title: Systems-level modeling of cancer-fibroblast interaction.
abstract: Cancer cells interact with surrounding stromal fibroblasts during tumorigenesis, but the complex molecular rules that govern these interactions remain poorly understood thus hindering the development of therapeutic strategies to target cancer stroma. We have taken a mathematical approach to begin defining these rules by performing the first large-scale quantitative analysis of fibroblast effects on cancer cell proliferation across more than four hundred heterotypic cell line pairings. Systems-level modeling of this complex dataset using singular value decomposition revealed that normal tissue fibroblasts variably express at least two functionally distinct activities, one which reflects transcriptional programs associated with activated mesenchymal cells, that act either coordinately or at cross-purposes to modulate cancer cell proliferation. These findings suggest that quantitative approaches may prove useful for identifying organizational principles that govern complex heterotypic cell-cell interactions in cancer and other contexts.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States of America.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Wadlow
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.forename: S Aidan
authors.initials: SA
authors.lastname: Finley
authors.forename: Henry
authors.initials: H
authors.lastname: Bergquist
authors.forename: Rabi
authors.initials: R
authors.lastname: Upadhyay
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
mesh_terms: D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D008962:Models, Theoretical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D010957:Plasmids / Q000378:metabolism; D014158:Transcription, Genetic