Détails de la réservation
- Le : 2 February 2018
- De : 10 h 30
- à : 11 h 30
- Salle : Salle de conférence
Détails de l'évènement
Gertraud Orend
INSERM U1109 – MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy,
Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), France
“The extracellular matrix molecule tenascin-C promotes metastasis by several stromal and tumor cell autonomous mechanisms”
Résumé
The extracellular matrix molecule tenascin-C is highly expressed in cancer tissue where its abundance correlates with metastasis and worsened patient survival (1). We had developed the first stochastic tumor model with abundant and no tenascin-C, and demonstrated that tenascin-C promotes lung metastasis and multiple steps on the road to metastasis such as survival, migration, the angiogenic switch and non-productive angiogenesis through Wnt signaling employing repression of the Wnt signaling inhibitor Dickkopf 1 (2, 3). Tenascin-C may impact on tumor and stromal cells residing in so called tenascin-C matrix tracks in an autocrine (4) as well as paracrine manner (5).
Metastasis is a major cause of death in patients with cancer, and a better knowledge of the molecular mechanisms underlying metastasis may improve patient survival. Vascular invasions are prognostic factors for tumor metastasis, however the cellular and molecular organization of vascular invasions is not well characterised, nor is it clear how these features drive metastasis. We defined a universal cellular anatomy of vascular invasions and identify tenascin-C as a key component of these blood vessel invasions in cancer. We also demonstrate in a transgenic murine MMTV-NeuNT model of metastasis, engineered to control tenascin-C expression levels, that tenascin-C promotes endothelialization of vascular invasions, tumor cell survival, and dissemination of circulating tumor cells into lung parenchyma. We further show that tenascin-C induces epithelial-to-mesenchymal transition through TGF-b signaling promoting migration and survival (Sun et al., submitted).
Tenascin-C can also trigger tumor cell-autonomous signaling mechanisms explaining how tenascin-C promotes cancer cell migration. We demonstrate that as soon as tenascin-C is expressed it has an impact on tumor cell behaviour. In a murine xenograft model of advanced human osteosarcoma we demonstrated that tenascin-C and its receptor integrin α9β1 are essential for lung metastasis of tumor cells. We determined that activation of this pathway reduces tumor cell-autonomous expression of target genes for the transcription factor YAP and promoted amoeboid-like migration of cancer cells. This action of tenascin-C might have significance for cancer patients as in clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact (6).
Taken together, our results illuminate how tenascin-C in the tumor microenvironment promotes stromal and tumor cell autonomous effects thus promoting survival, angiogenesis, invasive migration and metastatic progression in a tumor and context dependent manner.
Invitation Andreas Bikfalvi
Responsable
- Nom : Rocher Virginie