Collagen abundance controls melanoma phenotypes through lineage-specific microenvironment sensing
Zsofia Miskolczi1, Michael P Smith1, Emily J Rowling1
1Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, School of Medical Sciences, Division of Cancer Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
Oncogene
|March 17, 2018
Summary
Collagen stiffness drives melanoma cell differentiation via a YAP/PAX3/MITF pathway. This study uncovers complex YAP signaling in the tumor microenvironment and identifies biomarkers predicting poor melanoma survival.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Metastatic melanoma often exhibits a differentiated, pigmented phenotype, contrasting with the typical focus on dedifferentiation.
- The switch between differentiated and dedifferentiated states in melanoma is poorly understood, particularly the control mechanisms for differentiation.
Purpose of the Study:
- To investigate the role of collagen in regulating melanoma cell differentiation.
- To elucidate the molecular pathways involved in collagen-induced melanoma differentiation.
- To explore the complex function of YAP signaling in the tumor microenvironment and its impact on melanoma prognosis.
Main Methods:
- Investigated the effect of collagen stiffness on melanoma cell differentiation.
- Analyzed the YAP/PAX3/MITF signaling axis.
- Examined patient datasets to correlate collagen abundance, YAP localization, and gene expression with patient survival.
- Studied the influence of fibroblasts and TGF-β on YAP signaling.
Main Results:
- Collagen stiffness induces melanoma differentiation through a YAP/PAX3/MITF axis.
- Increased collagen correlates with nuclear YAP localization in melanoma patients.
- Tumor microenvironment complexity: fibroblasts and TGF-β modulate YAP signaling, promoting either differentiation or dedifferentiation.
- High collagen expression combined with MITF target gene expression (TRPM1, TYR, TYRP1, CDK4) indicates the worst patient prognosis.
Conclusions:
- Revealed a novel lineage-specific YAP signaling pathway regulating melanoma pigmentation.
- Identified collagen as a key regulator of melanoma cell differentiation.
- Uncovered potential biomarkers (collagen, MITF target genes) predictive of poor survival in melanoma patients.
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