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1.
Elife ; 122024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38973593

RESUMEN

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.


Asunto(s)
Presentación de Antígeno , Dihidroorotato Deshidrogenasa , Inhibidores de Puntos de Control Inmunológico , Animales , Ratones , Humanos , Presentación de Antígeno/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de Puntos de Control Inmunológico/farmacología , Quinoxalinas/farmacología , Inhibidores Enzimáticos/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Ratones Endogámicos C57BL , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Compuestos de Bifenilo , Quinaldinas
3.
Nat Cell Biol ; 26(4): 613-627, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38429478

RESUMEN

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.


Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Pancreáticas , Animales , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Línea Celular Tumoral , Acetatos/farmacología , Acetatos/metabolismo , Neoplasias Pancreáticas/genética , Poliaminas , Microambiente Tumoral
4.
Proc Natl Acad Sci U S A ; 121(14): e2315509121, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38547055

RESUMEN

Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully understood. In this study, we investigated the role of MUC1, a mucin protein overexpressed in pancreatic cancer, in regulating polyamine metabolism. Utilizing pancreatic cancer patient data, we noted a positive correlation between MUC1 expression and the expression of key polyamine metabolism pathway genes. Functional studies revealed that knockdown of spermidine/spermine N1-acetyltransferase 1 (SAT1), a key enzyme involved in polyamine catabolism, attenuated the oncogenic functions of MUC1, including cell survival and proliferation. We further identified a regulatory axis whereby MUC1 stabilized hypoxia-inducible factor (HIF-1α), leading to increased SAT1 expression, which in turn induced carbon flux into the tricarboxylic acid cycle. MUC1-mediated stabilization of HIF-1α enhanced the promoter occupancy of the latter on SAT1 promoter and corresponding transcriptional activation of SAT1, which could be abrogated by pharmacological inhibition of HIF-1α or CRISPR/Cas9-mediated knockout of HIF1A. MUC1 knockdown caused a significant reduction in the levels of SAT1-generated metabolites, N1-acetylspermidine and N8-acetylspermidine. Given the known role of MUC1 in therapy resistance, we also investigated whether inhibiting SAT1 would enhance the efficacy of FOLFIRINOX chemotherapy. By utilizing organoid and orthotopic pancreatic cancer mouse models, we observed that targeting SAT1 with pentamidine improved the efficacy of FOLFIRINOX, suggesting that the combination may represent a promising therapeutic strategy against pancreatic cancer. This study provides insights into the interplay between MUC1 and polyamine metabolism, offering potential avenues for the development of treatments against pancreatic cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Ratones , Animales , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poliaminas/metabolismo , Transducción de Señal , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Mucina-1
5.
Methods Mol Biol ; 2755: 201-212, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38319580

RESUMEN

The hypoxic microenvironment in solid tumors affects the metabolism of tumor cells and infiltrating immune cells, which aids in robust tumor growth and expansion. Myeloid-derived suppressor cells (MDSCs) are heterogenous immature myeloid cells in the TME, which play an essential role in immune evasion by subverting T/NK cell-mediated killing. The immunosuppressive function of MDSCs is tightly regulated to the metabolic pathways, in which hypoxia plays a critical role. In this chapter, we describe the isolation of murine MDSCs from bone marrows and the measurement of the transcriptomic changes of essential metabolic enzymes under hypoxic conditions. This method can be applied to study MDSCs function, mimicking the hypoxic environment in vitro. This method can be utilized to investigate the critical metabolic alterations under a given tumor context and help evaluate the efficacy of metabolic-targeted therapies in the long run.


Asunto(s)
Perfilación de la Expresión Génica , Células Mieloides , Animales , Ratones , Hidrolasas , Hipoxia , Evasión Inmune
6.
bioRxiv ; 2024 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-37066260

RESUMEN

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is 1) strictly dependent on pyrimidine nucleotide depletion, 2) independent of canonical antigen presentation pathway transcriptional regulators, and 3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

7.
Cancer Discov ; 14(1): 176-193, 2024 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-37931287

RESUMEN

Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK-cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and antitumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC. SIGNIFICANCE: The nutrient competition among the different tumor microenvironment components drives tumor growth, immune tolerance, and therapeutic resistance. PDAC cells demand a high amount of VB6, thus competitively causing NK-cell dysfunction. Supplying VB6 with blocking VB6-dependent one-carbon metabolism amplifies the NK-cell antitumor immunity and inhibits tumor growth in PDAC models. This article is featured in Selected Articles from This Issue, p. 5.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Vitamina B 6 , Microambiente Tumoral , Células Asesinas Naturales , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Carbono
8.
Cancer Res ; 83(11): 1759-1761, 2023 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-37264829

RESUMEN

Metastasis is a key contributor to mortality in patients with cancer. While many regulators of metastasis have been identified, critical targets to prevent and inhibit metastatic tumor growth remain elusive. A recent study in this issue of Cancer Research by Deng and colleagues compared gene expression signatures between primary esophageal squamous cell carcinoma tumors and metastatic tumors and combined the analysis with genes induced in metastatic cancer cell lines, which identified anoctamin 1 (ANO1) as a key driver of metastasis. ANO1 caused cholesterol accumulation by inhibiting LXR signaling and decreased cholesterol hydroxylation by downregulating the expression of cholesterol hydroxylase CYP27A1. ANO1 also regulated tumor cell-fibroblast cross-talk that contributed to inflammatory cytokine signaling (IL1ß) and metastasis. Through in silico analysis, the study identified a novel small-molecule inhibitor of ANO1 that decreased tumor burden at a metastatic site. These studies provide novel insights into the role of ANO1 in cellular cholesterol metabolism and associated signaling in mediating metastasis. See related article by Deng et al., p. 1851.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Anoctamina-1/genética , Anoctamina-1/metabolismo , Microambiente Tumoral , Colesterol , Proteínas de Neoplasias/metabolismo
9.
Oncogene ; 41(7): 971-982, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35001076

RESUMEN

Metabolic alterations regulate cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal adenocarcinoma (PDAC) to conventional immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic enzyme screen indicated that elevated expression of CD73, an ecto-5'-nucleotidase that generates adenosine, correlates with increased aggressiveness. Correspondingly, we observed increased interstitial adenosine levels in tumors from spontaneous PDAC mouse models. Diminishing CD73 by genetic manipulations ablated in vivo tumor growth, and decreased myeloid-derived suppressor cells (MDSC) in orthotopic mouse models of PDAC. A high-throughput cytokine profiling demonstrated decreased GM-CSF in mice implanted with CD73 knockdowns. Furthermore, we noted increased IFN-γ expression by intratumoral CD4+ and CD8+ T cells in pancreatic tumors with CD73 knockdowns. Depletion of CD4+ T cells, but not CD8+ T cells abrogated the beneficial effects of decreased CD73. We also observed that splenic MDSCs from Nt5e knockdown tumor-bearing mice were incompetent in suppressing T cell activation in the ex vivo assays. Replenishing GM-CSF restored tumor growth in Nt5e knockout tumors, which was reverted by MDSC depletion. Finally, anti-CD73 antibody treatment significantly improved gemcitabine efficacy in orthotopic models. Thus, targeting the adenosine axis presents a novel therapeutic opportunity for improving the anti-tumoral immune response against PDAC.


Asunto(s)
Células Supresoras de Origen Mieloide
10.
Trends Immunol ; 43(1): 78-92, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34942082

RESUMEN

Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies.


Asunto(s)
Aterosclerosis , Neoplasias , Animales , Antiinflamatorios , Colesterol/metabolismo , Humanos , Inmunidad Innata , Mamíferos , Neoplasias/tratamiento farmacológico
11.
Trends Immunol ; 43(2): 93-95, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34953686

RESUMEN

Tumor progression is known occur in a complex microenvironment that leads to genetic, cellular, and metabolic adaptations. Two articles from Martin et al. and Del Poggetto et al. enlighten us on the role of inflammation and the immune system in guiding the progression of preneoplastic cells to oncogenic transformation and on subsequent tumor evolution.


Asunto(s)
Neoplasias , Microambiente Tumoral , Carcinogénesis , Transformación Celular Neoplásica/genética , Humanos , Inflamación
12.
Mol Cancer Ther ; 20(12): 2457-2468, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34625505

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Inmunoglobulina E/uso terapéutico , Animales , Humanos , Inmunoglobulina E/farmacología , Ratones
13.
Gastroenterology ; 161(5): 1584-1600, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34245764

RESUMEN

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/enzimología , Metabolismo Energético , Neoplasias Pancreáticas/enzimología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Sirtuinas/deficiencia , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Aspartato Aminotransferasa Citoplasmática/genética , Aspartato Aminotransferasa Citoplasmática/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Progresión de la Enfermedad , Metabolismo Energético/efectos de los fármacos , Activación Enzimática , Activadores de Enzimas/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Mutación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal , Sirtuinas/genética , Carga Tumoral , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
14.
Cancers (Basel) ; 13(9)2021 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-34066839

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Tumor hypoxia plays an active role in promoting tumor progression, malignancy, and resistance to therapy in PDAC. We present evidence that nab-paclitaxel-gemcitabine (NPG) and/or a hypoxic tumor microenvironment (TME) up-regulate heme oxygenase-1 (HO-1), providing a survival advantage for tumors. Using PDAC cells in vitro and a PDAC mouse model, we found that NPG chemotherapy up-regulated expression of HO-1 in PDAC cells and increased its nuclear translocation. Inhibition of HO-1 with ZnPP and SnPP sensitized PDAC cells to NPG-induced cytotoxicity (p < 0.05) and increased apoptosis (p < 0.05). Additionally, HO-1 expression was increased in gemcitabine-resistant PDAC cells (p < 0.05), and HO-1 inhibition increased GEM-resistant PDAC sensitivity to NPG (p < 0.05). NPG combined with HO-1 inhibitor inhibited tumor size in an orthotopic model. In parallel, HO-1 inhibition abrogated the influx of macrophages and FoxP3+ cells, while increasing the proportion of CD8+ infiltration in the pancreatic tumors. These effects were mediated primarily by reducing expression of the immunosuppressive cytokine IL-10.

15.
Curr Protoc Pharmacol ; 91(1): e80, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33264501

RESUMEN

Cancer-associated cachexia is defined by loss of weight and muscle mass, and by the potential loss of adipose tissue accompanied by insulin resistance and increased resting energy expenditure. Cachexia is most prevalent in pancreatic cancer, the third leading cause of cancer-related deaths. While various factors interact to induce cachexia, the precise mechanisms underlying this clinical condition are not fully understood. Clinically relevant animal models of cachexia are needed given the lack of standard diagnostic methods or treatments for this condition. Described in this article are in vitro and in vivo models used to study the role of macrophages in the induction of cachexia in pancreatic cancer. Included are procedures for isolating and culturing bone marrow-derived macrophages, harvesting tumor- and macrophage-derived conditioned medium, and studying the effect of conditioned medium on C2C12 myotubes. Also described are procedures involving the use of an orthotopic model of pancreatic cancer, including a method for examining skeletal muscle atrophy in this model. © 2020 Wiley Periodicals LLC. Basic Protocol 1: In vitro model of pancreatic tumor-induced cachexia using C2C12 cell lines (myotube model) Support Protocol 1: Molecular evaluation of cachectic markers in C2C12 myotubes using real-time PCR and immunoblotting Basic Protocol 2: In vivo model to study cachectic phenotype in pancreatic tumor-bearing mice Support Protocol 2: Evaluation of cachectic markers in the skeletal muscle of tumor-bearing mice.


Asunto(s)
Caquexia/patología , Macrófagos/citología , Neoplasias Pancreáticas/patología , Animales , Técnicas de Cultivo de Célula , Línea Celular , Medios de Cultivo Condicionados , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/efectos de los fármacos , Músculo Esquelético/patología , Atrofia Muscular/patología , Neoplasias Pancreáticas
16.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188387, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32579889

RESUMEN

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Inmunoterapia/métodos , Neoplasias Pancreáticas/terapia , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Animales , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/patología , Vacunas contra el Cáncer/administración & dosificación , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante/métodos , Ensayos Clínicos como Asunto , Terapia Combinada/métodos , Modelos Animales de Enfermedad , Supervivencia sin Enfermedad , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Inmunidad Innata/efectos de los fármacos , Irinotecán/farmacología , Irinotecán/uso terapéutico , Leucovorina/farmacología , Leucovorina/uso terapéutico , Escisión del Ganglio Linfático , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Ratones , Ratones Transgénicos , Terapia Neoadyuvante/métodos , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Páncreas/inmunología , Páncreas/patología , Páncreas/cirugía , Pancreatectomía , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Bazo/inmunología , Bazo/patología , Bazo/cirugía , Esplenectomía , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/trasplante , Trasplante Autólogo/métodos
17.
J Exp Med ; 217(7)2020 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-32441762

RESUMEN

Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell-induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell-mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1-Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer-induced cachexia.


Asunto(s)
Caquexia/complicaciones , Caquexia/metabolismo , NADPH Oxidasa 4/metabolismo , Neoplasias/complicaciones , Neoplasias/metabolismo , Transducción de Señal , Sirtuina 1/metabolismo , Tejido Adiposo/patología , Animales , Línea Celular , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Factores de Transcripción Forkhead/metabolismo , Células HEK293 , Humanos , Metaboloma/efectos de los fármacos , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , FN-kappa B/metabolismo , Oxidación-Reducción , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Estabilidad Proteica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/farmacología , Transducción de Señal/efectos de los fármacos , Síndrome Debilitante/patología
18.
Cancer Lett ; 484: 29-39, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32344015

RESUMEN

Incidence of cachexia is highly prevalent in pancreatic ductal adenocarcinoma (PDAC); advanced disease stage directly correlates with decreased muscle and fat mass in PDAC patients. The pancreatic tumor microenvironment is central to the release of systemic factors that govern lipolysis, proteolysis, and muscle and fat degeneration leading to the cachectic phenotype in cancer patients. The current study explores the role of macrophages, a key immunosuppressive player in the pancreatic tumor microenvironment, in regulating cancer cachexia. We observed a negative correlation between CD163-positive macrophage infiltration and muscle-fiber cross sectional area in human PDAC patients. To investigate the role of macrophages in myodegeneration, we utilized conditioned media transplant assays and orthotopic models of PDAC-induced cachexia in immune-competent mice with and without macrophage depletion. We observed that macrophage-derived conditioned medium, in combination with tumor cell-conditioned medium, promoted muscle atrophy through STAT3 signaling. Furthermore, macrophage depletion attenuated systemic inflammation and muscle wasting in pancreatic tumor-bearing mice. Targeting macrophage-mediated STAT3 activation or macrophage-derived interleukin-1 alpha or interleukin-6 diminished myofiber atrophy. Taken together, the current study identified the critical association between macrophages and cachexia phenotype in pancreatic cancer.


Asunto(s)
Caquexia/inmunología , Macrófagos/inmunología , Músculo Esquelético/inmunología , Neoplasias Pancreáticas/inmunología , Factor de Transcripción STAT3/inmunología , Transducción de Señal/inmunología , Animales , Caquexia/metabolismo , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Citocinas/sangre , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/inmunología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neoplasias Pancreáticas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
19.
Clin Cancer Res ; 26(1): 6-8, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31628144

RESUMEN

Through metabolic subtyping, metabolic vulnerabilities can be exploited for developing efficacious treatments. A glycolytic subtype indicates poor survival in patients with pancreatic cancer, whereas a cholesterogenic subtype correlates with better outcomes potentially due to more energy expenditure. Personalized medicine holds great promise for improving therapy outcomes by optimally targeting metabolic pathways.See related article by Karasinska et al., p. 135.


Asunto(s)
Glucólisis , Neoplasias Pancreáticas , Colesterol , Humanos , Terapia Molecular Dirigida , Medicina de Precisión
20.
Trends Cancer ; 5(12): 822-834, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31813459

RESUMEN

Macrophages act as scavengers, modulating the immune response against pathogens and maintaining tissue homeostasis. Metabolism governs macrophage differentiation, polarization, mobilization, and the ability to mount an effective antitumor response. However, in cancer, the tumor microenvironment (TME) can actively reprogram macrophage metabolism either by direct exchange of metabolites or through cytokines and other signaling mediators. Thus, metabolic reprogramming holds potential for modulating macrophages and developing new therapeutic approaches. In this review, we provide an overview of macrophage metabolism as it relates to macrophage function and plasticity in cancer.


Asunto(s)
Macrófagos/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/inmunología , Humanos
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