Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment

Abstract

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.

V.S.-M.’s lab was supported by Cancer Research UK (CRUK) C33043/A12065 and C33043/A24478 (V.S.-M., E.C.-M., M.G., J.L.O., and B.F.), Royal Society RG110591 (V.S.-M.), The Harry J. Lloyd Charitable Trust (J.L.O. and V.S.-M.), Barts Charity (V.S.-M., J.L.O., O.M., I.R.-H., and E.C.-M.), NIHR Biomedical Research Centre (M.G.), Fundacion Alfonso Martin Escudero and Marie Sklodowska-Curie Action (H2020-MSCA-IF-2014-EF-ST) (I.R.H.), and Fundación Ramón Areces (E.C.-M.). S.N.-K.’s lab was supported by NIHR BRC at Guy's and St Thomas' NHS Foundation Trust and King’s College London (IS-BRC-1215-20006), Breast Cancer Now (147) (S.N.-K. and K.M.I.) CRUK (C30122/A11527; C30122/A15774), the Medical Research Council (MRC) (MR/L023091/1) (S.M. and S.N.-K.), the Academy of Medical Sciences (D.H.J., and S.N.-K.), and CR UK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587) (S.N.-K.). I.M.’s lab was supported by Francis Crick Institute core funding from CRUK (FC001112), the MRC (FC001112), and the Wellcome Trust (FC001112) (I.M. and A.P.). G.O.F.’s lab was supported by CRUK (C48390/A21153) and Worldwide Cancer Research (16-1135). R.M.M. was supported by FIS (PI12/00260 and PI15/00711) and FMTV-3 (201331-31). Tumor samples were obtained with support from Xarxa Catalana de Bancs de Tumours and the Tumour Banc Platform of RTICC (PT13/0010/0014).