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1.
Cancer Immunol Res ; 9(11): 1283-1297, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34426457

RESUMO

Suppressive myeloid cells inhibit antitumor immunity by preventing T-cell responses. Immunoglobulin-like transcript 3 (ILT3; also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. However, the ligand that engages ILT3 within the tumor microenvironment and renders tumor-associated myeloid cells suppressive is unknown. Using a screening approach, we identified fibronectin as a functional ligand for ILT3. The interaction of fibronectin with ILT3 polarized myeloid cells toward a suppressive state, and these effects were reversed with an ILT3-specific antibody that blocked the interaction of ILT3 with fibronectin. Furthermore, ex vivo treatment of human tumor explants with anti-ILT3 reprogrammed tumor-associated myeloid cells toward a stimulatory phenotype. Thus, the ILT3-fibronectin interaction represents a "stromal checkpoint" through which the extracellular matrix actively suppresses myeloid cells. By blocking this interaction, tumor-associated myeloid cells may acquire a stimulatory phenotype, potentially resulting in increased antitumor T-cell responses.


Assuntos
Fibronectinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Células Mieloides/metabolismo , Receptores Imunológicos/metabolismo , Diferenciação Celular , Linhagem Celular , Humanos
2.
Nat Metab ; 3(5): 728, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33953392

RESUMO

A Correction to this paper has been published: https://doi.org/10.1038/s42255-021-00397-5.

3.
Nat Metab ; 3(4): 513-522, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33846641

RESUMO

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colchicina/farmacologia , Citocinas/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Células Mieloides/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Antioxidantes/farmacologia , Colchicina/farmacocinética , Simulação por Computador , Citocinas/biossíntese , Fator 15 de Diferenciação de Crescimento/genética , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Peritonite/induzido quimicamente , Peritonite/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 6/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
Nat Med ; 26(8): 1264-1270, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32661391

RESUMO

Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2-4. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer5-8, and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described9-12. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.


Assuntos
Caquexia/tratamento farmacológico , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator 15 de Diferenciação de Crescimento/genética , Complexos Multiproteicos/ultraestrutura , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-ret/genética , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Anticorpos Monoclonais , Caquexia/complicações , Caquexia/genética , Caquexia/imunologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/ultraestrutura , Fator 15 de Diferenciação de Crescimento/ultraestrutura , Xenoenxertos , Humanos , Peroxidação de Lipídeos , Camundongos , Complexos Multiproteicos/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Neoplasias/complicações , Neoplasias/genética , Neoplasias/imunologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/ultraestrutura , Transdução de Sinais , Redução de Peso
5.
EBioMedicine ; 16: 51-62, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28159572

RESUMO

Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of ß-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Taxoides/farmacologia , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Células A549 , Animais , Antineoplásicos/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Western Blotting , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipoilação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Microtúbulos/metabolismo , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , beta Catenina/genética , beta Catenina/metabolismo
6.
EBioMedicine ; 2(8): 808-24, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26425687

RESUMO

Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and ß-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics. RESEARCH IN CONTEXT: Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.


Assuntos
Apoptose , Membrana Celular/metabolismo , Ácido Graxo Sintase Tipo I/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Neoplasias/metabolismo , Ácido Palmítico/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Membrana Celular/patologia , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/patologia
7.
Clin Cancer Res ; 13(12): 3713-23, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17575237

RESUMO

PURPOSE: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. EXPERIMENTAL DESIGN: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors. RESULTS: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. CONCLUSIONS: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.


Assuntos
Antineoplásicos/farmacologia , Compostos Azabicíclicos/farmacologia , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Cloridrato de Erlotinib , Feminino , Gefitinibe , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Camundongos SCID , Mutação , Fosforilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Genet ; 36(3): 283-7, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14981521

RESUMO

With the availability of complete genome sequence for Drosophila melanogaster, one of the next strategic goals for fly researchers is a complete gene knockout collection. The P-element transposon, the workhorse of D. melanogaster molecular genetics, has a pronounced nonrandom insertion spectrum. It has been estimated that 87% saturation of the approximately 13,500-gene complement of D. melanogaster might require generating and analyzing up to 150,000 insertions. We describe specific improvements to the lepidopteran transposon piggyBac and the P element that enabled us to tag and disrupt genes in D. melanogaster more efficiently. We generated over 29,000 inserts resulting in 53% gene saturation and a more diverse collection of phenotypically stronger insertional alleles. We found that piggyBac has distinct global and local gene-tagging behavior from that of P elements. Notably, piggyBac excisions from the germ line are nearly always precise, piggyBac does not share chromosomal hotspots associated with P and piggyBac is more effective at gene disruption because it lacks the P bias for insertion in 5' regulatory sequences.


Assuntos
Elementos de DNA Transponíveis , Drosophila melanogaster/genética , Genes de Insetos , Animais , Mutagênese Insercional
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