title: Stromal-Based Signatures for the Classification of Gastric Cancer.
abstract: Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Uhlik
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Falcon
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
authors.forename: Seema
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Julie
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
authors.forename: Hilal
authors.initials: H
authors.lastname: Celikkaya
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
authors.forename: Marguerita
authors.initials: M
authors.lastname: O'Mahony
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sevinsky
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Christina
authors.initials: C
authors.lastname: Lowes
authors.affiliation: Department of Pathology, Wood Hudson Medical Center, Covington, Kentucky.
authors.forename: Larry
authors.initials: L
authors.lastname: Douglass
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Diane
authors.initials: D
authors.lastname: Bodenmiller
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Chintharlapalli
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fischl
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
authors.forename: Damien
authors.initials: D
authors.lastname: Gerald
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xue
authors.affiliation: Department of Hematology-Oncology, Samsung Medical Center, Seoul, Seoul Korea.
authors.forename: Jee-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Alberto
authors.initials: A
authors.lastname: Santamaria-Pang
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Kofahi
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Sui
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Keyur
authors.initials: K
authors.lastname: Desai
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Thompson
authors.initials: T
authors.lastname: Doman
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Amit
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Department of Pathology, Wood Hudson Medical Center, Covington, Kentucky.
authors.forename: Julia H
authors.initials: JH
authors.lastname: Carter
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.affiliation: Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shou-Ching
authors.initials: SC
authors.lastname: Jaminet
authors.affiliation: General Electric Global Research Center, Niskayuna, New York.
authors.forename: Fiona
authors.initials: F
authors.lastname: Ginty
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Nasir
authors.affiliation: Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Nagy
authors.affiliation: Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Harold F
authors.initials: HF
authors.lastname: Dvorak
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, New York, New York. lbenjami@mac.com.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D064593:Heterografts; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000145:classification* / Q000235:genetics*; D046888:Tissue Array Analysis; D059467:Transcriptome / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A