Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer

Research output: Contribution to journalArticle

  • External authors:
  • Darrell Green
  • Heather Eyre
  • Archana Singh
  • Jessica Taylor
  • Lee Jeys
  • Vaiyapuri P. Sumathi
  • Aman Coonar
  • Doris Rassl
  • Muhammad Babur
  • Duncan Forster
  • Saba Alzabin
  • Frida Ponthan
  • Tristan Reekie
  • Michael Kassiou
  • Tamas Dalmay
  • William D Fraser

Abstract

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 MAPK7/MMP9 signalling as a driver for primary bone cancer metastasis. RNAi 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.

Bibliographical metadata

Original languageEnglish
JournalOncogene
Publication statusAccepted/In press - 22 May 2020