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We demonstrate geostationary satellite monitoring of large transient methane point sources with the US Geostationary Operational Environmental Satellites (GOES). GOES provides continuous 5- to 10-min coverage of the Americas at 1 to 2 km nadir pixel resolution in two shortwave infrared spectral bands from which large methane plumes can be retrieved. We track the full evolution of an extreme methane release from the El Encino-La Laguna natural gas pipeline in Durango, Mexico on 12 May 2019. The release lasted 3 h at a variable rate of 260 to 550 metric tons of methane per hour and totaled 1,130 to 1,380 metric tons. We report several other detections of transient point sources from oil/gas infrastructure, from which we infer a detection limit of 10 to 100 t h-1. Our results show that extreme releases of methane can last less than an hour, as from deliberate venting, and would thus be difficult to identify and quantify with low-Earth orbit satellites.
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Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV-PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Neoplasias da Mama/genética , Lipocalina-2/metabolismo , Neoplasias Pulmonares/secundário , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Lipocalina-2/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Células Estromais/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Drug delivery across the blood-brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam-bridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human-cell-based BBB model. Furthermore, MiniAp-4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.
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Apamina/química , Peptidomiméticos/administração & dosagem , Peçonhas/administração & dosagem , Sequência de Aminoácidos , Barreira Hematoencefálica , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Peptidomiméticos/química , Peptidomiméticos/farmacocinéticaRESUMO
OBJECTIVE: To assess whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor with anti-cancer properties, has an inhibitory effect on tumour establishment and progression of prostate cancer (PCa) bone metastases. MATERIALS AND METHODS: PC-3 stable luciferase-expressing cells were injected into male nude mice by intracardiac (i.c.) and intratibial (i.t.) injections, and the effect of celecoxib on bone metastases was then recorded using bioluminescence image analysis. In cases of chemoprevention, mice received 3 mg/kg celecoxib from 1 week before cell implantation until the end of the study, and to test the therapeutic effect, mice received celecoxib 1 week after cell implantation until the end of the study. Tumour tissue samples were histologically examined and COX-2 expression was quantified at the protein level. RESULTS: Celecoxib significantly decreased cell viability and the proliferation of human PCa cells in vitro in a dose-dependent manner. Bone metastases were detected after i.c. injection in nude mice. Celecoxib (15 ppm) administered before i.c. injection did not inhibit the cellular metastatic potential, as the numbers of bone metastases were similar in both groups. However, celecoxib did decrease metastatic progression in the osseous environment when cells were injected directly into the tibia (P < 0.05). At the protein level, COX-2 expression was significantly decreased in the celecoxib treatment group (P < 0.01). CONCLUSION: In a preclinical mice model, celecoxib administered orally at the standard human dose inhibits the progression of established PCa bone metastases.
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Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Celecoxib , Ciclo-Oxigenase 2 , Progressão da Doença , Masculino , Camundongos NusRESUMO
Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology. Here, we show that the less studied member of this family, Immediate Early Response 5 like (IER5L), is upregulated in aggressive prostate cancer. Interestingly, the upregulation of IER5L expression exhibits a robust association with metastatic disease in prostate and is recapitulated in other cancer types. In line with this observation, IER5L silencing reduces foci formation, migration and invasion ability in a variety of human and murine prostate cancer cell lines. In vivo, using zebrafish and immunocompromised mouse models, we demonstrate that IER5L-silencing reduces prostate cancer tumor growth, dissemination, and metastasis. Mechanistically, we characterize the transcriptomic and proteomic landscapes of IER5L-silenced cells. This approach allowed us to identify DNA replication and monomeric G protein regulators as downstream programs of IER5L through a pathway that is consistent with the regulation of PP2A. In sum, we report the alteration of IER5L in prostate cancer and beyond and provide biological and molecular evidence of its contribution to tumor aggressiveness.
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Progressão da Doença , Neoplasias da Próstata , Proteína Fosfatase 2 , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Humanos , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/genética , Animais , Camundongos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Peixe-Zebra , Movimento Celular/genética , Proliferação de CélulasRESUMO
Metastasis requires numerous biological functions that jointly provide tumor cells from a primary site to seed and colonize a distant organ. Some of these activities are selected for in the primary site, whereas others are acquired at the metastatic niche. We provide molecular evidence showing that the BMP inhibitor, NOG, provides metastatic breast cancer cells with the ability to colonize the bone. NOG expression is acquired during the late events of metastasis, once cells have departed from the primary site, because it is not enriched in primary tumors with high risk of bone relapse. On the contrary, breast cancer bone metastatic lesions do select for high levels of NOG expression when compared with metastasis to the lung, liver, and brain. Pivotal to the bone colonization functions is the contribution of NOG to metastatic autonomous and nonautonomous cell functions. Using genetic approaches, we show that when NOG is expressed in human breast cancer cells, it facilitates bone colonization by fostering osteoclast differentiation and bone degradation and also contributes to metastatic lesions reinitiation. These findings reveal how aggressive cancer cell autonomous and nonautonomous functions can be mechanistically coupled to greater bone metastatic potential.
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Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Proteínas de Transporte/biossíntese , Regulação Neoplásica da Expressão Gênica , Osteoclastos/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Metástase Neoplásica , Especificidade de Órgãos/genética , Osteoclastos/patologiaRESUMO
A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.
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Antineoplásicos , Fibroblastos Associados a Câncer , Neoplasias Colorretais , Humanos , Fibroblastos Associados a Câncer/patologia , Oxaliplatina/farmacologia , Distribuição Tecidual , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Microambiente Tumoral , Fibroblastos/patologia , Linhagem Celular TumoralRESUMO
MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.
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Neoplasias da Mama , Epigênese Genética , Receptor alfa de Estrogênio , Amplificação de Genes , Proteínas Proto-Oncogênicas c-maf , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cromatina , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Proteínas Proto-Oncogênicas c-maf/genéticaRESUMO
About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.
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Neoplasias da Mama , Fibroblastos Associados a Câncer , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Fatores Imunológicos , Imunoterapia , Interleucina-2 , Receptor ErbB-2 , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Microambiente TumoralRESUMO
Metastasis is the main cause of death for cancer patients, but our ability to improve clinical outcome first requires a better understanding of the dynamics, cellular mechanisms, and kinetics of metastasis. In prostate cancer (PCa), metastatic tumor cells preferentially colonize to bone. However, a lack of applicable mouse models has limited our ability to study this process accurately. Here, we describe a strategy to bypass this limitation: human PCa cells are injected into immunodeficient mice (at tibia, the left ventricle of heart and the iliac artery). Using this novel technique, the metastatic capabilities of these human PCa cells (e.g., colonization and proliferation potential) can be analyzed in bone with an in vivo imaging system.
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Neoplasias Ósseas/secundário , Modelos Animais de Doenças , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Células Cultivadas , Humanos , Masculino , CamundongosRESUMO
About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients' quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells' migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b's role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.
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Carcinoma development in colorectal cancer is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates colorectal cancer metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic colorectal cancer cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with colorectal cancer tumors. Higher levels of EMGS expression were detected in the colorectal cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain-of-function and loss-of-function studies in several colorectal cancer cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation. SIGNIFICANCE: These findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer cells as a driver of tumor-stroma interactions that favor formation of metastases in the liver.
Assuntos
Angiopoietina-2/biossíntese , Neoplasias do Colo/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Invasividade Neoplásica/patologia , Receptores CXCR4/biossíntese , Animais , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos , Humanos , Neoplasias Hepáticas/secundário , Camundongos , Invasividade Neoplásica/genética , Regulação para CimaRESUMO
Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.
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Neoplasias da Próstata/enzimologia , Proteínas Serina-Treonina Quinases/genética , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP , Animais , Linhagem Celular Tumoral , Progressão da Doença , Epitélio/enzimologia , Epitélio/patologia , Células HEK293 , Heterozigoto , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Mutantes/metabolismo , Metástase Neoplásica , PTEN Fosfo-Hidrolase/metabolismo , Próstata/enzimologia , Próstata/patologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
In the version of this Article originally published, the boxes framing the two plots in Fig. 1g were misaligned from the axes due to a technical error. This has now been corrected in all versions of the Article.
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For many patients with breast cancer, symptomatic bone metastases appear after years of latency. How micrometastatic lesions remain dormant and undetectable before initiating colonization is unclear. Here, we describe a mechanism involved in bone metastatic latency of oestrogen receptor-positive (ER+) breast cancer. Using an in vivo genome-wide short hairpin RNA screening, we identified the kinase MSK1 as an important regulator of metastatic dormancy in breast cancer. In patients with ER+ breast cancer, low MSK1 expression associates with early metastasis. We show that MSK1 downregulation impairs the differentiation of breast cancer cells, increasing their bone homing and growth capacities. MSK1 controls the expression of genes required for luminal cell differentiation, including the GATA3 and FOXA1 transcription factors, by modulating their promoter chromatin status. Our results indicate that MSK1 prevents metastatic progression of ER+ breast cancer, suggesting that stratifying patients with breast cancer as high or low risk for early relapse based on MSK1 expression could improve prognosis.
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Neoplasias da Mama/genética , Fator de Transcrição GATA3/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Adulto , Idoso , Animais , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Diferenciação Celular/genética , Cromatina/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Humanos , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , RNA Interferente Pequeno/genética , Receptores de Estrogênio/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This corrects the article DOI: 10.1038/ncb3357.
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The mechanisms that allow breast cancer (BCa) cells to metabolically sustain rapid growth are poorly understood. Here we report that BCa cells are dependent on a mechanism to supply precursors for intracellular lipid production derived from extracellular sources and that the endothelial lipase (LIPG) fulfils this function. LIPG expression allows the import of lipid precursors, thereby contributing to BCa proliferation. LIPG stands out as an essential component of the lipid metabolic adaptations that BCa cells, and not normal tissue, must undergo to support high proliferation rates. LIPG is ubiquitously and highly expressed under the control of FoxA1 or FoxA2 in all BCa subtypes. The downregulation of either LIPG or FoxA in transformed cells results in decreased proliferation and impaired synthesis of intracellular lipids.
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Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Lipase/metabolismo , Metabolismo dos Lipídeos/genética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Transporte Biológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxiciclina/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Fator 3-alfa Nuclear de Hepatócito/antagonistas & inibidores , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/antagonistas & inibidores , Fator 3-beta Nuclear de Hepatócito/genética , Humanos , Lactonas/farmacologia , Lipase/antagonistas & inibidores , Lipase/genética , Células MCF-7 , Camundongos , Camundongos Nus , Invasividade Neoplásica , Orlistate , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.
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Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Camundongos , Metástase Neoplásica/patologia , Neoplasias da Próstata/patologia , Receptores de Estrogênio/metabolismo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.
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Neoplasias da Mama/secundário , Neoplasias da Mama/terapia , Proteína da Leucemia Promielocítica/antagonistas & inibidores , Proteína da Leucemia Promielocítica/metabolismo , Animais , Trióxido de Arsênio , Arsenicais/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Camundongos , Invasividade Neoplásica/genética , Óxidos/farmacologia , Regiões Promotoras Genéticas , Proteína da Leucemia Promielocítica/genética , Fatores de Transcrição SOX9/genética , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mammary cancer stem cells (MCSC) have been operationally defined as cells that re-form secondary tumors upon transplantation into immunodeficient mice. Building on this observation, it has also been suggested that MCSCs are responsible for metastasis as well as evasion and resistance to therapeutic treatments. MCSC reinitiating potential is usually tested by implantation of limited amounts of cells orthotopically or subcutaneously, yet this poorly recapitulates the metastatic niche where truly metastatic reinitiation will occur. Herein, we describe the implantation of small amounts of MCSC selected populations in the bone (intra tibiae injection) and the lung (intra thoracic injection) to test for their metastatic reinitiation capabilities.