Neurofibromin Deficiency and Extracellular Matrix Cooperate to Increase Transforming Potential through FAK-Dependent Signaling
| Autor: | Sandra Giustini, Vincent M Riccardi, Alberto Gambalunga, Anna Stocco, Andrea Rasola, Franco Bassetto, Amedeo Ferlosio, Martina Grigatti, Gianluca Tadini, Andrea Errico, Debora Garozzo, Andrea Trevisan, Federica Chiara, Stefano Ferraresi |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Stromal cell extracellular matrix Settore MED/08 neurofibromatosis type 1 Article Extracellular matrix Focal adhesion 03 medical and health sciences 0302 clinical medicine Protein kinase B RC254-282 FAK MEK inhibitor Neurofibromatosis type 1 Tumor therapy biology Chemistry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neurofibromin 1 Cell biology 030104 developmental biology Oncology 030220 oncology & carcinogenesis tumor therapy biology.protein Signal transduction |
| Zdroj: | Cancers Volume 13 Issue 10 Cancers, Vol 13, Iss 2329, p 2329 (2021) |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Neurofibromatosis type 1 is a genetic disease that predisposes to tumors of the nervous system, primarily the neurofibroma. Plexiform neurofibromas (Pnfs) are of the greatest concern because of location, size, and frequent progression to malignancy. Although research is making great progress, the lack of in-depth understanding of the molecular mechanisms driving neoplastic progression results in the absence of prognostic indicators and therapeutic targets. We document that cell–cell cooperativity and the dynamics of the extracellular matrix play important roles in the growth and transformation of Pnf cells, directly through the cooperation of RAS and focal adhesion kinase (FAK) signaling. In turn, we found that treatment of Pnf cells with both MEK and FAK inhibitors is effective in abolishing the transforming ability of these cells. Abstract Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/− milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell–cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM. |
| Databáze: | OpenAIRE |
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