title: Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1.
abstract: The cancer invasion front (CIF), a spatially-recognized area due to the frequent presence of peritumoral desmoplastic reaction, represents a cancer site where many hallmarks of cancer metastasis occur. It is now strongly suggested that the desmoplastic microenvironment holds crucial information for determining tumor development and progression. Despite extensive research on tumor-host cell interactions at CIFs, the exact paracrine molecular network that is hardwired into the proteome of the stromal and cancer subpopulations remains partially understood. Here, we interrogated the signaling pathways and the molecular functional signatures across the proteome of a desmoplastic coculture model system of colorectal cancer progression. We discovered a group of bone morphogenetic protein (BMP) antagonists that coordinates major biological programs in CIFs, including cell proliferation, invasion, migration and differentiation processes. Using a mathematical model of cancer cell progression, coupled to in vitro cell migration assays, we demonstrated that the prominent BMP antagonist gremlin-1 (GREM1) may trigger motility of cancer cell cohorts. Our data collectively demonstrate that the desmoplastic CIFs deploy a microenvironmental signature, based on BMP antagonism, in order to regulate the motogenic fates of cancer cell cohorts invading the adjacent stroma.
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: George S
authors: GS
authors: Karagiannis
authors: Aaron
authors: A
authors: Berk
authors: Apostolos
authors: A
authors: Dimitromanolakis
authors: Eleftherios P
authors: EP
authors: Diamandis
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000473:pathology*; D019295:Computational Biology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008958:Models, Molecular
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: ATCC; American type culture collection; BMP(I); Bone morphogenetic protein; CAF; CIF; COL12A1; CRC; Cancer-associated fibroblasts; Colorectal cancer; DMEM; DPD; Desmoplasia; Dulbecco's modified Eagle's medium; ECM; EMT; FBS; FST; FSTL3; GO; GREM1; Gremlin-1; HGF; HTRA3; IPA; IPKB; LOX; Migration; PDGF; TGF-β; VEGF(R2); alpha-smooth muscle actin; bone morphogenetic protein (inhibitor); cancer invasion front; cancer-associated fibroblast; collagen type XII; colorectal cancer; desmoplastic protein dataset; epithelial-to-mesenchymal transition; extracellular matrix; fetal bovine serum; follistatin; follistatin-like 3; gene ontology; gremlin-1; hepatocyte growth factor; high temperature requirement A3; ingenuity pathway analysis; ingenuity pathway knowledgebase; lysine-6-oxidase; platelet-derived growth factor; transforming growth factor-beta; uPA; urokinase-type plasminogen activator; vascular endothelial growth factor (receptor-2); α-SMA
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