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1.
Nature ; 568(7752): 410-414, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30918400

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2-4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and-in the case of PDAC-the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface-where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth-is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.


Asunto(s)
Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Pinocitosis , Sindecano-1/metabolismo , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Masculino , Ratones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal
2.
Nature ; 542(7641): 362-366, 2017 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-28178232

RESUMEN

Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.


Asunto(s)
Mesodermo/patología , Neoplasias Pancreáticas/patología , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Estrés del Retículo Endoplásmico/genética , Femenino , Genes myc , Genes ras , Humanos , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Mesodermo/metabolismo , Ratones , Mosaicismo , Proteína Oncogénica p55(v-myc)/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína SMARCB1/deficiencia , Proteína SMARCB1/metabolismo , Transcriptoma/genética , Gemcitabina
3.
BMC Cancer ; 22(1): 794, 2022 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-35854230

RESUMEN

BACKGROUND: Prostate cancer (PCa) is the second most common cancer in men worldwide. The standard non-surgical approach for localized PCa is radiotherapy (RT), but one of the limitations of high-dose RT is the potential increase in gastrointestinal and genitourinary toxicities. We present the protocol of the Microstyle study, a multicentre randomized two-arm crossover clinical trial. The primary outcome will be assessed at the end of 6-month intervention, by measuring the change in adherence to a healthy lifestyle score. The hypothesis is that modifying lifestyle we change microbiome and improve quality of life and decrease side effects of RT. METHODS: Study participants will be recruited among men undergoing RT in two Italian centers (Milan and Naples). We foresee to randomize 300 patients in two intervention arms: Intervention Group (IG) and Control Group (CG). Participants allocated to the IG will meet a dietitian and a physiotherapist before RT to receive personalized diet and exercise recommendations, according to their health status, to improve overall lifestyle and reduce side effects (bowel and/or urinary problems). Dietitian and physiotherapist will work together to set individualized goals to reduce or eliminate side effects and pain according to their health status. All participants (IG) will be given a pedometer device (steps counter) in order to monitor and to spur participants to increase physical activity and reduce sedentary behavior. Participants included in the CG will receive baseline general advice and materials available for patients undergoing RT. According to the cross-over design, the CG will cross to the intervention approach after 6-month, to actively enhance compliance towards suggested lifestyle recommendations for all patients. DISCUSSION: This trial is innovative in its design because we propose a lifestyle intervention during RT, that includes both dietary and physical activity counselling, as well as monitoring changes in microbiome and serum biomarkers. The promotion of healthy behaviour will be initiated before initiation of standard care, to achieve long lasting effects, controlling side effects, coping with feelings of anxiety and depression and improve efficacy of RT. TRIAL REGISTRATION: ClincalTrial.gov registration number: NCT05155618 . Retrospectively registered on December 13, 2021. The first patient was enrolled on October 22, 2021.


Asunto(s)
Estilo de Vida , Microbiota , Neoplasias de la Próstata , Estudios Cruzados , Humanos , Masculino , Estudios Multicéntricos como Asunto , Neoplasias de la Próstata/microbiología , Neoplasias de la Próstata/radioterapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Conducta Sedentaria
4.
Nature ; 514(7524): 628-32, 2014 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-25119024

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Mitocondrias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Autofagia , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Respiración de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Genes p53/genética , Glucólisis , Lisosomas/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Mutación/genética , Recurrencia Local de Neoplasia/prevención & control , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fosforilación Oxidativa/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Recurrencia , Transducción de Señal , Neoplasias Pancreáticas
5.
Proc Natl Acad Sci U S A ; 114(43): E9086-E9095, 2017 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-29073105

RESUMEN

An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)-associated factor (PAF) up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumor-initiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways. PAF interacts with PCNA and regulates PCNA-associated DNA translesion synthesis (TLS); consequently, PAF depletion in combination with radiation generated fewer tumorspheres compared with radiation alone. Correspondingly, pharmacological impairment of DNA replication and TLS phenocopied the effect of PAF depletion in compromising GSC self-renewal and radioresistance, providing preclinical proof of principle that combined TLS inhibition and radiation therapy may be a viable therapeutic option in the treatment of glioblastoma multiforme (GBM).


Asunto(s)
Neoplasias Encefálicas/radioterapia , Proteínas Portadoras/genética , Glioblastoma/radioterapia , Células Madre Neoplásicas/efectos de la radiación , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Proteínas Portadoras/metabolismo , Daño del ADN/genética , Daño del ADN/efectos de la radiación , Reparación del ADN/genética , Reparación del ADN/efectos de la radiación , Replicación del ADN/efectos de los fármacos , Proteínas de Unión al ADN , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Proteínas Fluorescentes Verdes/genética , Humanos , Ratones SCID , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Pirimidinas/biosíntesis , Tolerancia a Radiación , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Proc Natl Acad Sci U S A ; 113(9): E1296-305, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26884185

RESUMEN

PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2(E824)*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57(KIP2)). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.


Asunto(s)
Factores de Intercambio de Guanina Nucleótido/metabolismo , Melanoma Experimental/metabolismo , Mutación , Animales , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Melanoma Experimental/genética , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal
7.
Nature ; 482(7383): 53-8, 2012 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-22258507

RESUMEN

The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.


Asunto(s)
Aneuploidia , Rotura Cromosómica , Micronúcleos con Defecto Cromosómico , Mitosis , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Segregación Cromosómica , Ensayo Cometa , Fragmentación del ADN , Replicación del ADN , Humanos , Mitosis/genética , Neoplasias/etiología , Neoplasias/genética , Neoplasias/patología
8.
Nature ; 488(7411): 337-42, 2012 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-22895339

RESUMEN

Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Genes Esenciales/genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Terapia Molecular Dirigida/métodos , Eliminación de Secuencia/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Cromosomas Humanos Par 1/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Genes Supresores de Tumor , Glioblastoma/patología , Homocigoto , Humanos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Ratones , Trasplante de Neoplasias , Ácido Fosfonoacético/análogos & derivados , Ácido Fosfonoacético/farmacología , Ácido Fosfonoacético/uso terapéutico , Fosfopiruvato Hidratasa/antagonistas & inhibidores , Fosfopiruvato Hidratasa/deficiencia , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , ARN Interferente Pequeño/genética , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética
10.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167311, 2024 10.
Artículo en Inglés | MEDLINE | ID: mdl-38909851

RESUMEN

Tumours exhibit significant heterogeneity in their molecular profiles across patients, largely influenced by the tissue of origin, where certain driver gene mutations are predominantly associated with specific cancer types. Here, we unveil an additional layer of complexity: some cancer types display anatomic location-specific mutation profiles akin to tissue-specificity. To better understand this phenomenon, we concentrate on colon cancer. While prior studies have noted changes of the frequency of molecular alterations along the colon, the underlying reasons and whether those changes occur rather gradual or are distinct between the left and right colon, remain unclear. Developing and leveraging stringent statistical models on molecular data from 522 colorectal tumours from The Cancer Genome Atlas, we reveal disparities in molecular properties between the left and right colon affecting many genes. Interestingly, alterations in genes responsive to environmental cues and properties of the tumour ecosystem, including metabolites which we quantify in a cohort of 27 colorectal cancer patients, exhibit continuous trends along the colon. Employing network methodologies, we uncover close interactions between metabolites and genes, including drivers of colon cancer, showing continuous abundance or alteration profiles. This underscores how anatomic biases in the composition and interactions within the tumour ecosystem help explaining gradients of carcinogenesis along the colon.


Asunto(s)
Colon , Mutación , Humanos , Colon/metabolismo , Colon/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica
11.
Biofabrication ; 17(1)2024 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-39332448

RESUMEN

The dysregulation of the immune system plays a crucial role in the pathogenesis of manyfold diseases, among which we find rheumatoid arthritis (RA), an autoimmune disease characterized by chronic inflammation in synovial joints, leading to pain and disability. Immune cells such as pro-inflammatory macrophages and T helper 1 (Th1) cells drive the inflammatory cascade. Thus, including immune system inin vitromodels is pivotal to recapitulate and better understand the complex interactions between these immune cell subsets and their secreted mediators. Here, a compartmentalized microfluidic platform is presented, for precise confinement of circulating immune cells in organs-on-chip. The integration of innovative normally-closed sieving valves allows, through minimal waste of biological material, to co-culture different immune cell types (e.g. macrophages and Th1). Moreover, the platform allows to stimulate cell subsets separately, and to assess their cross-talk at desired time points. Functional validation of the platform demonstrates its ability to create stable chemotactic gradients, allowing for induction and evaluation of Th1 cells migration. In a proof-of-concept study, the platform allowed to assess Th1 T cells migration towards pro-inflammatory macrophages, thus replicating a characteristic interaction among immune cells triggered during RA onset. These results thus support the suitability of the platform to study immune cells cross-talk and migration phenomena, being potentially applicable to a manyfold immune cell mechanisms, both involved in RA progression and in different immune-mediated pathologies.


Asunto(s)
Artritis Reumatoide , Macrófagos , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Dispositivos Laboratorio en un Chip , Células TH1/inmunología , Movimiento Celular , Técnicas de Cocultivo , Comunicación Celular , Microfluídica/instrumentación , Microfluídica/métodos
12.
Nat Commun ; 15(1): 7366, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39191730

RESUMEN

The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.


Asunto(s)
Linfocitos T CD8-positivos , Histona Demetilasas , Inmunoterapia Adoptiva , Ratones Endogámicos C57BL , Animales , Histona Demetilasas/metabolismo , Histona Demetilasas/antagonistas & inhibidores , Inmunoterapia Adoptiva/métodos , Ratones , Femenino , Linfocitos T CD8-positivos/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Línea Celular Tumoral , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Humanos , Melanoma/inmunología , Melanoma/terapia
13.
EBioMedicine ; 99: 104914, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38113759

RESUMEN

BACKGROUND: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. METHODS: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. FINDINGS: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. INTERPRETATION: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.


Asunto(s)
Hemangioma Cavernoso del Sistema Nervioso Central , Animales , Humanos , Masculino , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/etiología , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Asociadas a Microtúbulos/genética , Pez Cebra/metabolismo , Biomarcadores , Convulsiones , Antígenos de Neoplasias , Moléculas de Adhesión Celular
14.
Nat Med ; 30(3): 785-796, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38365950

RESUMEN

Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.


Asunto(s)
Microbioma Gastrointestinal , Melanoma , Microbiota , Humanos , Microbioma Gastrointestinal/genética , Melanoma/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Cognición
15.
Cell Metab ; 35(6): 907-909, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-37285805

RESUMEN

The composition of nutrients in the tumor microenvironment is a key determinant of anti-tumor CD8+ T cell response. In this issue of Cell Metabolism, Jiang and colleagues unveil that tumor-derived fumarate dampens TCR signaling in CD8+ T cells, resulting in defective activation, loss of effector functions, and associated failure of tumor control.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Linfocitos T CD8-positivos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias/metabolismo , Transducción de Señal , Microambiente Tumoral
16.
Cell Host Microbe ; 31(6): 919-920, 2023 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-37321175

RESUMEN

The use of bacterial colonists as therapy carriers is gaining interest for treating cancer. In a recent publication in Science, the work by Chen et al. proposes the engineering of a commensal bacterium of the human skin microbiota to cross-present tumor antigens to T cells and counteract tumor progression.


Asunto(s)
Microbiota , Neoplasias , Humanos , Piel/microbiología , Bacterias/genética , Linfocitos T , Neoplasias/terapia
17.
Genome Med ; 15(1): 32, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-37131219

RESUMEN

BACKGROUND: The association between microbes and cancer has been reported repeatedly; however, it is not clear if molecular tumour properties are connected to specific microbial colonisation patterns. This is due mainly to the current technical and analytical strategy limitations to characterise tumour-associated bacteria. METHODS: Here, we propose an approach to detect bacterial signals in human RNA sequencing data and associate them with the clinical and molecular properties of the tumours. The method was tested on public datasets from The Cancer Genome Atlas, and its accuracy was assessed on a new cohort of colorectal cancer patients. RESULTS: Our analysis shows that intratumoural microbiome composition is correlated with survival, anatomic location, microsatellite instability, consensus molecular subtype and immune cell infiltration in colon tumours. In particular, we find Faecalibacterium prausnitzii, Coprococcus comes, Bacteroides spp., Fusobacterium spp. and Clostridium spp. to be strongly associated with tumour properties. CONCLUSIONS: We implemented an approach to concurrently analyse clinical and molecular properties of the tumour as well as the composition of the associated microbiome. Our results may improve patient stratification and pave the path for mechanistic studies on microbiota-tumour crosstalk.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Microbiota , Humanos , Neoplasias Colorrectales/genética , Neoplasias del Colon/genética , Bacterias/genética , Análisis de Secuencia de ARN
18.
Nat Metab ; 5(9): 1563-1577, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37653041

RESUMEN

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.


Asunto(s)
Glicerol , Neoplasias Ováricas , Humanos , Femenino , Adipocitos , Glucosa , Fosfatos , Microambiente Tumoral
19.
Cell Metab ; 35(4): 633-650.e9, 2023 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-36898381

RESUMEN

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.


Asunto(s)
Linfocitos T CD8-positivos , Ácido Linoleico , Ácido Linoleico/metabolismo , Transducción de Señal
20.
Nat Commun ; 13(1): 6752, 2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-36347862

RESUMEN

CD8+ T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8+ T effector memory cells (TEM) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8+ T cells. As a consequence of the contact-mediated interaction with neutrophils, CD8+ T cells are skewed to produce high levels of GZMK, which in turn decreases E-cadherin on the intestinal epithelium and favors tumor progression. Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in non-metastatic CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias Colorrectales , Humanos , Neutrófilos , Neoplasias Colorrectales/patología , Linfocitos Infiltrantes de Tumor
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