Proteomics,Multiomics

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Carcinoma-associated fibroblasts stimulate cancer cell invasion by mechanically remodeling the basement membrane


ABSTRACT: The first step in metastasis is dissemination of tumor cells into the surrounding tissue, or stroma. In carcinomas, cancers of epithelial origin, tumor cells must first breach the basement membrane (BM), a network that encapsulates the tumor. As tumor progresses, other cell types that reside in the stroma, such as carcinoma-associated fibroblasts (CAFs) accumulate around the tumor. Whether CAFs can help cancer cells to breach the BM remains an open question. Here we show that CAFs promote cancer cell invasion by physically remodeling the BM. Using a novel 3D in vitro model we observed that primary CAFs isolated from colon cancer patients stimulate cancer cell invasion through a native mesenteric BM. This stimulated invasion is the result of the physical presence of CAFs rather than an increased invasive potential of cancer cells. In the presence of CAFs, cancer cells can invade the BM in a matrix metalloproteinase-independent manner. Using live imaging, we found that CAFs actively pull and stretch the BM, leading to the formation of gaps through which cancer cells can migrate. Notably, CAF-mediated gap-widening is independent of proteolysis but relies on actomyosin contractility. We propose that CAFs exert mechanical forces that alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion.

OTHER RELATED OMICS DATASETS IN: PRJNA314489

INSTRUMENT(S): LTQ Orbitrap, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell

SUBMITTER: Guillaume Arras  

LAB HEAD: Damarys Loew

PROVIDER: PXD003670 | Pride | 2017-09-18

REPOSITORIES: Pride

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Publications


At the stage of carcinoma in situ, the basement membrane (BM) segregates tumor cells from the stroma. This barrier must be breached to allow dissemination of the tumor cells to adjacent tissues. Cancer cells can perforate the BM using proteolysis; however, whether stromal cells play a role in this process remains unknown. Here we show that an abundant stromal cell population, cancer-associated fibroblasts (CAFs), promote cancer cell invasion through the BM. CAFs facilitate the breaching of the B  ...[more]

Publication: 1/2

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