TY - JOUR
T1 - Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer
AU - Green, Darrell
AU - Eyre, Heather
AU - Singh, Archana
AU - Taylor, Jessica T.
AU - Chu, Jason
AU - Jeys, Lee
AU - Sumathi, Vaiyapuri
AU - Coonar, Aman
AU - Rassl, Doris
AU - Babur, Muhammad
AU - Forster, Duncan
AU - Alzabin, Saba
AU - Ponthan, Frida
AU - McMahon, Adam
AU - Bigger, Brian
AU - Reekie, Tristan
AU - Kassiou, Michael
AU - Williams, Kaye
AU - Dalmay, Tamas
AU - Fraser, William D.
AU - Finegan, Katherine G.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/8/13
Y1 - 2020/8/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087824309&partnerID=8YFLogxK
U2 - 10.1038/s41388-020-1379-0
DO - 10.1038/s41388-020-1379-0
M3 - Article
C2 - 32655131
AN - SCOPUS:85087824309
SN - 0950-9232
VL - 39
SP - 5553
EP - 5569
JO - Oncogene
JF - Oncogene
IS - 33
ER -