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1.
Cell Death Dis ; 15(4): 255, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600086

RESUMEN

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.


Asunto(s)
Neoplasias del Colon , Indoles , Interleucina-11 , Humanos , Interleucina-11/uso terapéutico , Línea Celular Tumoral , Interleucina-6/metabolismo , Receptor gp130 de Citocinas/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Apoptosis
2.
Nat Commun ; 15(1): 3363, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38637494

RESUMEN

Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.


Asunto(s)
Neoplasias Colorrectales , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Colorrectales/patología , Células Madre Neoplásicas/metabolismo , Fenotipo
3.
Genome Biol ; 25(1): 81, 2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38553769

RESUMEN

The use of single-cell technologies for clinical applications requires disconnecting sampling from downstream processing steps. Early sample preservation can further increase robustness and reproducibility by avoiding artifacts introduced during specimen handling. We present FixNCut, a methodology for the reversible fixation of tissue followed by dissociation that overcomes current limitations. We applied FixNCut to human and mouse tissues to demonstrate the preservation of RNA integrity, sequencing library complexity, and cellular composition, while diminishing stress-related artifacts. Besides single-cell RNA sequencing, FixNCut is compatible with multiple single-cell and spatial technologies, making it a versatile tool for robust and flexible study designs.


Asunto(s)
Genómica , ARN , Humanos , Animales , Ratones , Fijación del Tejido/métodos , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN/métodos , ARN/genética , Genómica/métodos , Análisis de la Célula Individual/métodos
4.
J Hepatol ; 80(4): 634-644, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38160941

RESUMEN

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Animales , Humanos , Ratones , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Línea Celular Tumoral , Interleucina-10 , Neoplasias Hepáticas/patología , Receptores de Interleucina-10 , Microambiente Tumoral
5.
EMBO J ; 42(9): e111494, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-36919984

RESUMEN

Tumor growth is influenced by a complex network of interactions between multiple cell types in the tumor microenvironment (TME). These constrained conditions trigger the endoplasmic reticulum (ER) stress response, which extensively reprograms mRNA translation. When uncontrolled over time, chronic ER stress impairs the antitumor effector function of CD8 T lymphocytes. How cells promote adaptation to chronic stress in the TME without the detrimental effects of the terminal unfolded protein response (UPR) is unknown. Here, we find that, in effector CD8 T lymphocytes, RNA-binding protein CPEB4 constitutes a new branch of the UPR that allows cells to adapt to sustained ER stress, yet remains decoupled from the terminal UPR. ER stress, induced during CD8 T-cell activation and effector function, triggers CPEB4 expression. CPEB4 then mediates chronic stress adaptation to maintain cellular fitness, allowing effector molecule production and cytotoxic activity. Accordingly, this branch of the UPR is required for the antitumor effector function of T lymphocytes, and its disruption in these cells exacerbates tumor growth.


Asunto(s)
Estrés del Retículo Endoplásmico , Neoplasias , Humanos , Estrés del Retículo Endoplásmico/genética , Respuesta de Proteína Desplegada , Neoplasias/metabolismo , Linfocitos T CD8-positivos/metabolismo , Adaptación Fisiológica , Microambiente Tumoral , Proteínas de Unión al ARN/metabolismo
6.
Nat Commun ; 14(1): 746, 2023 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-36765091

RESUMEN

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.


Asunto(s)
Antineoplásicos , Fibroblastos Asociados al Cáncer , Neoplasias Colorrectales , Humanos , Fibroblastos Asociados al Cáncer/patología , Oxaliplatino/farmacología , Distribución Tisular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Microambiente Tumoral , Fibroblastos/patología , Línea Celular Tumoral
7.
J Med Chem ; 66(5): 3348-3355, 2023 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-36808993

RESUMEN

The relative success of platinum (Pt)-based chemotherapy comes at the cost of severe adverse side effects and is associated with a high risk of pro-oncogenic activation in the tumor microenvironment. Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptide conjugate showing a reduced impact against nonmalignant cells. In vitro and in vivo evaluation using patient-derived tumor organoids and laser ablation inductively coupled plasma mass spectrometry indicates that C-POC maintains robust anticancer efficacy while displaying diminished accumulation in healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy. Likewise, C-POC uptake is significantly lowered in the noncancerous cells populating the tumor microenvironment. This results in the downregulation of versican, a biomarker of metastatic spreading and chemoresistance that we found upregulated in patients treated with standard Pt-based therapy. Altogether, our findings underscore the importance of considering the off-target impact of anticancer treatment on normal cells to improve drug development and patient care.


Asunto(s)
Antineoplásicos , Platino (Metal) , Humanos , Platino (Metal)/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Péptidos/farmacología , Péptidos/uso terapéutico , Línea Celular Tumoral
8.
Nat Commun ; 14(1): 373, 2023 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-36690670

RESUMEN

Neural stem cells (NSCs) in the adult murine subependymal zone balance their self-renewal capacity and glial identity with the potential to generate neurons during the lifetime. Adult NSCs exhibit lineage priming via pro-neurogenic fate determinants. However, the protein levels of the neural fate determinants are not sufficient to drive direct differentiation of adult NSCs, which raises the question of how cells along the neurogenic lineage avoid different conflicting fate choices, such as self-renewal and differentiation. Here, we identify RNA-binding protein MEX3A as a post-transcriptional regulator of a set of stemness associated transcripts at critical transitions in the subependymal neurogenic lineage. MEX3A regulates a quiescence-related RNA signature in activated NSCs that is needed for their return to quiescence, playing a role in the long-term maintenance of the NSC pool. Furthermore, it is required for the repression of the same program at the onset of neuronal differentiation. Our data indicate that MEX3A is a pivotal regulator of adult murine neurogenesis acting as a translational remodeller.


Asunto(s)
Células-Madre Neurales , Neurogénesis , Ratones , Animales , Neurogénesis/genética , Neuronas/fisiología , Células-Madre Neurales/metabolismo , Diferenciación Celular/genética , Proteínas de Unión al ARN/metabolismo
9.
Br J Cancer ; 128(7): 1333-1343, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36717674

RESUMEN

BACKGROUND: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach. Here we utilise, develop and test a set of options for human-to-mouse CMS classifications of CRC tissue. METHODS: Using transcriptional data from established collections of CRC tumours, including human (TCGA cohort; n = 577) and mouse (n = 57 across n = 8 genotypes) tumours with combinations of random forest and nearest template prediction algorithms, alongside gene ontology collections, we comprehensively assess the performance of a suite of new dual-species classifiers. RESULTS: We developed three approaches: MmCMS-A; a gene-level classifier, MmCMS-B; an ontology-level approach and MmCMS-C; a combined pathway system encompassing multiple biological and histological signalling cascades. Although all options could identify tumours associated with stromal-rich CMS4-like biology, MmCMS-A was unable to accurately classify the biology underpinning epithelial-like subtypes (CMS2/3) in mouse tumours. CONCLUSIONS: When applying human-based transcriptional classifiers to mouse tumour data, a pathway-level classifier, rather than an individual gene-level system, is optimal. Our R package enables researchers to select suitable mouse models of human CRC subtype for their experimental testing.


Asunto(s)
Neoplasias Colorrectales , Humanos , Animales , Ratones , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Transducción de Señal
10.
Nature ; 611(7936): 603-613, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36352230

RESUMEN

Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.


Asunto(s)
Neoplasias Colorrectales , Metástasis de la Neoplasia , Proteínas de Neoplasias , Recurrencia Local de Neoplasia , Neoplasia Residual , Receptores de Superficie Celular , Animales , Humanos , Ratones , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Progresión de la Enfermedad , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/patología , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Metástasis de la Neoplasia/terapia , Modelos Animales de Enfermedad , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Neoadyuvante , Inmunoterapia
11.
J Exp Clin Cancer Res ; 41(1): 315, 2022 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-36289544

RESUMEN

BACKGROUND: Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood. METHODS: LAMC2 transcriptional levels were evaluated using publicly available transcriptome data sets, and LAMC2 immunohistochemistry was performed using a tissue microarray composed of PDAC and normal pancreas tissues. Silencing and tracing of LAMC2 was performed using lentiviral shRNA constructs and CRISPR/Cas9-mediated homologous recombination, respectively. The contribution of LAMC2 to PDAC tumorigenicity was explored in vitro by tumor cell invasion, migration, sphere-forming and organoids assays, and in vivo by tumor growth and metastatic assays. mRNA sequencing was performed to identify key cellular pathways upregulated in LAMC2 expressing cells. Metastatic spreading induced by LAMC2- expressing cells was blocked by pharmacological inhibition of transforming growth factor beta (TGF-ß) signaling. RESULTS: We report a LAMC2-expressing cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation and differentiation, and drives metastasis. mRNA profiling of these cells indicates a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-ß signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of the TGF-ß type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated lung metastasis, primarily originating from LAMC2-expressing cells. CONCLUSIONS: We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/patología , Receptor Tipo I de Factor de Crecimiento Transformador beta , ARN Interferente Pequeño , Neoplasias Pancreáticas/patología , Células Madre Neoplásicas/metabolismo , Factor de Crecimiento Transformador beta , ARN Mensajero , Receptores de Activinas , Movimiento Celular/genética , Línea Celular Tumoral , Laminina/genética , Laminina/metabolismo , Neoplasias Pancreáticas
12.
Adv Healthc Mater ; 11(22): e2201172, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36073021

RESUMEN

Gradients of signaling pathways within the intestinal stem cell (ISC) niche are instrumental for cellular compartmentalization and tissue function, yet how are they sensed by the epithelium is still not fully understood. Here a new in vitro model of the small intestine based on primary epithelial cells (i), apically accessible (ii), with native tissue mechanical properties and controlled mesh size (iii), 3D villus-like architecture (iv), and precisely controlled biomolecular gradients of the ISC niche (v) is presented. Biochemical gradients are formed through hydrogel-based scaffolds by free diffusion from a source to a sink chamber. To confirm the establishment of spatiotemporally controlled gradients, light-sheet fluorescence microscopy and in-silico modeling are employed. The ISC niche biochemical gradients coming from the stroma and applied along the villus axis lead to the in vivo-like compartmentalization of the proliferative and differentiated cells, while changing the composition and concentration of the biochemical factors affects the cellular organization along the villus axis. This novel 3D in vitro intestinal model derived from organoids recapitulates both the villus-like architecture and the gradients of ISC biochemical factors, thus opening the possibility to study in vitro the nature of such gradients and the resulting cellular response.


Asunto(s)
Mucosa Intestinal , Organoides , Mucosa Intestinal/metabolismo , Organoides/metabolismo , Intestinos , Intestino Delgado , Diferenciación Celular/fisiología
13.
Nat Cancer ; 3(9): 1052-1070, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35773527

RESUMEN

Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5+ tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5+ cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a+ cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a+ cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a+ cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP+ fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC.


Asunto(s)
Neoplasias Colorrectales , Organoides , Animales , Diferenciación Celular , Neoplasias Colorrectales/tratamiento farmacológico , Ratones , Células Madre Neoplásicas , Recurrencia
14.
Nat Cancer ; 3(4): 418-436, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35469014

RESUMEN

Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.


Asunto(s)
Anticuerpos Biespecíficos , Neoplasias Glandulares y Epiteliales , Anticuerpos Biespecíficos/farmacología , Receptores ErbB/metabolismo , Humanos , Imidazoles , Neoplasias Glandulares y Epiteliales/metabolismo , Células Madre Neoplásicas/metabolismo , Organoides , Pirazinas , Receptores Acoplados a Proteínas G/metabolismo
15.
J Mol Diagn ; 24(6): 674-686, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35447336

RESUMEN

Serrated polyposis syndrome (SPS) is associated with a high risk for colorectal cancer. Intense promoter hypermethylation is a frequent molecular finding in the serrated pathway and may be present in normal mucosa, predisposing to the formation of serrated lesions. To identify novel biomarkers for SPS, fresh-frozen samples of normal mucosa from 50 patients with SPS and 19 healthy individuals were analyzed by using the 850K BeadChip Technology (Infinium). Aberrant methylation levels were correlated with gene expression using a next-generation transcriptome profiling tool. Two validation steps were performed on independent cohorts: first, on formalin-fixed, paraffin-embedded tissue of the normal mucosa; and second, on 24 serrated lesions. The most frequently hypermethylated genes were HLA-F, SLFN12, HLA-DMA, and RARRES3; and the most frequently hypomethylated genes were PIWIL1 and ANK3 (Δß = 10%; P < 0.05). Expression levels of HLA-F, SLFN12, and HLA-DMA were significantly different between SPS patients and healthy individuals and correlated well with the methylation status of the corresponding differentially methylated region (fold change, >20%; r > 0.55; P < 0.001). Significant hypermethylation of CpGs in the gene body of HLA-F was also found in serrated lesions (Δß = 23%; false discovery rate = 0.01). Epigenome-wide methylation profiling has revealed numerous differentially methylated CpGs in normal mucosa from SPS patients. Significant hypermethylation of HLA-F is a novel biomarker candidate for SPS.


Asunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Colorrectales , Poliposis Adenomatosa del Colon/genética , Proteínas Argonautas/genética , Biomarcadores , Neoplasias Colorrectales/genética , Metilación de ADN/genética , Epigenoma , Antígenos de Histocompatibilidad Clase I , Humanos , Membrana Mucosa/patología
16.
Immunity ; 55(4): 701-717.e7, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35364006

RESUMEN

Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathway activated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 were expressed by the majority of human primary CRCs and metastases, which was associated with low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependent pathway controls anti-tumor immunity, revealing additional targets for immune checkpoint inhibition in microsatellite-stable CRC.


Asunto(s)
Neoplasias Colorrectales , Microbiota , Animales , Antígenos B7 , Linfocitos T CD8-positivos , Calcineurina/metabolismo , Neoplasias Colorrectales/metabolismo , Ratones , Factores de Transcripción NFATC/metabolismo , Inhibidor 1 de la Activación de Células T con Dominio V-Set
17.
iScience ; 25(2): 103790, 2022 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-35243213

RESUMEN

Upon tissue injury, cytokine expression reprogramming transiently remodels the inflammatory immune microenvironment to activate repair processes and subsequently return to homeostasis. However, chronic inflammation induces permanent changes in cytokine production which exacerbate tissue damage and may even favor tumor development. Here, we address the contribution of post-transcriptional regulation, by the RNA-binding protein CPEB4, to intestinal immune homeostasis and its role in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) development. We found that intestinal damage induces CPEB4 expression in adaptive and innate immune cells, which is required for the translation of cytokine mRNA(s) such as the one encoding interleukin-22. Accordingly, CPEB4 is required for the development of gut-associated lymphoid tissues and to maintain intestinal immune homeostasis, mediating repair and remodeling after acute inflammatory tissue damage and promoting the resolution of intestinal inflammation. CPEB4 is chronically overexpressed in inflammatory cells in patients with IBD and in CRC, favoring tumor development.

18.
Nat Rev Cancer ; 22(1): 25-44, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34671117

RESUMEN

Transforming growth factor-ß (TGFß) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGFß exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGFß controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGFß exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGFß to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGFß-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies - including immune checkpoint blockade - to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGFß pathway, many of which are currently in clinical evaluation.


Asunto(s)
Neoplasias , Factor de Crecimiento Transformador beta , Humanos , Evasión Inmune , Inmunoterapia , Neoplasias/patología , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/uso terapéutico , Microambiente Tumoral
19.
PLoS Pathog ; 17(9): e1009931, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34547046

RESUMEN

The capped Small segment mRNA (SmRNA) of the Andes orthohantavirus (ANDV) lacks a poly(A) tail. In this study, we characterize the mechanism driving ANDV-SmRNA translation. Results show that the ANDV-nucleocapsid protein (ANDV-N) promotes in vitro translation from capped mRNAs without replacing eukaryotic initiation factor (eIF) 4G. Using an RNA affinity chromatography approach followed by mass spectrometry, we identify the human RNA chaperone Mex3A (hMex3A) as a SmRNA-3'UTR binding protein. Results show that hMex3A enhances SmRNA translation in a 3'UTR dependent manner, either alone or when co-expressed with the ANDV-N. The ANDV-N and hMex3A proteins do not interact in cells, but both proteins interact with eIF4G. The hMex3A-eIF4G interaction showed to be independent of ANDV-infection or ANDV-N expression. Together, our observations suggest that translation of the ANDV SmRNA is enhanced by a 5'-3' end interaction, mediated by both viral and cellular proteins.


Asunto(s)
Proteínas de la Nucleocápside/metabolismo , Orthohantavirus/genética , Fosfoproteínas/metabolismo , Biosíntesis de Proteínas/fisiología , ARN Viral/genética , Proteínas de Unión al ARN/metabolismo , Regulación Viral de la Expresión Génica/fisiología , Humanos , ARN Mensajero/genética
20.
Genome Res ; 31(10): 1913-1926, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34548323

RESUMEN

The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients, and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing published data sets of >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying colocalization patterns of immune, stromal, and cancer cells in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immunotherapy.


Asunto(s)
Neoplasias , Biomarcadores de Tumor/genética , Humanos , Inmunoterapia , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , Pronóstico , Microambiente Tumoral
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