Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance

Jose L Orgaz; Eva Crosas-Molist; Amine Sadok; Anna Perdrix-Rosell; Oscar Maiques; Irene Rodriguez-Hernandez; Jo Monger; Silvia Mele; Mirella Georgouli; Victoria Bridgeman; Panagiotis Karagiannis; Rebecca Lee; Pahini Pandya; Lena Boehme; Fredrik Wallberg; Chris Tape; Sophia N Karagiannis; Ilaria Malanchi; Victoria Sanz-Moreno

doi:10.1016/j.ccell.2019.12.003

Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance

Cancer Cell. 2020 Jan 13;37(1):85-103.e9. doi: 10.1016/j.ccell.2019.12.003.

Authors

Jose L Orgaz¹, Eva Crosas-Molist², Amine Sadok³, Anna Perdrix-Rosell⁴, Oscar Maiques², Irene Rodriguez-Hernandez², Jo Monger⁵, Silvia Mele⁶, Mirella Georgouli⁷, Victoria Bridgeman⁸, Panagiotis Karagiannis⁹, Rebecca Lee¹⁰, Pahini Pandya⁷, Lena Boehme⁷, Fredrik Wallberg¹¹, Chris Tape¹², Sophia N Karagiannis⁶, Ilaria Malanchi⁸, Victoria Sanz-Moreno¹³

Affiliations

¹ Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK. Electronic address: j.orgaz@qmul.ac.uk.
² Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
³ Translational Cancer Discovery Team, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
⁴ Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK; Tumour Host Interaction, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
⁵ Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK.
⁶ St. John's Institute of Dermatology, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London SE1 9RT, UK.
⁷ Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
⁸ Tumour Host Interaction, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
⁹ St. John's Institute of Dermatology, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, London SE1 9RT, UK; Department of Oncology, Haematology and Stem Cell Transplantation, University Hospital of Hamburg Eppendorf, Hamburg 20246, Germany.
¹⁰ Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
¹¹ The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
¹² Cell Communication Lab, UCL Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK.
¹³ Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK. Electronic address: v.sanz-moreno@qmul.ac.uk.

Abstract

Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.

Keywords: MAPK; Rho-kinase; cytoskeletal remodeling; immunotherapy; melanoma therapy resistance; myosin II; phosphoproteomics and transcriptomics; regulatory T cells; transcriptional rewiring; tumor-promoting macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B7-H1 Antigen / metabolism
Cell Cycle
Cell Line, Tumor
Cytoskeleton / metabolism*
DNA Damage
Drug Resistance, Neoplasm*
Female
Humans
Immunotherapy
MAP Kinase Signaling System
Male
Melanoma / immunology
Melanoma / metabolism*
Melanoma / therapy
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Myosin Type II / metabolism*
Oxidative Stress
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins B-raf / genetics
Reactive Oxygen Species
T-Lymphocytes, Regulatory / immunology
Treatment Outcome
Tumor Microenvironment / immunology
rho-Associated Kinases / metabolism

Substances

B7-H1 Antigen
CD274 protein, human
Protein Kinase Inhibitors
Reactive Oxygen Species
Proto-Oncogene Proteins B-raf
rho-Associated Kinases
Myosin Type II

Abstract

Publication types

MeSH terms

Substances

Grants and funding