Open AccessEnrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin‐1
Author(s) -
Karagiannis George S.,
Berk Aaron,
Dimitromanolakis Apostolos,
Diamandis Eleftherios P.
Publication year - 2013
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2013.04.002
Subject(s) - stromal cell , biology , metastasis , cancer research , tumor progression , colorectal cancer , bone morphogenetic protein , paracrine signalling , cancer cell , tumor microenvironment , cancer , cancer associated fibroblasts , bone metastasis , carcinogenesis , cell migration , proteome , motility , cell , microbiology and biotechnology , bioinformatics , receptor , genetics , gene , tumor cells
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.