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1.
Mol Cell ; 81(2): 386-397.e7, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33340488

RESUMO

In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fosfoglicerato Desidrogenase/genética , Serina/biossíntese , Animais , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirolimo/farmacologia
2.
Nat Cancer ; 4(3): 344-364, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36732635

RESUMO

Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation; however, some nutrients available at distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that pre-metastatic niche formation increases palmitate availability only in the lung, whereas a high-fat diet increases it in both organs. In line with this, targeting palmitate processing inhibits breast cancer-derived lung metastasis formation. Mechanistically, breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a-dependent manner. Concomitantly, lysine acetyltransferase 2a expression is promoted by palmitate, linking the available acetyl-CoA to the acetylation of the nuclear factor-kappaB subunit p65. Deletion of lysine acetyltransferase 2a or carnitine palmitoyltransferase 1a reduces metastasis formation in lean and high-fat diet mice, and lung and liver metastases from patients with breast cancer show coexpression of both proteins. In conclusion, palmitate-rich environments foster metastases growth by increasing p65 acetylation, resulting in a pro-metastatic nuclear factor-kappaB signaling.


Assuntos
Lisina Acetiltransferases , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Acetilação , Acetilcoenzima A/metabolismo , Palmitatos , Lisina Acetiltransferases/metabolismo
3.
Cell Rep ; 41(7): 111639, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384124

RESUMO

T cells dynamically rewire their metabolism during an immune response. We applied single-cell RNA sequencing to CD8+ T cells activated and differentiated in vitro in physiological medium to resolve these metabolic dynamics. We identify a differential time-dependent reliance of activating T cells on the synthesis versus uptake of various non-essential amino acids, which we corroborate with functional assays. We also identify metabolic genes that potentially dictate the outcome of T cell differentiation, by ranking them based on their expression dynamics. Among them, we find asparagine synthetase (Asns), whose expression peaks for effector T cells and decays toward memory formation. Disrupting these expression dynamics by ASNS overexpression promotes an effector phenotype, enhancing the anti-tumor response of adoptively transferred CD8+ T cells in a mouse melanoma model. We thus provide a resource of dynamic expression changes during CD8+ T cell activation and differentiation, and identify ASNS expression dynamics as a modulator of CD8+ T cell differentiation.


Assuntos
Linfócitos T CD8-Positivos , Melanoma , Camundongos , Animais , Análise de Célula Única , Ativação Linfocitária , Diferenciação Celular , Melanoma/metabolismo , Modelos Animais de Doenças
4.
Cancer Res ; 81(8): 1988-2001, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33687947

RESUMO

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC. SIGNIFICANCE: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.


Assuntos
Carcinoma Hepatocelular/etiologia , Dieta Hiperlipídica , Gorduras na Dieta/metabolismo , Glucose/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/etiologia , Animais , Carcinoma Hepatocelular/metabolismo , Transformação Celular Neoplásica , Ciclo do Ácido Cítrico/fisiologia , Ácidos Graxos/metabolismo , Teste de Tolerância a Glucose , Humanos , Ácido Láctico/biossíntese , Metabolismo dos Lipídeos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Palmitatos/farmacologia , Peroxissomos/metabolismo , Proteômica , Piruvato Carboxilase/metabolismo , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Serina/metabolismo , Ativação Transcricional
5.
Cell Rep ; 31(12): 107806, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32579932

RESUMO

Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo.


Assuntos
Ácidos Graxos Dessaturases/genética , Regulação Neoplásica da Expressão Gênica , Ácidos Palmíticos/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Ácidos Graxos Dessaturases/metabolismo , Humanos , Camundongos , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica
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