RESUMO
Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1ß (IL-1ß), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.
Assuntos
Candidíase/imunologia , Células Dendríticas/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Tirosina Quinases/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Células Th17/imunologia , Motivos de Aminoácidos/genética , Animais , Antígenos de Fungos/imunologia , Células Cultivadas , Citocinas/metabolismo , Ativação Enzimática , Mediadores da Inflamação/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação Linfocitária , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptores de IgE/genética , Receptores de IgE/metabolismo , Transdução de Sinais , Quinase SykRESUMO
Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.
Assuntos
Caderinas/fisiologia , Polaridade Celular , Próstata/citologia , Fuso Acromático/fisiologia , Animais , Caderinas/genética , Carcinogênese , Divisão Celular , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Epitélio , Deleção de Genes , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Neoplasias da Próstata/patologiaRESUMO
Acute pancreatitis (AP) is a sterile inflammation, in which inflammatory monocytes (CD11b+Ly-6Chi) are recruited into the inflamed tissue at the onset of disease. Monocyte infiltration and activation at the site of inflammation are critical to the pathogenesis of AP. Our previous studies have shown a protective role for CO in AP, which is partially mediated by inhibition of macrophage activation via TLR4 signaling. In the current study, to gain a better understanding of CO's therapeutic effect, we further investigated whether CO could affect inflammatory monocyte trafficking during AP. In a mouse model of AP, we found that treatment with CO-releasing molecule-2 (CORM-2) impaired recruitment of inflammatory monocytes, but not that of neutrophils, from peripheral blood to inflamed pancreas. During the early stage of AP, a single dose of CORM-2 decreased pancreatic CCL2 and soluble ICAM-1 expression. In addition, using in vivo and in vitro experiments, we found that CORM-2 had the ability to inhibit CD11b+Ly-6Chi monocyte migration via blockade of CCR2 endocytosis. Notably, we showed that CORM-2 inhibited CCR2 endocytosis of inflammatory monocytes (CD14hiCD16-) from AP patients. Taken together, our results highlighted CO's effect on inflammatory monocyte trafficking, shedding additional light on its therapeutic potential in AP.
Assuntos
Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Monóxido de Carbono/farmacologia , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Monócitos/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Receptores CCR2/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Compostos Organometálicos/farmacologia , Pâncreas/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismoRESUMO
RATIONALE: Angiogenic hypersprouting and leaky vessels are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs of miR302-367 cluster in angiogenesis and tumors has not yet been fully evaluated. OBJECTIVE: To investigate the functions of miR302-367 in developmental angiogenesis and tumor angiogenesis and explore the molecular mechanisms of microRNA for the treatment of pathological neovascularization-related diseases. METHODS AND RESULTS: Here, we show that miR302-367 elevation in endothelial cells reduces retinal sprouting angiogenesis and promotes vascular stability in vivo, ex vivo, and in vitro. Erk1/2 is identified as direct target of miR302-367, and downregulation of Erk1/2 on miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the antiangiogenic and vascular stabilizing effect of miR302-367 in mice. Tumor angiogenesis shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways. CONCLUSIONS: MiR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth.
Assuntos
Fatores de Transcrição Kruppel-Like/biossíntese , Sistema de Sinalização das MAP Quinases/fisiologia , MicroRNAs/biossíntese , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Receptores de Lisoesfingolipídeo/biossíntese , Inibidores da Angiogênese/biossíntese , Animais , Carcinoma Pulmonar de Lewis , Técnicas de Cocultura , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Neoplasias/patologia , Neoplasias/prevenção & controle , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Receptores de Esfingosina-1-Fosfato , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Previous data suggested a negative role of phosphatase and tensin homolog (Pten) and a positive function of SH2-containing tyrosine phosphatase (Shp2)/Ptpn11 in myelopoiesis and leukemogenesis. Herein we demonstrate that ablating Shp2 indeed suppressed the myeloproliferative effect of Pten loss, indicating directly opposing functions between pathways regulated by these two enzymes. Surprisingly, the Shp2 and Pten double-knockout mice suffered lethal anemia, a phenotype that reveals previously unappreciated cooperative roles of Pten and Shp2 in erythropoiesis. The lethal anemia was caused collectively by skewed progenitor differentiation and shortened erythrocyte lifespan. Consistently, treatment of Pten-deficient mice with a specific Shp2 inhibitor suppressed myeloproliferative neoplasm while causing anemia. These results identify concerted actions of Pten and Shp2 in promoting erythropoiesis, while acting antagonistically in myeloproliferative neoplasm development. This study illustrates cell type-specific signal cross-talk in blood cell lineages, and will guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.
Assuntos
Anemia/genética , Eritropoese/fisiologia , Mielopoese/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Anemia/etiologia , Animais , Diferenciação Celular/genética , Primers do DNA/genética , Eritrócitos/fisiologia , Genótipo , Técnicas Histológicas , Camundongos , Camundongos Knockout , Mutagênese , PTEN Fosfo-Hidrolase/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Análise de SobrevidaRESUMO
Despite the important role of the gastric stem cell in tissue homeostasis and gastric carcinogenesis, its residence and identity remain poorly understood. In a recent paper in The Journal of Pathology, Vange et al suggest ASPM as a candidate stem/progenitor cell marker for oxyntic glands. Identification of ASPM was achieved by genome-wide gene expression analysis of the micro-dissected isthmus zone, where the majority of stem/progenitor cells are believed to reside. ASPM-positive cells, scattered in the proliferative isthmus region, do not express most differentiated cell markers and are largely quiescent. Together with ASPM, 11 other genes that are uniquely expressed in the isthmus zone constitute a regulatory network downstream of the core transcription factor E2F1. The authors further demonstrated that up-regulation of E2F1 and ASPM is associated with gastric cancers. This study provides novel candidates for future lineage-tracing experiments that will lead to the ultimate discovery of bona fide gastric stem cell markers. Additionally, the E2F1-ASPM axis may represent a new mechanism for gastric carcinogenesis.
Assuntos
Adenocarcinoma/patologia , Mucosa Gástrica/citologia , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/biossíntese , Neoplasias Gástricas/patologia , Animais , HumanosRESUMO
One of the major challenges in prostate cancer therapy remains the development of effective treatments for castration-resistant prostate cancer (CRPC), as the underlying mechanisms for its progression remain elusive. Previous studies showed that androgen receptor (AR) is crucially involved in regulation of metabolism in prostate cancer (PCa) cells throughout the transition from early stage, androgen-sensitive PCa to androgen-independent CRPC. AR achieves such metabolic rewiring directively either via its transcriptional activity or via interactions with AMP-activated protein kinase (AMPK). However, due to the heterogeneous expression and activity status of AR in PCa cells, it remains a challenge to investigate the links between AR status and metabolic alterations. To this end, we compared the proteomes of three pairs of androgen-sensitive (AS) and androgen-independent (AI) PCa cell lines, namely, PC3-AR(+)/PC3, 22Rv1/Du145, and LNCaP/C42B, using an iTRAQ labeling approach. Our results revealed that most of the differentially expressed proteins between each pair function in metabolism, indicating a metabolic shift between AS and AI cells, as further validated by multiple reaction monitoring (MRM)-based quantification of nucleotides and relative comparison of fatty acids between these cell lines. Furthermore, increased adenylate kinase isoenzyme 1 (AK1) in AS relative to AI cells may result in activation of AMPK, representing a major regulatory factor involved in the observed metabolic shift in PCa cells.
Assuntos
Peptídeos/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Proteínas Quinases Ativadas por AMP/metabolismo , Acetilcoenzima A/metabolismo , Adenilato Quinase/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Análise por Conglomerados , Ácidos Graxos/metabolismo , Humanos , Marcação por Isótopo/métodos , Masculino , Mitocôndrias/metabolismo , Modelos Biológicos , Nucleotídeos/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteoma/classificação , Receptores Androgênicos/metabolismo , Reprodutibilidade dos Testes , Transdução de SinaisRESUMO
BACKGROUND & AIMS: Little is known about factors that promote gastric carcinogenesis. We analyzed multiple microarray data sets for messenger RNAs (mRNAs) that were increased significantly in human gastric tumor samples, compared with the adjacent normal gastric tissue. We found expression of tripartite motif 59 (TRIM59), which encodes a putative ubiquitin ligase, to be increased, and investigated its effects in gastric cancer cell lines. METHODS: We analyzed microarray data sets from the Oncomine database. We used quantitative polymerase chain reaction and immunoblotting to measure levels of TRIM59 mRNA and protein in 50 human gastric cancer and paired normal tissues, obtained from Renji Hospital and the First Affiliated Hospital of Nanchang University, in China. We also measured protein levels in the gastric epithelial cell line GES-1; the cancer cell lines MKN45, AGS, SGC7901, BGC823, Snu5, N87, and Snu1; and in tissue arrays of 108 human gastric tumors. TRIM59 was knocked down and overexpressed in gastric cancer cell lines, and the effects on proliferation, clone formation, migration, and growth of xenograft tumors in nude mice were assessed. TRIM59-related signaling pathways were examined by immunoblotting and quantitative polymerase chain reaction. We analyzed interactions among TRIM59, P53, and ubiquitin in immunoprecipitation studies. RESULTS: Levels of TRIM59 mRNA and protein were increased significantly in gastric tumors compared with nontumor tissues; increased levels were associated with advanced tumor stage and shorter patient survival times. TRIM59 knockdown reduced proliferation, clone formation, and migration of gastric cancer cell lines, as well as growth of xenograft tumors in nude mice; overexpression of TRIM59 had the opposite effects. TRIM59 interacted physically with P53, increasing its ubiquitination and degradation. Increased levels of TRIM59 in human gastric tumors correlated with reduced expression of P53 target genes. CONCLUSIONS: The putative ubiquitin ligase TRIM59 is up-regulated in human gastric tumors compared with nontumor tissues. Levels of TRIM59 correlate with tumor progression and patient survival times. TRIM59 interacts with P53, promoting its ubiquitination and degradation, and TRIM59 might promote gastric carcinogenesis via this mechanism.
Assuntos
Proteínas de Membrana/metabolismo , Metaloproteínas/metabolismo , Processamento de Proteína Pós-Traducional , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana/genética , Metaloproteínas/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Modelos de Riscos Proporcionais , Proteólise , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Transfecção , Proteínas com Motivo Tripartido , Carga Tumoral , Ubiquitinação , Regulação para CimaRESUMO
Tumor-associated endothelial cells (TECs) limit antitumor immunity via inducing apoptosis of infiltrating T lymphocytes through a Fas ligand (FasL) mediated mechanism. Herein, this work creates a peptide-drug conjugate (PDC) by linking 7-ethyl-10-hydroxycamptothecin (SN38) to hydrophilic segments with either RGDR or HKD motif at their C-terminus through a glutathione-responsive linker. The PDCs spontaneously assemble into filaments in aqueous solution. The PDC filaments containing 1% of SN38-RGDR (SN38-HKD/RGDR) effectively target triple-negative breast cancer (TNBC) cells and TECs with upregulated expression of integrin, and induce immunogenic cell death (ICD) of tumor cells and FasL downregulation of TECs. SN38-HKD/RGDR increases infiltration, activity, and viability of CD8+ T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy.
Assuntos
Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Linfócitos T CD8-Positivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células Endoteliais , Neoplasias Pulmonares/secundário , Apoptose , Linhagem Celular TumoralRESUMO
Current cytotoxic T lymphocyte (CTL) activating immunotherapy requires a major histocompatibility complex I (MHC-I)-mediated presentation of tumor-associated antigens, which malfunctions in around half of patients with triple-negative breast cancer (TNBC). Here, we create a LCL161-loaded macrophage membrane decorated nanoparticle (LMN) for immunotherapy of MHC-I-deficient TNBC. SIRPα on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161, which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells. The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds. LMNs also block CD47-mediated phagocytosis suppression. LMNs inhibit the growth of MHC-I-deficient TNBC tumors, as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel, and prolong the survival of animals, during which process CTLs also play important roles. This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophage-mediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.
RESUMO
Immunotoxicity remains a major hindrance to chemotherapy in cancer therapy. Nanocarriers may alleviate the immunotoxicity, but the optimal design remains unclear. Here, we created two variants of maytansine (DM1)-loaded synthetic high-density lipoproteins (D-sHDL) with either physically entrapped (ED-sHDL) or chemically conjugated (CD-sHDL) DM1. We found that CD-sHDL showed less accumulation in the tumor draining lymph nodes (DLNs) and femur, resulting in a lower toxicity against myeloid cells than ED-sHDL via avoiding scavenger receptor class B type 1 (SR-B1)-mediated DM1 transportation into the granulocyte-monocyte progenitors and dendritic cells. Therefore, higher densities of lymphocytes in the tumors, DLNs, and blood were recorded in mice receiving CD-sHDL, leading to a better efficacy and immune memory of CD-sHDL against colon cancer. Furthermore, liposomes with conjugated DM1 (CD-Lipo) showed lower immunotoxicity than those with entrapped drug (ED-Lipo) through the same mechanism after apolipoprotein opsonization. Our findings highlight the critical role of drug loading patterns in dictating the biological fate and activity of nanomedicine.
Assuntos
Nanopartículas , Animais , Nanopartículas/química , Camundongos , Linhagem Celular Tumoral , Humanos , Receptores Depuradores Classe B/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Lipoproteínas HDL/metabolismo , Portadores de Fármacos/química , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Lipossomos/química , Lipídeos/químicaRESUMO
Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.
Assuntos
Neoplasias da Próstata , Homeobox 1 de Ligação a E-box em Dedo de Zinco , Masculino , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Humanos , Animais , Cromatina/metabolismo , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Camundongos , Regulação Neoplásica da Expressão Gênica , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/genética , Plasticidade Celular , Glicólise , Montagem e Desmontagem da CromatinaRESUMO
Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.
RESUMO
The stem cell factor (SCF)/Kit system has served as a classic model in deciphering molecular signaling events in the hematopoietic compartment, and Kit expression is a most critical marker for hematopoietic stem cells (HSCs) and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. Herein we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit and other RTKs, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling axis. Inducible ablation of PTPN11/Shp2 resulted in severe cytopenia in BM, spleen, and peripheral blood in mice. Shp2 removal suppressed the functional pool of HSCs/progenitors, and Shp2-deficient HSCs failed to reconstitute lethally irradiated recipients because of defects in homing, self-renewal, and survival. We show that Shp2 regulates coordinately multiple signals involving up-regulation of Kit expression via Gata2. Therefore, this study reveals a critical role of Shp2 in maintenance of a functional HSC/progenitor pool in adult mammals, at least in part through a kinase-phosphatase-kinase cascade.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Anemia Aplástica , Animais , Apoptose , Sequência de Bases , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea , Proliferação de Células , Regulação para Baixo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Retroalimentação Fisiológica , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Hematopoese , Hemoglobinúria Paroxística/etiologia , Leucopenia/etiologia , Camundongos , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas c-kit/genética , RNA Interferente Pequeno/genética , Transdução de SinaisRESUMO
The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of secondgeneration androgen receptor (AR) pathway inhibitors (ARPIs). Neuroendocrine differentiation (NED) is closely associated with ARPI treatment failure and poor prognosis in prostate cancer (PCa) patients. However, the molecular mechanisms of NED are not fully understood. Here we report that upregulation of TRIM59, a TRIM family protein, is strongly correlated with ARPI treatment mediated NED and shorter patient survival in PCas. AR binds to TRIM59 promoter and represses its transcription. ARPI treatment leads to a reversal of repressive epigenetic modifications on TRIM59 gene and the transcriptional restraint on TRIM59 by AR. Upregulated TRIM59 then drives the NED of PCa by enhancing the degradation of RB1 and P53 and upregulating downstream lineage plasticity-promoting transcription factor SOX2. Altogether, TRIM59 is negatively regulated by AR and acts as a key driver for NED in PCas. Our study provides a novel prognostic marker for PCas and shed new light on the molecular pathogenesis of t-NEPC, a deadly variant of PCa.
Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Proteínas com Motivo Tripartido , Humanos , Masculino , Antagonistas de Receptores de Andrógenos , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Regulação para CimaRESUMO
Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Masculino , Humanos , Histonas/metabolismo , Mitocôndrias/metabolismo , Diferenciação Celular , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1ß in TAMs. IL-1ß induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1ß antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1ß is an important androgen-responsive immunotherapeutic target for advanced PCa.
Assuntos
Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Antagonistas de Androgênios , Androgênios , Imunoterapia , Macrófagos/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Microambiente TumoralRESUMO
An accurate estimate of patient survival at diagnosis is critical to plan efficient therapeutic options. A simple and multiapplication tool is needed to move forward the precision medicine era. Taking advantage of the broad and high CD10 expression in stem and cancers cells, we evaluated the molecular identity of aggressive cancer cells. We used epithelial primary cells and developed a breast cancer stem cellbased progressive model. The superiority of the early-transformed isolated molecular index was evaluated by large-scale analysis in solid cancers. BMP2-driven cell transformation increases CD10 expression which preserves stemness properties. Our model identified a unique set of 159 genes enriched in G2M cell-cycle phases and spindle assembly complex. Using samples predisposed to transformation, we confirmed the value of an early neoplasia index associated to CD10 (ENI10) to discriminate premalignant status of a human tissue. Using a stratified Cox model, a large-scale analysis (>10,000 samples, The Cancer Genome Atlas Pan-Cancer) validated a strong risk gradient (HRs reaching HR = 5.15; 95% confidence interval: 4.006.64) for high ENI10 levels. Through different databases, Cox regression model analyses highlighted an association between ENI10 and poor progression-free intervals for more than 50% of cancer subtypes tested, and the potential of ENI10 to predict drug efficacy. The ENI10 index constitutes a robust tool to detect pretransformed tissues and identify high-risk patients at diagnosis. Owing to its biological link with refractory cancer stem cells, the ENI10 index constitutes a unique way of identifying effective treatments to improve clinical care. SIGNIFICANCE: We identified a molecular signature called ENI10 which, owing to its biological link with stem cell properties, predicts patient outcome and drugs efficiency in breast and several other cancers. ENI10 should allow early and optimized clinical management of a broad number of cancers, regardless of the stage of tumor progression.
Assuntos
Neoplasias , Humanos , Neoplasias/diagnóstico , Biomarcadores Tumorais/genética , NeprilisinaRESUMO
Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes MYCN and RICTOR mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.
Assuntos
Adenocarcinoma , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Proteína Proto-Oncogênica N-Myc/genética , Retroalimentação , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Fenótipo , Adenocarcinoma/genética , Linhagem Celular Tumoral , Proteína Semelhante a ELAV 3/genéticaRESUMO
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.