. Wani,
IN THIS ISSUE
NEWSIN BRIEF
NEWSIN DEPTH
RESEARCH WATCH
ONLINE
VIEWS
RESEARCHBRIEF
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AUGUST 2016�CANCER DISCOVERY | iii
Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression . . . 870
M.M. Kaneda, P. Cappello, A.V. Nguyen, N. Ralainirina, C.R. Hardamon, P. Foubert, M.C. Schmid, P. Sun, E. Mose, M. Bouvet, A.M. Lowy, M.A. Valasek, R. Sasik, F. Novelli, E. Hirsch, and J.A. Varner
Précis: Inhibition of PI3Kγ expressed by tumor-
associated macrophages restores antitumor
CD8+ T-cell responses and suppresses pancreatic
cancer growth and metastasis in mice.
GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer . . . . . . . . . 886
M. Waghray, M. Yalamanchili, M. Dziubinski, M. Zeinali, M. Erkkinen, H. Yang, K.A. Schradle, S. Urs, M. Pasca Di Magliano, T.H. Welling, P.L. Palmbos, E.V. Abel, V. Sahai, S. Nagrath, L. Wang, and D.M. Simeone
Précis: Expression of GM-CSF by cancer-associated
mesenchymal stem cells promotes pancreatic ductal
adenocarcinoma growth and metastasis.
CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplifi ed Genomic Regions . . . . . . . . . . 900
D.M. Munoz, P.J. Cassiani, L. Li, E. Billy, J.M. Korn, M.D. Jones, J. Golji, D.A. Ruddy, K. Yu, G. McAllister,
A. DeWeck, D. Abramowski, J. Wan, M.D. Shirley, S.Y. Neshat, D. Rakiec, R. de Beaumont, O. Weber,A. Kauffmann, E.R. McDonald III, N. Keen, F. Hofmann, W.R. Sellers, T. Schmelzle, F. Stegmeier, and M.R. Schlabach
Précis: CRISPR/Cas9-based screens identify
more essential cancer genes than RNAi-based
screens, including false-positive hits in targeted
regions with genomic amplifi cations.
See commentary, p. 824
See related article, p. 914
Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting . . . . . . . . . . . . . . 914
A.J. Aguirre, R.M. Meyers, B.A. Weir, F. Vazquez, C.-Z. Zhang, U. Ben-David, A. Cook, G. Ha, W.F. Harrington, M.B. Doshi, M. Kost-Alimova, S. Gill, H. Xu, L.D. Ali, G. Jiang, S. Pantel, Y. Lee, A. Goodale, A.D. Cherniack, C. Oh, G. Kryukov, G.S. Cowley, L.A. Garraway, K. Stegmaier, C.W. Roberts, T.R. Golub, M. Meyerson, D.E. Root, A. Tsherniak, and W.C. Hahn
Précis: CRISPR/Cas9 targeting reduces cancer cell
proliferation and survival in a gene-independent
manner based on target loci copy number.
See commentary, p. 824
See related article, p. 900
Pearson and colleagues performed a translational clinical trial in which
patients with FGFR alterations were treated with the pan-FGFR inhibitor
AZD4547. Responses occurred in 12.5% of patients with FGFR1-amplified
breast cancer, and 33% patients with FGFR2-amplified gastroesophageal
cancer. High-level, but not low-level, copy-number amplification of FGFR2
was associated with response to AZD4547, and was detectable in the plasma
DNA of responding patients. FGFR1- and FGFR2-amplified cells both exhibited
oncogene addiction with dependence on MAPK signaling, and high-level FGFR2-
amplified cells also exhibited a unique dependence on FGFR-mediated PI3K–AKT
signaling. These findings indicate that FGFR inhibitors may be more effective in tu-
mors with high-level FGFR amplification and may guide clinical development of in-
hibitors targeting FGFR or other amplified receptor tyrosine kinases. For details,
please see the article by Pearson and colleagues on page 838.
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2016;6:OF13-929. Cancer Discov 6 (8)
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