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1.
Breast Cancer Res ; 26(1): 96, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849928

RESUMO

BACKGROUND: Metabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to regulate breast cancer progression are not fully understood. We identify hypoxia-mediated suppression of pyruvate carboxylase (PC), and subsequent induction of lactate production, as a metabolic regulator of immunosuppression. METHODS: We used qPCR, immunoblot, and reporter assays to characterize repression of PC in hypoxic primary tumors. Steady state metabolomics were used to identify changes in metabolite pools upon PC depletion. In vivo tumor growth and metastasis assays were used to evaluate the impact of PC manipulation and pharmacologic inhibition of lactate transporters. Immunohistochemistry, flow cytometry, and global gene expression analyzes of tumor tissue were employed to characterize the impact of PC depletion on tumor immunity. RESULTS: PC is essential for metastatic colonization of the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This effect was only observed in immune competent animals, supporting the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments, we demonstrate that hypoxia potently downregulated PC. In the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors. CONCLUSIONS: We present a dimorphic role for PC in primary mammary tumors vs. pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immunity.


Assuntos
Neoplasias da Mama , Piruvato Carboxilase , Piruvato Carboxilase/metabolismo , Piruvato Carboxilase/genética , Animais , Feminino , Camundongos , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Ácido Láctico/metabolismo , Regulação Neoplásica da Expressão Gênica , Hipóxia Celular , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Tolerância Imunológica
2.
Cancer Metastasis Rev ; 41(3): 607-625, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35752704

RESUMO

Obesity, exceptionally prevalent in the USA, promotes the incidence and progression of numerous cancer types including breast cancer. Complex, interacting metabolic and immune dysregulation marks the development of both breast cancer and obesity. Obesity promotes chronic low-grade inflammation, particularly in white adipose tissue, which drives immune dysfunction marked by increased pro-inflammatory cytokine production, alternative macrophage activation, and reduced T cell function. Breast tissue is predominantly composed of white adipose, and developing breast cancer readily and directly interacts with cells and signals from adipose remodeled by obesity. This review discusses the biological mechanisms through which obesity promotes breast cancer, the role of obesity in breast cancer health disparities, and dietary interventions to mitigate the adverse effects of obesity on breast cancer. We detail the intersection of obesity and breast cancer, with an emphasis on the shared and unique patterns of immune dysregulation in these disease processes. We have highlighted key areas of breast cancer biology exacerbated by obesity, including incidence, progression, and therapeutic response. We posit that interception of obesity-driven breast cancer will require interventions that limit protumor signaling from obese adipose tissue and that consider genetic, structural, and social determinants of the obesity-breast cancer link. Finally, we detail the evidence for various dietary interventions to offset obesity effects in clinical and preclinical studies of breast cancer. In light of the strong associations between obesity and breast cancer and the rising rates of obesity in many parts of the world, the development of effective, safe, well-tolerated, and equitable interventions to limit the burden of obesity on breast cancer are urgently needed.


Assuntos
Neoplasias da Mama , Tecido Adiposo/metabolismo , Neoplasias da Mama/complicações , Neoplasias da Mama/etiologia , Feminino , Humanos , Inflamação/metabolismo , Obesidade/complicações , Obesidade/metabolismo
3.
Cell ; 184(20): 5215-5229.e17, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34559986

RESUMO

Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Sequência de Bases , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/química , Fator de Iniciação Eucariótico 4G/genética , Fator de Iniciação Eucariótico 4G/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica , Humanos , Camundongos Endogâmicos NOD , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Oncogenes , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Splicing de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Tamoxifeno/farmacologia , Proteína 1 de Ligação a X-Box/metabolismo
4.
Cell Rep ; 35(13): 109321, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34192540

RESUMO

The major cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), an ancient protein required for translation of all eukaryotic genomes, is a surprising yet potent oncogenic driver. The genetic interactions that maintain the oncogenic activity of this key translation factor remain unknown. In this study, we carry out a genome-wide CRISPRi screen wherein we identify more than 600 genetic interactions that sustain eIF4E oncogenic activity. Our data show that eIF4E controls the translation of Tfeb, a key executer of the autophagy response. This autophagy survival response is triggered by mitochondrial proteotoxic stress, which allows cancer cell survival. Our screen also reveals a functional interaction between eIF4E and a single anti-apoptotic factor, Bcl-xL, in tumor growth. Furthermore, we show that eIF4E and the exon-junction complex (EJC), which is involved in many steps of RNA metabolism, interact to control the migratory properties of cancer cells. Overall, we uncover several cancer-specific vulnerabilities that provide further resolution of the cancer translatome.


Assuntos
Testes Genéticos , Neoplasias/genética , Biossíntese de Proteínas , Transdução de Sinais , Regiões 5' não Traduzidas/genética , Animais , Apoptose/genética , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Éxons/genética , Genoma Humano , Humanos , Masculino , Metaloendopeptidases/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias/patologia , Peptídeo Hidrolases/metabolismo , Biossíntese de Proteínas/genética , Transdução de Sinais/genética , Estresse Fisiológico , Proteína bcl-X/metabolismo
5.
Front Endocrinol (Lausanne) ; 12: 632284, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815289

RESUMO

The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Metabolismo Energético/fisiologia , Resistência à Insulina/fisiologia , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Humanos , Inflamação/metabolismo , Fatores de Risco
6.
Nat Med ; 25(2): 301-311, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643286

RESUMO

Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.


Assuntos
Imunoterapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Biossíntese de Proteínas , Regiões 5' não Traduzidas/genética , Animais , Antígeno B7-H1/metabolismo , Sequência de Bases , Progressão da Doença , Regulação para Baixo , Fator de Iniciação 4E em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Evasão da Resposta Imune , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Fases de Leitura Aberta/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Transcrição Gênica , Microambiente Tumoral , Regulação para Cima/genética
7.
Diabetes ; 67(4): 662-673, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29321172

RESUMO

Pharmacological dosing of all-trans-retinoic acid (atRA) controls adiposity in rodents by inhibiting adipogenesis and inducing fatty acid oxidation. Retinol dehydrogenases (Rdh) catalyze the first reaction that activates retinol into atRA. This study examined postnatal contributions of Rdh10 to atRA biosynthesis and physiological functions of endogenous atRA. Embryonic fibroblasts from Rdh10 heterozygote hypomorphs or with a total Rdh10 knockout exhibit decreased atRA biosynthesis and escalated adipogenesis. atRA or a retinoic acid receptor (RAR) pan-agonist reversed the phenotype. Eliminating one Rdh10 copy in vivo (Rdh10+/- ) yielded a modest decrease (≤25%) in the atRA concentration of liver and adipose but increased adiposity in male and female mice fed a high-fat diet (HFD); increased liver steatosis, glucose intolerance, and insulin resistance in males fed an HFD; and activated bone marrow adipocyte formation in females, regardless of dietary fat. Chronic dosing with low-dose atRA corrected the metabolic defects. These data resolve physiological actions of endogenous atRA, reveal sex-specific effects of atRA in vivo, and establish the importance of Rdh10 to metabolic control by atRA. The consequences of a modest decrease in tissue atRA suggest that impaired retinol activation may contribute to diabesity, and low-dose atRA therapy may ameliorate adiposity and its sequelae of glucose intolerance and insulin resistance.


Assuntos
Adipogenia/genética , Tecido Adiposo/metabolismo , Oxirredutases do Álcool/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Tretinoína/metabolismo , Adipogenia/efeitos dos fármacos , Adiposidade/genética , Animais , Dieta Hiperlipídica , Feminino , Fibroblastos/metabolismo , Intolerância à Glucose/metabolismo , Heterozigoto , Resistência à Insulina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxirredução , Receptores do Ácido Retinoico/agonistas , Fatores Sexuais , Tretinoína/farmacologia , Vitamina A/metabolismo
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