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1.
Mol Cell ; 81(2): 386-397.e7, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33340488

RESUMEN

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.


Asunto(s)
Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Mamarias Experimentales/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Fosfoglicerato-Deshidrogenasa/genética , Serina/biosíntesis , Animales , Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfoglicerato-Deshidrogenasa/antagonistas & inhibidores , Fosfoglicerato-Deshidrogenasa/metabolismo , Ácido Pirúvico/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Sirolimus/farmacología
2.
Nature ; 605(7911): 747-753, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35585241

RESUMEN

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlow cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvß3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow cancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness.


Asunto(s)
Neoplasias de la Mama , Metástasis de la Neoplasia , Fosfoglicerato-Deshidrogenasa , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Femenino , Silenciador del Gen , Humanos , Ratones , Fosfoglicerato-Deshidrogenasa/genética , Serina/metabolismo
3.
Nature ; 568(7750): 117-121, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30814728

RESUMEN

The extracellular matrix is a major component of the local environment-that is, the niche-that determines cell behaviour1. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth2,3. However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen, because nutrients dictate which enzymatic reactions are active in cancer cells4,5. Here we show that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodelling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (P4HA). Inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast-cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodelling and the nutrient environment in the metastatic niche.


Asunto(s)
Neoplasias de la Mama/patología , Metástasis de la Neoplasia/patología , Ácido Pirúvico/metabolismo , Animales , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Colágeno/química , Colágeno/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Humanos , Hidroxilación/efectos de los fármacos , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Procolágeno-Prolina Dioxigenasa/metabolismo , Ácido Pirúvico/farmacología , Microambiente Tumoral/efectos de los fármacos
6.
Nat Chem Biol ; 14(11): 1032-1042, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30297875

RESUMEN

α-Ketoglutarate (αKG) is a key node in many important metabolic pathways. The αKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit αKG-dependent dioxygenases. However, whether NOG interference with other αKG-dependent processes contributes to its mode of action remains poorly understood. Here we show that, in aqueous solutions, DMOG is rapidly hydrolyzed, yielding methyloxalylglycine (MOG). MOG elicits cytotoxicity in a manner that depends on its transport by monocarboxylate transporter 2 (MCT2) and is associated with decreased glutamine-derived tricarboxylic acid-cycle flux, suppressed mitochondrial respiration and decreased ATP production. MCT2-facilitated entry of MOG into cells leads to sufficiently high concentrations of NOG to inhibit multiple enzymes in glutamine metabolism, including glutamate dehydrogenase. These findings reveal that MCT2 dictates the mode of action of NOG by determining its intracellular concentration and have important implications for the use of (D)MOG in studying αKG-dependent signaling and metabolism.


Asunto(s)
Aminoácidos Dicarboxílicos/química , Ácidos Cetoglutáricos/química , Transportadores de Ácidos Monocarboxílicos/metabolismo , Adenosina Trifosfato/química , Animales , Fenómenos Bioquímicos , Bovinos , Línea Celular Tumoral , Ciclo del Ácido Cítrico , Perfilación de la Expresión Génica , Glutamina/metabolismo , Humanos , Hidrólisis , Concentración 50 Inhibidora , Células MCF-7 , Metabolómica , Ratones , Mitocondrias/metabolismo , Oxígeno/química , Puromicina/química , Transducción de Señal , Ácidos Tricarboxílicos/química
7.
Nat Cancer ; 5(8): 1206-1226, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38844817

RESUMEN

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.


Asunto(s)
Resistencia a Antineoplásicos , Inmunoterapia , Uridina Difosfato , Humanos , Uridina Difosfato/metabolismo , Inmunoterapia/métodos , Resistencia a Antineoplásicos/inmunología , Animales , Ratones , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/tratamiento farmacológico , Citidina Desaminasa/metabolismo , Citidina Desaminasa/genética , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Línea Celular Tumoral , Receptores Purinérgicos P2/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Nucleótidos/metabolismo , Tolerancia Inmunológica , Receptor de Muerte Celular Programada 1
8.
J Exp Clin Cancer Res ; 42(1): 92, 2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37072838

RESUMEN

BACKGROUND: One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance. METHODS: Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity. RESULTS: We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity. CONCLUSIONS: We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.


Asunto(s)
Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Especies Reactivas de Oxígeno/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Lípidos de la Membrana/farmacología , Lípidos de la Membrana/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos
9.
Nat Cancer ; 4(3): 344-364, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36732635

RESUMEN

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.


Asunto(s)
Lisina Acetiltransferasas , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Carnitina O-Palmitoiltransferasa/metabolismo , Acetilación , Acetilcoenzima A/metabolismo , Palmitatos , Lisina Acetiltransferasas/metabolismo
10.
Cancer Res ; 80(19): 4087-4102, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32718996

RESUMEN

Cancer stem-like cells (CSC) induce aggressive tumor phenotypes such as metastasis formation, which is associated with poor prognosis in triple-negative breast cancer (TNBC). Repurposing of FDA-approved drugs that can eradicate the CSC subcompartment in primary tumors may prevent metastatic disease, thus representing an effective strategy to improve the prognosis of TNBC. Here, we investigated spheroid-forming cells in a metastatic TNBC model. This strategy enabled us to specifically study a population of long-lived tumor cells enriched in CSCs, which show stem-like characteristics and induce metastases. To repurpose FDA-approved drugs potentially toxic for CSCs, we focused on pyrvinium pamoate (PP), an anthelmintic drug with documented anticancer activity in preclinical models. PP induced cytotoxic effects in CSCs and prevented metastasis formation. Mechanistically, the cell killing effects of PP were a result of inhibition of lipid anabolism and, more specifically, the impairment of anabolic flux from glucose to cholesterol and fatty acids. CSCs were strongly dependent upon activation of lipid biosynthetic pathways; activation of these pathways exhibited an unfavorable prognostic value in a cohort of breast cancer patients, where it predicted high probability of metastatic dissemination and tumor relapse. Overall, this work describes a new approach to target aggressive CSCs that may substantially improve clinical outcomes for patients with TNBC, who currently lack effective targeted therapeutic options. SIGNIFICANCE: These findings provide preclinical evidence that a drug repurposing approach to prevent metastatic disease in TNBC exploits lipid anabolism as a metabolic vulnerability against CSCs in primary tumors.


Asunto(s)
Antineoplásicos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Compuestos de Pirvinio/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Colesterol/metabolismo , Reposicionamiento de Medicamentos , Femenino , Glucosa/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Ratones Endogámicos NOD , Células Madre Neoplásicas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Nat Commun ; 11(1): 1393, 2020 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-32170132

RESUMEN

Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.


Asunto(s)
Aminoácidos/metabolismo , Carcinoma Hepatocelular/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Hepatocitos/metabolismo , Neoplasias Hepáticas/metabolismo , Diferenciación Celular/fisiología , Línea Celular Tumoral , Citocromo P-450 CYP3A , Femenino , Técnicas de Inactivación de Genes , Células Hep G2 , Factor Nuclear 1-alfa del Hepatocito , Factor Nuclear 3-gamma del Hepatocito , Ensayos Analíticos de Alto Rendimiento , Proteínas de Homeodominio , Humanos , Hígado , Masculino , Ingeniería Metabólica , Redes y Vías Metabólicas , Persona de Mediana Edad , Células Madre Pluripotentes , Células Madre , Transcriptoma , Proteínas Supresoras de Tumor
12.
Front Oncol ; 9: 219, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31069166

RESUMEN

Metastasis formation is the leading cause of death in cancer patients. Thus, understanding and targeting this process is an unmet need. Crucial steps during the establishment of metastases include the (pre)metastatic niche formation. This process relies on the interaction of the primary tumor with the environment of distant organs (premetastatic niche) and the interaction of cancer cells with their environment when arriving in a distant organ (metastatic niche). Here, we summarize the current knowledge on the interactions in the tumor environment that result in (pre)metastatic niche formation, specifically in the context of tumor secreted factors, extracellular matrix, immune as well as stromal cells, and nutrient availability. We further highlight strategies to disrupt these interactions as therapeutic interventions against metastases.

13.
Trends Cell Biol ; 28(8): 673-684, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29747903

RESUMEN

Metastasis to distant organs is a predictor of poor prognosis. Therefore, it is of paramount importance to understand the mechanisms that impinge on the different steps of the metastatic cascade. Recent work has revealed that particular metabolic pathways are rewired in cancer cells to support their transition through the metastatic cascade, resulting in the formation of secondary tumors in distant organs. Indeed, metabolic rewiring induces signaling pathways during initial cancer invasion, circulating cancer cells depend on enhanced antioxidant defenses, and cancer cells colonizing a distant organ require increased ATP production. Moreover, the local environment of the metastatic niche dictates the metabolic pathways secondary tumors rely on. Here we describe mechanisms of metabolic rewiring associated with distinct steps of metastasis formation.


Asunto(s)
Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , Adenosina Trifosfato/metabolismo , Animales , Humanos
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