title: PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.
abstract: Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ), which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12), while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11). Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without the need for large-scale immunostaining experiments.
authors.affiliation: Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America.|Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Kartha
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Stawski
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Haines
authors.affiliation: Division of Oral Pathology, Boston University School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Gallagher
authors.affiliation: Division of Oral Pathology, Boston University School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Vikki
authors.initials: V
authors.lastname: Noonan
authors.affiliation: Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Kukuruzinska
authors.affiliation: Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000235:genetics; D030561:Databases, Nucleic Acid; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology*; D012334:RNA, Neoplasm / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C000601279:COL1A2 protein, human; C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D012334:RNA, Neoplasm; C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta