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A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth
Published on: December 22, 2020
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Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition
Delphine Morales1, Pascale Vigneron1, Ines Ferreira1
1Université de Technologie de Compiègne, CNRS, Biomechanics and Bioengineering, Centre de Recherche Royallieu-CS 60 319, CEDEX, 60203 Compiègne, France.
Cancers
|October 13, 2021
Summary
Melanoma cell sensitivity to targeted drugs is influenced by the tumor microenvironment. Three-dimensional (3D) models reveal how cancer-associated fibroblasts impact drug effectiveness, crucial for preclinical studies.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Melanoma cell sensitivity to targeted therapies is modulated by the tumor microenvironment.
- Three-dimensional (3D) in vitro coculture systems offer a more accurate representation of tissue architecture and cellular interactions than traditional 2D cultures.
- Understanding these interactions is vital for optimizing drug efficacy in melanoma treatment.
Purpose of the Study:
- To investigate the influence of the tumor microenvironment, specifically fibroblasts, on the sensitivity of metastatic melanoma (MM) cells to targeted therapy.
- To compare the efficacy of a BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) combination in 2D versus 3D coculture systems.
- To evaluate the differential effects of healthy dermal fibroblasts and cancer-associated fibroblasts (CAFs) on MM cell response to treatment.
Main Methods:
- Metastatic melanoma cells (BRAF V600E mutant and BRAF wild-type) were cultured in 2D monolayers and 3D cocultures with dermal equivalents containing fibroblasts.
- Cells were treated with a combination of vemurafenib (BRAFi) and cobimetinib (MEKi).
- Conditioned media from healthy fibroblasts and CAFs were used to assess their impact on MM cell drug sensitivity.
Main Results:
- The BRAFi/MEKi drug combination effectively inhibited proliferation and survival in both 2D and 3D MM cultures, irrespective of BRAF mutation status.
- Both 2D and 3D cancer-associated fibroblasts demonstrated sensitivity to the targeted therapy.
- Supernatants from healthy fibroblasts enhanced drug efficacy on MM cells, whereas supernatants from CAFs promoted cell survival.
Conclusions:
- Fibroblast secretory profiles significantly influence metastatic melanoma cell sensitivity to combined BRAFi and MEKi treatment.
- The study underscores the importance of 3D in vitro coculture models that incorporate cancer-associated fibroblasts for accurate preclinical drug evaluation.
- Complex crosstalk between melanoma and CAFs must be considered in the development of targeted therapies.
