| Added by | tchardes |
|---|---|
| Group name | EquipeELC |
| Item Type | Journal Article |
| Title | A Feed-Forward Mechanosignaling Loop Confers Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutant Melanoma |
| Creator | Girard et al. |
| Author | Christophe A. Girard |
| Author | Margaux Lecacheur |
| Author | Rania Ben Jouira |
| Author | Ilona Berestjuk |
| Author | Serena Diazzi |
| Author | Aude Mallavialle |
| Author | Frédéric Larbret |
| Author | Maéva Gesson |
| Author | Sébastien Schaub |
| Author | Sabrina Pisano |
| Author | Stéphane Audebert |
| Author | Bernard Mari |
| Author | Cédric Gaggioli |
| Author | Eleonora Leucci |
| Author | Jean-Christophe Marine |
| Author | Marcel Deckert |
| Author | Sophie Tartare-Deckert |
| Abstract | Aberrant extracellular matrix (ECM) deposition and stiffening is a physical hallmark of several solid cancers and is associated with therapy failure. BRAF-mutant melanomas treated with BRAF and MEK inhibitors almost invariably develop resistance that is frequently associated with transcriptional reprogramming and a de-differentiated cell state. Melanoma cells secrete their own ECM proteins, an event that is promoted by oncogenic BRAF inhibition. Yet, the contribution of cancer cell-derived ECM and tumor mechanics to drug adaptation and therapy resistance remains poorly understood. Here, we show that melanoma cells can adapt to targeted therapies through a mechanosignaling loop involving the autocrine remodeling of a drug-protective ECM. Analyses revealed that therapy-resistant cells associated with a mesenchymal dedifferentiated state displayed elevated responsiveness to collagen stiffening and force-mediated ECM remodeling through activation of actin-dependent mechanosensors Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF). Short-term inhibition of MAPK pathway also induced mechanosignaling associated with deposition and remodeling of an aligned fibrillar matrix. This provided a favored ECM reorganization that promoted tolerance to BRAF inhibition in a YAP- and MRTF-dependent manner. Matrix remodeling and tumor stiffening were also observed in vivo upon exposure of BRAF-mutant melanoma cell lines or patient-derived xenograft models to MAPK pathway inhibition. Importantly, pharmacologic targeting of YAP reversed treatment-induced excessive collagen deposition, leading to enhancement of BRAF inhibitor efficacy. We conclude that MAPK pathway targeting therapies mechanically reprogram melanoma cells to confer a drug-protective matrix environment. Preventing melanoma cell mechanical reprogramming might be a promising therapeutic strategy for patients on targeted therapies. SIGNIFICANCE: These findings reveal a biomechanical adaptation of melanoma cells to oncogenic BRAF pathway inhibition, which fuels a YAP/MRTF-dependent feed-forward loop associated with tumor stiffening, mechanosensing, and therapy resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/1927/F1.large.jpg. |
| Publication | Cancer Research |
| Volume | 80 |
| Issue | 10 |
| Pages | 1927-1941 |
| Date | 2020-05-15 |
| Journal Abbr | Cancer Res |
| Language | eng |
| DOI | 10.1158/0008-5472.CAN-19-2914 |
| ISSN | 1538-7445 |
| Library Catalog | PubMed |
| Extra | PMID: 32179513 |
| Tags | Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, MAP Kinase Signaling System, Melanoma, Mice, Mice, Nude, Mutation, original, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Tumor Microenvironment, Xenograft Model Antitumor Assays |
| Date Added | 2021/03/19 - 17:03:11 |
| Date Modified | 2021/03/19 - 17:21:11 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
Institut de Recherche en Cancérologie de
