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

Orgaz, José L.; Crosas‐Molist, Eva; Sadok, Amine; Perdrix-Rosell, Anna; Maiques, Óscar; Rodríguez-Hernández, Irene; Monger, Jo; Mele, Silvia; Georgouli, Mirella; Bridgeman, Victoria L.; Karagiannis, Panagiotis; Lee, Rebecca; Pandya, Pahini; Boehme, Lena; Wållberg, Fredrik; Tape, Christopher J.; Karagiannis, Sophia N.; Malanchi, Ilaria; Sanz-Moreno, Victoria

doi:10.1016/j.ccell.2019.12.003

Cited by 110 publications

(185 citation statements)

References 97 publications

(192 reference statements)

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“…2a ). Of note, we also found that amoeboid cells express genes from NC and invasive signatures associated with drug resistance 4 , 24 (Figs. 1 a, 2a ).…”

Section: Resultsmentioning

confidence: 52%

“…We next investigated in vitro self-renewal capacity of melanoma cells in low adherent conditions. We introduced another pair of melanoma cell lines, WM983B (metastatic, rounded-amoeboid and high Myosin II) and WM983A (primary tumour, elongated and low Myosin II) 15 , 24 derived from the same patient. Using these two models, we performed serial sphere passages of elongated melanoma cells with low levels of Myosin II 12 , 15 , 24 (A375P and WM983A) (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

et al. 2020

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Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.

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“…2a ). Of note, we also found that amoeboid cells express genes from NC and invasive signatures associated with drug resistance 4 , 24 (Figs. 1 a, 2a ).…”

Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

et al. 2020

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“…Orgaz and colleagues have recently demonstrated the role of ROCK inhibition in acquired resistance to both targeted and immune therapy (Orgaz et al, 2020). Our data demonstrate that the Rho-ROCK-myosin axis is differentially activated depending on MITF levels.…”

Section: Discussionsupporting

confidence: 50%

“…Dysregulation of Rho-ROCK-myosin signaling has been extensively linked to cancer (Chin et al, 2015;Martino et al, 2018;Morgan-Fisher et al, 2013). Recently, Rho-ROCK-myosin signaling has been shown to play a central role in melanoma acquired therapy resistance (Orgaz et al, 2020). Furthermore, this mechanism is known to influence spheroid architecture and compaction (Napolitano et al, 2007;Sodek et al, 2009;Tzanakakis et al, 2001).…”

Section: Rock Inhibition Phenocopies the Effects Of High Mitf Levels mentioning

confidence: 99%

Phenotypic melanoma heterogeneity is regulated through cell-matrix interaction-dependent changes in tumor microarchitecture

Spoerri

Tonnessen-Murray

Gunasingh

et al. 2020

Preprint

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Phenotypic and functional cancer cell heterogeneity limits the efficacy of targeted and immuno-therapies. The transcription factor MITF is known to regulate melanoma cell plasticity and, consequently, response to drugs. However, the underlying mechanisms of this phenomenon remain incompletely understood. Here, we show that MITF levels control functional melanoma cell heterogeneity by fine-tuning the ability to contract the extracellular matrix, the maturation of focal adhesions and ROCK-mediated melanoma cell contractility.Modulation of MITF expression alters extracellular matrix organization, melanoma cell morphology and solid stress in three-dimensional melanoma spheroids, thereby accounting for spatial differences in cell cycle dynamics. Together, our data identify MITF as a master regulator of the melanoma micro-architecture and point towards novel targeting strategies for cancer cell heterogeneity.Significance. Development of drug resistance is a major cause of melanoma therapy failure.The role of MITF in melanoma response to therapy has been discussed controversially, which can be explained, at least in part, through the rheostat model linking MITF activity to cell proliferation. Heterogeneity is widely associated with therapy resistance, however, whether cell phenotype switching, mediated by MITF, is responsible for treatment resistance is not known. Our findings provide an in-depth mechanistic understanding of the MITF-mediated regulation of cell cycle behavior and physical regulation of the tumor architecture. As MITF is not amenable to direct drug targeting, the identification of mediators of MITF-triggered functional heterogeneity reveals novel targets that can be deployed to control this phenomenon.

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“…6,7 Therefore, in our latest study, we assessed if Myosin II and cytoskeletal remodeling could play a role in therapy-cross-resistance. 8 Rho GTPase signaling and cytoskeletal remodeling were top enriched processes in the phospho-proteome of melanoma cells after a 24 h treatment of melanoma cells with MAPKi. MAPK inhibition decreased Myosin II activity (p-MLC2 levels), regardless of genetic background (BRAF mutant, BRAF mutant/ PTEN-null, NRAS mutant).…”

mentioning

confidence: 97%

What does not kill you makes you stronger: surviving anti-cancer therapies by cytoskeletal remodeling and Myosin II reactivation

Sanz-Moreno

2020

Molecular & Cellular Oncology

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Myosin II and its regulator Rho-associated coiled-coil containing protein kinase (ROCK) are essential for cell invasion and metastatic dissemination. Our recent findings show that this molecular machinery is also involved in drug resistance in melanoma by playing a dual role: protection of tumor cells from reactive oxygen species (ROS) and DNA damage (intrinsic), and co-option of myeloid and lymphoid populations to establish immunosuppression (extrinsic).

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

Cited by 110 publications

References 97 publications

WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

Phenotypic melanoma heterogeneity is regulated through cell-matrix interaction-dependent changes in tumor microarchitecture

What does not kill you makes you stronger: surviving anti-cancer therapies by cytoskeletal remodeling and Myosin II reactivation

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