RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

Lionarons, Daniël A.; Hancock, David C.; Rana, Sareena; East, Philip; Moore, Christopher; Murillo, Miguel; Carvalho, Joana; Spencer‐Dene, Bradley; Herbert, Eleanor; Stamp, Gordon; Damry, Djamil; Calado, Dinis Pedro; Rosewell, Ian; Fritsch, Ralph; Neubig, Richard R.; Molina‐Arcas, Míriam; Downward, Julian

doi:10.1016/j.ccell.2019.05.015

Cited by 103 publications

(115 citation statements)

References 54 publications

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“…(C) Kaplan-Meier survival curves for percent survival of mice in B ( n = 10 mice per group). (D) Model showing oncogenic RAC1 P29S driven activation of MRTF, leading to increased tumorigenicity (Lionarons et al, 2019). Acta: actin family of proteins, ABPs: actin binding proteins.…”

Section: Resultsmentioning

confidence: 99%

“…While there are no reported MRTF gain-of-function mutations in human solid tumors, MRTF signaling is strongly induced by the constitutively active P29S mutant form of the small GTPase RAC1 (Fig. 4D) (Lionarons et al, 2019). RAC1 P29S and related mutations (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…RAC1 P29S and related mutations (e.g. RAC1 P29L ) are found in ~5 % of human melanomas, a particularly aggressive subset that exhibits resistance to BRAF inhibitors in the clinic (Lionarons et al, 2019; Van Allen et al, 2014; Watson et al, 2014). Using the TCGA database, we were able to corroborate a link between these mutations and the MRTF-SRF pathway in human melanoma.…”

Section: Resultsmentioning

confidence: 99%

“…The RAC1 P29S/L allele is generally associated with enhanced melanoma malignancy and resistance to targeted therapies (Lionarons et al, 2019; Van Allen et al, 2014; Watson et al, 2014), including the BRAF inhibitor vemurafenib. Our results, however, indicate that this mutation actually increases tumor responsiveness to ICB, implying that RAC1 P29S/L may be useful as a positive predictive indicator for this class of treatments.…”

Section: Discussionmentioning

confidence: 99%

“…In the steady state, MRTF isoforms are sequestered in the cytoplasm via binding to monomeric globular actin (G-actin). Cytoskeletal growth, often induced by Rho-family GTPases like RAC1, depletes this G-actin pool, liberating MRTFA and MRTFB to enter the nucleus (Gau and Roy, 2018; Gualdrini et al, 2016; Kim et al, 2017; Lionarons et al, 2019; Medjkane et al, 2009; Olson and Nordheim, 2010). Once localized in this manner, MRTFs form complexes with the DNA-binding protein serum response factor (SRF) to drive expression of more G-actin and cytoskeletal components.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Tello-Lafoz

Srpan

et al. 2020

Preprint

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33 34 Immune cells identify cancer cells by recognizing characteristic biochemical 35 features indicative of oncogenic transformation. Cancer cells have characteristic 36 mechanical features, as well, but whether these biophysical properties also contribute to 37 destruction by the immune system is not known. In the present study, we found that 38 enhanced expression of myocardin related transcription factors (MRTFs), which promote 39 migration and metastatic invasion, paradoxically compromised lung colonization by 40 melanoma and breast carcinoma cells in an immune-mediated manner. Cancer cells with 41 increased MRTF signaling were also more sensitive to immune checkpoint blockade 42 therapy in mice and humans. The basis for this vulnerability was not biochemical, but 43 biophysical. MRTF expression strengthened the actin cytoskeleton, increasing the 44 rigidity of cancer cells and thereby making them more vulnerable to cytotoxic T 45 lymphocytes and natural killer cells. These results reveal a mechanical dimension of 46 immunosurveillance, which we call mechanosurveillance, that is particularly relevant to 47 109 cytoskeletal components. Morphoregulation by MRTF is absolutely required for metastatic 110 invasion and subsequent proliferative expansion (Er et al., 2018). However, because analogous 111 shape changes have been shown to increase cell stifffness (Kasza et al., 2009), it is tempting to 112 speculate that MRTF signaling might also mechanically sensitize cancer cells to cytotoxic 113 lymphocytes. 114In the present study, we explored this hypothesis by analyzing the effects of MRTF on 115 the mechanical properties of cancer cells, their immune sensitivity, and their capacity to colonize 116 tissues in vivo. Our results reveal a novel, mechanical form of immunosurveillance that enables 117 cytotoxic lymphocytes to target the specific biophysical features of metastatic cancer cells. 118 119 120 5 RESULTS 121 122 MRTF overexpression sensitizes metastatic cells to the immune system 123 Given the importance of MRTF-mediated mechanotransduction for migration and 124 metastasis, and the unique position of MRTF in F-actin regulation, we reasoned that 125 manipulating MRTFA and MRTFB levels might reveal novel vulnerabilities associated with 126 cancer cell architecture (Fig. 1A). To explore this idea, we employed an established model of 127 metastatic colonization in which malignant cancer cells expressing luciferase are injected 128 intravenously into congenic mice and their subsequent growth in the lung monitored by 129 bioluminescent imaging (Fig. 1B). shRNA-mediated suppression of MRTFA and MRTFB130 reduced lung colonization by both B16F10 melanoma and E0771 breast cancer cells in this 131 model (Fig. 1C-D and Fig. S1A), consistent with previous data showing that MRTF is required 132 for metastatic seeding (Er et al., 2018; Kim et al., 2017; Medjkane et al., 2009). However, 133 B16F10 and E0771 cell lines overexpressing MRTFB (B16F10-MRTFB and E0771-MRTFB) 134 exhibited dramatically reduced lung colonization ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Tello-Lafoz

Srpan

et al. 2020

Preprint

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Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT‐PD‐L1 Axis

Wang,

Jiang,

et al. 2024

Advanced Science

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Immunotherapy targeting PD‐L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine‐threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD‐L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN‐γ‐mediated PD‐L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti‐PD‐1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD‐L1/PD‐1 signaling and is a promising target for combined immunotherapy.

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Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

Huang

Zhang

Zhou

et al. 2022

MedComm

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Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.

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RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

Cited by 103 publications

References 54 publications

Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT‐PD‐L1 Axis

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

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