Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
17
03
2020
accepted:
23
06
2020
revised:
24
05
2020
pubmed:
14
7
2020
medline:
15
12
2020
entrez:
14
7
2020
Statut:
ppublish
Résumé
Metastasis is the leading cause of cancer-related death. This multistage process involves contribution from both tumour cells and the tumour stroma to release metastatic cells into the circulation. Circulating tumour cells (CTCs) survive circulatory cytotoxicity, extravasate and colonise secondary sites effecting metastatic outcome. Reprogramming the transcriptomic landscape is a metastatic hallmark, but detecting underlying master regulators that drive pathological gene expression is a key challenge, especially in childhood cancer. Here we used whole tumour plus single-cell RNA-sequencing in primary bone cancer and CTCs to perform weighted gene co-expression network analysis to systematically detect coordinated changes in metastatic transcript expression. This approach with comparisons applied to data collected from cell line models, clinical samples and xenograft mouse models revealed mitogen-activated protein kinase 7/matrix metallopeptidase 9 (MAPK7/MMP9) signalling as a driver for primary bone cancer metastasis. RNA interference knockdown of MAPK7 reduces proliferation, colony formation, migration, tumour growth, macrophage residency/polarisation and lung metastasis. Parallel to these observations were reduction of activated interleukins IL1B, IL6, IL8 plus mesenchymal markers VIM and VEGF in response to MAPK7 loss. Our results implicate a newly discovered, multidimensional MAPK7/MMP9 signalling hub in primary bone cancer metastasis that is clinically actionable.
Identifiants
pubmed: 32655131
doi: 10.1038/s41388-020-1379-0
pii: 10.1038/s41388-020-1379-0
pmc: PMC7426263
doi:
Substances chimiques
MAPK7 protein, human
EC 2.7.11.24
Mitogen-Activated Protein Kinase 7
EC 2.7.11.24
Matrix Metalloproteinase 9
EC 3.4.24.35
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5553-5569Références
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