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Deregulation of transcription factors (TFs) leading to uncontrolled proliferation of tumor cells within the microenvironment represents a hallmark of cancer. However, the biological and clinical impact of transcriptional interference, particularly in multiple myeloma (MM) cells, remains poorly understood. The present study shows for the first time that MYC and JUNB, two crucial TFs implicated in MM pathogenesis, orchestrate distinct transcriptional programs. Specifically, our data revealed that expression levels of MYC, JUNB, and their respective downstream targets do not correlate and that their global chromatin-binding patterns are not significantly overlapping. Mechanistically, MYC expression was not affected by JUNB knockdown, and conversely, JUNB expression and transcriptional activity were not affected by MYC knockdown. Moreover, suppression of MYC levels in MM cells via targeting the master regulator BRD4 by either siRNA-mediated knockdown or treatment with the novel proteolysis targeting chimera (PROTAC) MZ-1 overcame bone marrow (BM) stroma cell/IL-6-induced MYC- but not MEK-dependent JUNB-upregulation and transcriptional activity. Consequently, targeting of the two non-overlapping MYC- and JUNB-transcriptoms by MZ-1 in combination with genetic or pharmacological JUNB-targeting approaches synergistically enhanced MM cell death, both in 2D and our novel dynamic 3D models of the BM milieu as well as in murine xenografts. In summary, our data emphasize the opportunity to employ MYC and JUNB dual-targeting treatment strategies in MM as another exciting approach to further improve patient outcomes.
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Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo , Proteínas Proto-Oncogênicas c-myc , Fatores de Transcrição , Mieloma Múltiplo/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/metabolismo , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas c-jun/genéticaRESUMO
Introduction: Anti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels. Methods: This multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike's information criterion as metric was applied to refine the logistic regression model. Results: A total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23 mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5 mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40-30.05, p < 0.001). Conclusion: Despite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies.
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Acute myeloid leukemia (AML) is a heterogenous disease characterized by the clonal expansion of myeloid progenitor cells. Despite recent advancements in the treatment of AML, relapse still remains a significant challenge, necessitating the development of innovative therapies to eliminate minimal residual disease. One promising approach to address these unmet clinical needs is natural killer (NK) cell immunotherapy. To implement such treatments effectively, it is vital to comprehend how AML cells escape the NK-cell surveillance. Signal transducer and activator of transcription 3 (STAT3), a component of the Janus kinase (JAK)-STAT signaling pathway, is well-known for its role in driving immune evasion in various cancer types. Nevertheless, the specific function of STAT3 in AML cell escape from NK cells has not been deeply investigated. In this study, we unravel a novel role of STAT3 in sensitizing AML cells to NK-cell surveillance. We demonstrate that STAT3-deficient AML cell lines are inefficiently eliminated by NK cells. Mechanistically, AML cells lacking STAT3 fail to form an immune synapse as efficiently as their wild-type counterparts due to significantly reduced surface expression of intercellular adhesion molecule 1 (ICAM-1). The impaired killing of STAT3-deficient cells can be rescued by ICAM-1 overexpression proving its central role in the observed phenotype. Importantly, analysis of our AML patient cohort revealed a positive correlation between ICAM1 and STAT3 expression suggesting a predominant role of STAT3 in ICAM-1 regulation in this disease. In line, high ICAM1 expression correlates with better survival of AML patients underscoring the translational relevance of our findings. Taken together, our data unveil a novel role of STAT3 in preventing AML cells from escaping NK-cell surveillance and highlight the STAT3/ICAM-1 axis as a potential biomarker for NK-cell therapies in AML.
Assuntos
Molécula 1 de Adesão Intercelular , Células Matadoras Naturais , Leucemia Mieloide Aguda , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/metabolismo , Humanos , Leucemia Mieloide Aguda/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/genética , Vigilância Imunológica , Linhagem Celular Tumoral , Evasão Tumoral , Transdução de Sinais , Citotoxicidade ImunológicaRESUMO
Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3ß. While STAT3α is predominantly described as an oncogenic driver, STAT3ß has been suggested to act as a tumor suppressor. To elucidate the role of STAT3ß in AML, we established a mouse model of STAT3ß-deficient, MLL-AF9-driven AML. STAT3ß deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3ß. Accordingly, STAT3ß-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3ß expression. Together, our data corroborate the tumor suppressive role of STAT3ß in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3ß/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3ß/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.
Assuntos
Leucemia Mieloide Aguda , Fator de Transcrição STAT3 , Animais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Humanos , Fator de Transcrição STAT3/metabolismo , Camundongos , Transdução de Sinais , Interferons/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/metabolismo , Receptor de Interferon alfa e beta/genética , Linhagem Celular Tumoral , Nitrilas , Pirazóis , PirimidinasRESUMO
Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.
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Diabetes Mellitus Tipo 2 , Metformina , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metformina/farmacologia , Recidiva Local de Neoplasia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Ribosomally synthesized and post-translationally modified peptides, such as plant cyclotides, are a diverse group of natural products well known as templates in drug discovery and therapeutic lead development. The cyclotide kalata B1 (kB1) has previously been discovered as immunosuppressive agent on T-lymphocytes, and a synthetic version of this peptide, [T20K]kB1 (T20K), has been effective in reducing clinical symptoms, such as inflammation and demyelination, in a mouse model of multiple sclerosis. Based on its T-cell modulatory impact we studied the effects of T20K and several analogs on the proliferation of anaplastic large cell lymphoma (ALCL), a heterogeneous group of clinically aggressive diseases associated with poor prognosis. T20K, as a prototype drug candidate, induces apoptosis and a proliferation arrest in human lymphoma T-cell lines (SR786, Mac-2a and the Jurkat E6.1) in a concentration dependent fashion, at least partially via increased STAT5 and p53 signaling. In contrary to its effect on IL-2 signaling in lymphocytes, the cytokine levels are not altered in lymphoma cells. In vivo mouse experiments revealed a promising activity of T20K on these cancer cells including decreased tumor weight and increased apoptosis. This study opens novel avenues for developing cyclotide-based drug candidates for therapy of patients with ALCL.
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Ciclotídeos , Linfoma Anaplásico de Células Grandes , Animais , Ciclotídeos/farmacologia , Citocinas/farmacologia , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Camundongos , Linfócitos TRESUMO
Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses in vivo. In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.
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Células Matadoras Naturais , Neoplasias , Fator de Transcrição STAT3 , Citocinas/metabolismo , Humanos , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente TumoralRESUMO
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.
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Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfoma Anaplásico de Células Grandes/genética , Receptores de Interleucina-2/genética , Proteínas Repressoras/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoconjugados/farmacologia , Interleucina-15/farmacologia , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Antígeno Ki-1/genética , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Sequências Reguladoras de Ácido Nucleico , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.
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Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell-mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon-γ (IFN-γ) signaling by aberrant activation of TANK-binding kinase 1 (TBK1) and increased downstream expression and activation of signal transducer and activator of transcription 1 (STAT1). Interrupting this autocrine feed forward loop by knocking out IFN-α/ß receptor completely restored infiltration of cytotoxic T cells and rescued loss of A20 depending tumorigenesis. Downstream of STAT1, programmed death ligand 1 (PD-L1) was highly expressed in A20 knockout lung tumors. Accordingly, immune checkpoint blockade (ICB) treatment was highly efficient in mice harboring A20-deficient lung tumors. Furthermore, an A20 loss-of-function gene expression signature positively correlated with survival of melanoma patients treated with anti-programmed cell death protein 1. Together, we have identified A20 as a master immune checkpoint regulating the TBK1-STAT1-PD-L1 axis that may be exploited to improve ICB therapy in patients with lung adenocarcinoma.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Adenocarcinoma de Pulmão/genética , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Regulação para Baixo , Humanos , Interferon gama/metabolismo , Neoplasias Pulmonares/genética , Camundongos , Transdução de SinaisRESUMO
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.
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Acute myeloid leukemia (AML) is a very heterogeneous type of blood cancer, which presents with a high rate of mortality especially in elderly patients. Better understanding of critical players, such as molecules with tumor suppressive properties, may help to fine-tune disease classification and thereby treatment modalities for this detrimental disease. Here, we summarize well-known and established tumor suppressors as well as emerging tumor suppressors, including transcription factors (TCFs) and other transcriptional regulators, such as epigenetic modulators. In addition, we look into the versatile field of miRNAs also interfering with tumorigenesis and progression, which offer new possibilities in AML diagnosis, prognosis, and therapy.
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Leucemia Mieloide Aguda , MicroRNAs , Idoso , Carcinogênese , Transformação Celular Neoplásica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , MicroRNAs/genética , PrognósticoRESUMO
Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/patologia , Proteínas dos Microfilamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Antraciclinas/administração & dosagem , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/genética , Proteínas de Neoplasias/genética , Prognóstico , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Taxa de SobrevidaRESUMO
Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.
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Tecido Adiposo/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Obesidade/metabolismo , Receptores Imunológicos/metabolismo , Animais , Dieta Hiperlipídica , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Camundongos , Regulação para CimaRESUMO
Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a-deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain, and liver metastases. Whole-genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in the upregulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CAAT Box Enhancer Binding Protein (CEBP) expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.
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Proteína beta Intensificadora de Ligação a CCAAT/genética , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição STAT3/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanócitos/efeitos dos fármacos , Melanoma/patologia , Camundongos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Beyond their crucial role in hemostasis, platelets are increasingly recognized as regulators of inflammation. Via modulation of the immune system by direct and indirect interactions with leukocytes, platelets regulate several aspects of tumor-associated pathology. They influence inflammatory processes in cancer at various stages: platelets alter the activation status of the endothelium, recruit leukocytes to tumor sites and attune the inflammatory milieu at sites of primary and metastatic tumors. Patients with cancer show systemic changes of platelet activation. Tumor-associated platelet activation facilitates initiation of the coagulation cascade and constitutes a significant risk for thrombosis. Tumor-activated platelets further contribute to cancer progression by promoting critical processes such as angiogenesis and metastasis. Platelets modulate innate leukocyte effector functions such as antigen presentation by dendritic cells, monocyte recruitment and differentiation or neutrophil extracellular trap formation, which sculpture immune responses but also promote thrombosis and metastasis. On the other hand, responses of the adaptive immune system are also regulated by platelets. They are also involved in T-helper cell 17 differentiation, which represents a double-edged sword in cancer progression, as these cells propagate angiogenesis and immunosuppressive activities but are also involved in recruiting immune cells into tumors and stimulating effector CD8+ T cells. Moreover, platelets fine-tune tumor surveillance processes by modulating natural killer cell-mediated cancer cell recognition and effector functions. This review aims at summarizing the role of platelet-leukocyte interactions in the development and progression of cancer and puts its focus on cancer-related alterations of platelet and leukocyte functions and their impact on cancer pathology.
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Plaquetas/patologia , Carcinogênese/patologia , Progressão da Doença , Leucócitos/patologia , Neoplasias/patologia , Animais , Comunicação Celular , HumanosRESUMO
Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.
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Leucemia Mieloide Aguda/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Receptor Notch4/genética , Tretinoína/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Células Mieloides/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismoRESUMO
The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high CALCRL expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, in silico analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that CALCRL is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML.