title: Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.
abstract: The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, South Yorkshire, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Bradford
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wappett
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Garry
authors.initials: G
authors.lastname: Beran
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Armelle
authors.initials: A
authors.lastname: Logie
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Oona
authors.initials: O
authors.lastname: Delpuech
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Brown
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Boros
authors.affiliation: Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Camp
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McEwen
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Gatehouse Park, Massachusetts, USA.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Mazzola
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Gatehouse Park, Massachusetts, USA.
authors.forename: Celina
authors.initials: C
authors.lastname: D'Cruz
authors.affiliation: Oncology iMED, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, UK.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor
keywords: RNA-Seq; biomarker discovery; patient-derived xenograft; pre-clinical research; tumor stroma