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1.
Cell ; 184(2): 334-351.e20, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33434495

RESUMEN

Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations.


Asunto(s)
Neoplasias/genética , Transcripción Genética , Adenocarcinoma/genética , Animales , Línea Celular Tumoral , Neoplasias del Colon/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Células HEK293 , Humanos , Ratones Desnudos , Mutación/genética , Reproducibilidad de los Resultados
2.
Cell ; 184(19): 5015-5030.e16, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-34407392

RESUMEN

Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.


Asunto(s)
Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Progresión de la Enfermedad , Inmunidad Innata , Inmunoterapia , Linfocitos/inmunología , Animales , Comunicación Celular/efectos de los fármacos , Plasticidad de la Célula/efectos de los fármacos , Neoplasias del Colon/microbiología , Heces/microbiología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunidad Innata/efectos de los fármacos , Inflamación/inmunología , Inflamación/patología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/patología , Intestinos/patología , Linfocitos/efectos de los fármacos , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Invasividad Neoplásica , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Donantes de Tejidos
3.
Cell ; 181(2): 442-459.e29, 2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32302573

RESUMEN

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.


Asunto(s)
Neoplasias del Colon/patología , Células Mieloides/metabolismo , Análisis de la Célula Individual/métodos , Adulto , Anciano , Anciano de 80 o más Años , Animales , Secuencia de Bases/genética , Linfocitos T CD8-positivos/inmunología , China , Neoplasias del Colon/terapia , Neoplasias Colorrectales/patología , Células Dendríticas/inmunología , Femenino , Humanos , Inmunoterapia , Macrófagos/inmunología , Masculino , Ratones , Persona de Mediana Edad , Análisis de Secuencia de ARN/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
4.
Cell ; 177(4): 803-805, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31051104

RESUMEN

Vasaikar et al. report a comprehensive proteogenomic analysis of 110 colon cancer samples to identify a variety of potential signaling and metabolic targets, neoantigens, and biomarkers. This resource helps expand our understanding of the fundamental pathophysiology of this tumor type, and future mechanistic studies should help guide novel therapeutic strategies for colon cancer treatment.


Asunto(s)
Neoplasias del Colon , Proteogenómica , Antígenos , Humanos
5.
Cell ; 177(4): 1035-1049.e19, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31031003

RESUMEN

We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.


Asunto(s)
Neoplasias del Colon/genética , Neoplasias del Colon/terapia , Proteogenómica/métodos , Apoptosis/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos , Proliferación Celular/genética , Neoplasias del Colon/metabolismo , Genómica/métodos , Glucólisis , Humanos , Inestabilidad de Microsatélites , Mutación , Fosforilación , Estudios Prospectivos , Proteómica/métodos , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo
6.
Nat Immunol ; 22(2): 193-204, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33398181

RESUMEN

Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.


Asunto(s)
Linfocitos T CD8-positivos/enzimología , Neoplasias del Colon/enzimología , Metabolismo Energético , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/enzimología , Melanoma Experimental/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Citotoxicidad Inmunológica , Estabilidad de Enzimas , Femenino , Glucosafosfato Deshidrogenasa/metabolismo , Glucólisis , Hexoquinasa/genética , Hexoquinasa/metabolismo , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Masculino , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Ratones Noqueados , NADP/metabolismo , Fenotipo , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Microambiente Tumoral , Quinasa de Factor Nuclear kappa B
7.
Nat Immunol ; 22(2): 179-192, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33462452

RESUMEN

Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias del Colon/metabolismo , Metabolismo Energético , Linfocitos Infiltrantes de Tumor/metabolismo , Melanoma Experimental/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/metabolismo , Timo/metabolismo , Microambiente Tumoral , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Linaje de la Célula , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Femenino , Glucosa/metabolismo , Glucólisis , Humanos , Inmunoterapia Adoptiva , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Metabolismo de los Lípidos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Técnicas de Cultivo de Órganos , Fenotipo , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante , Timo/inmunología , Carga Tumoral
8.
Nat Immunol ; 22(9): 1152-1162, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34385712

RESUMEN

The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.


Asunto(s)
Neoplasias del Colon/patología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/inmunología , Animales , Proliferación Celular/fisiología , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Factor Nuclear 1-alfa del Hepatocito/genética , Memoria Inmunológica/inmunología , Inflamación/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Transcripción Genética/genética , Proteínas Supresoras de Tumor/metabolismo
9.
Nat Immunol ; 20(10): 1335-1347, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31527834

RESUMEN

CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.


Asunto(s)
Adenocarcinoma/inmunología , Linfocitos T CD8-positivos/fisiología , Neoplasias del Colon/inmunología , Inmunoterapia/métodos , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Células Progenitoras Linfoides/fisiología , Melanoma/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Neoplasias Cutáneas/inmunología , Animales , Senescencia Celular , Citotoxicidad Inmunológica , Femenino , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Tolerancia Inmunológica , Interferón Tipo I/metabolismo , Masculino , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Transducción de Señal , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo
10.
Cell ; 165(2): 317-30, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-27058664

RESUMEN

BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Células Cultivadas , Neoplasias del Colon/clasificación , Neoplasias del Colon/tratamiento farmacológico , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Chaperonas Moleculares/genética , Trasplante de Neoplasias , Proteínas de Complejo Poro Nuclear/genética , Proteínas Proto-Oncogénicas B-raf/genética , Vinblastina/administración & dosificación , Vinblastina/farmacología , Vinorelbina
11.
Cell ; 167(7): 1803-1813.e12, 2016 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-27984728

RESUMEN

There is growing evidence that stress-coping mechanisms represent tumor cell vulnerabilities that may function as therapeutically beneficial targets. Recent work has delineated an integrated stress adaptation mechanism that is characterized by the formation of cytoplasmic mRNA and protein foci, termed stress granules (SGs). Here, we demonstrate that SGs are markedly elevated in mutant KRAS cells following exposure to stress-inducing stimuli. The upregulation of SGs by mutant KRAS is dependent on the production of the signaling lipid molecule 15-deoxy-delta 12,14 prostaglandin J2 (15-d-PGJ2) and confers cytoprotection against stress stimuli and chemotherapeutic agents. The secretion of 15-d-PGJ2 by mutant KRAS cells is sufficient to enhance SG formation and stress resistance in cancer cells that are wild-type for KRAS. Our findings identify a mutant KRAS-dependent cell non-autonomous mechanism that may afford the establishment of a stress-resistant niche that encompasses different tumor subclones. These results should inform the design of strategies to eradicate tumor cell communities.


Asunto(s)
Adenocarcinoma/patología , Neoplasias del Colon/metabolismo , Gránulos Citoplasmáticos/metabolismo , Neoplasias Pancreáticas/patología , Prostaglandina D2/análogos & derivados , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Animales , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Resistencia a Antineoplásicos , Factor 4A Eucariótico de Iniciación/metabolismo , Femenino , Xenoinjertos , Humanos , Ratones , Mutación , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Prostaglandina D2/biosíntesis , Prostaglandina D2/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Regulación hacia Arriba
12.
Nat Immunol ; 19(12): 1319-1329, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30397348

RESUMEN

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.


Asunto(s)
Adenocarcinoma/inmunología , Macrófagos/inmunología , Melanoma/inmunología , Escape del Tumor/inmunología , Microambiente Tumoral/inmunología , Acidosis/inmunología , Adenocarcinoma/metabolismo , Animales , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Glucólisis/inmunología , Humanos , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
13.
Nat Immunol ; 19(7): 723-732, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29915296

RESUMEN

Checkpoint blockade enhances effector T cell function and has elicited long-term remission in a subset of patients with a broad spectrum of cancers. TIGIT is a checkpoint receptor thought to be involved in mediating T cell exhaustion in tumors; however, the relevance of TIGIT to the dysfunction of natural killer (NK) cells remains poorly understood. Here we found that TIGIT, but not the other checkpoint molecules CTLA-4 and PD-1, was associated with NK cell exhaustion in tumor-bearing mice and patients with colon cancer. Blockade of TIGIT prevented NK cell exhaustion and promoted NK cell-dependent tumor immunity in several tumor-bearing mouse models. Furthermore, blockade of TIGIT resulted in potent tumor-specific T cell immunity in an NK cell-dependent manner, enhanced therapy with antibody to the PD-1 ligand PD-L1 and sustained memory immunity in tumor re-challenge models. This work demonstrates that TIGIT constitutes a previously unappreciated checkpoint in NK cells and that targeting TIGIT alone or in combination with other checkpoint receptors is a promising anti-cancer therapeutic strategy.


Asunto(s)
Células Asesinas Naturales/inmunología , Neoplasias Experimentales/inmunología , Receptores Inmunológicos/metabolismo , Inmunidad Adaptativa , Animales , Línea Celular , Neoplasias del Colon/inmunología , Humanos , Memoria Inmunológica , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma Experimental/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Experimentales/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/genética
14.
Cell ; 162(6): 1365-78, 2015 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-26359988

RESUMEN

The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.


Asunto(s)
Caquexia/tratamiento farmacológico , Neoplasias/patología , Receptores del Factor de Necrosis Tumoral/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/administración & dosificación , Atrofia/tratamiento farmacológico , Caquexia/patología , Muerte Celular , Neoplasias del Colon/tratamiento farmacológico , Citocina TWEAK , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Desarrollo de Músculos , Neoplasias/metabolismo , Receptores del Factor de Necrosis Tumoral/química , Receptores del Factor de Necrosis Tumoral/metabolismo , Alineación de Secuencia , Transducción de Señal , Receptor de TWEAK , Factores de Necrosis Tumoral/metabolismo
15.
CA Cancer J Clin ; 72(4): 372-401, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35472088

RESUMEN

Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000-000.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Humanos , Medicina de Precisión , Pronóstico , Microambiente Tumoral
16.
Cell ; 157(5): 1104-16, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24855947

RESUMEN

Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.


Asunto(s)
Mucosa Intestinal/fisiología , MicroARNs/metabolismo , Animales , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Sulfato de Dextran , Humanos , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Mucosa Intestinal/citología , Mesodermo/metabolismo , Ratones , MicroARNs/genética , Miofibroblastos/metabolismo , Comunicación Paracrina , Regeneración , Somatomedinas/metabolismo
17.
Cell ; 158(1): 171-84, 2014 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-24954536

RESUMEN

Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Supervivencia Celular , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares/tratamiento farmacológico , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas ras/metabolismo , Animales , Proteínas de Ciclo Celular , Neoplasias del Colon/metabolismo , Sistemas de Liberación de Medicamentos , Células HCT116 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal , Factores de Transcripción , Activación Transcripcional , Proteínas Señalizadoras YAP
18.
Cell ; 158(1): 11-2, 2014 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-24995973

RESUMEN

It is of great therapeutic importance to understand why tumors relapse after the failure of therapies targeting oncogenes to which cancer cells are addicted. In this issue, Kapoor et al. and Shao et al. identify the transcriptional coactivator YAP1 as a central driver of compensation for the loss of K-Ras signaling in K-Ras-dependent cancers.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Supervivencia Celular , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas ras/metabolismo , Animales , Proteínas de Ciclo Celular , Humanos , Factores de Transcripción , Proteínas Señalizadoras YAP
19.
Nature ; 613(7945): 743-750, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36631610

RESUMEN

DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. Here, in contrast to other cancer types3-5, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of ß2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy.


Asunto(s)
Neoplasias del Colon , Genes MHC Clase I , Antígenos de Histocompatibilidad Clase I , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Receptores de Antígenos de Linfocitos T gamma-delta , Linfocitos T , Humanos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T/inmunología , Microglobulina beta-2/deficiencia , Microglobulina beta-2/genética , Reparación de la Incompatibilidad de ADN/genética , Receptores KIR , Línea Celular Tumoral , Organoides , Presentación de Antígeno , Genes MHC Clase I/genética
20.
Nat Immunol ; 17(3): 277-85, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26808230

RESUMEN

Regulatory T (Treg) cells respond to immune and inflammatory signals to mediate immunosuppression, but how the functional integrity of Treg cells is maintained under activating environments is unclear. Here we show that autophagy is active in Treg cells and supports their lineage stability and survival fitness. Treg cell-specific deletion of Atg7 or Atg5, two essential genes in autophagy, leads to loss of Treg cells, greater tumor resistance and development of inflammatory disorders. Atg7-deficient Treg cells show increased apoptosis and readily lose expression of the transcription factor Foxp3, especially after activation. Mechanistically, autophagy deficiency upregulates metabolic regulators mTORC1 and c-Myc and glycolysis, which contribute to defective Treg function. Therefore, autophagy couples environmental signals and metabolic homeostasis to protect lineage and survival integrity of Treg cells in activating contexts.


Asunto(s)
Apoptosis/genética , Autofagia/genética , Factores de Transcripción Forkhead/genética , Proteínas Asociadas a Microtúbulos/genética , Complejos Multiproteicos/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Linfocitos T Reguladores/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Adenocarcinoma/inmunología , Traslado Adoptivo , Animales , Apoptosis/inmunología , Autofagia/inmunología , Proteína 5 Relacionada con la Autofagia , Proteína 7 Relacionada con la Autofagia , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Metilación de ADN , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Glucólisis , Homeostasis , Immunoblotting , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Trasplante de Neoplasias , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia Arriba
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