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1.
Mol Oncol ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38957016

RESUMEN

MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene-specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription-replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell-autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard-wired to the biology of the MYC protein family. We show why the cell-autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy.

2.
Nat Commun ; 15(1): 1446, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38365788

RESUMEN

In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.


Asunto(s)
Fenómenos Bioquímicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas c-myc , Animales , Ratones , Carcinoma Ductal Pancreático/patología , Proliferación Celular , ARN Polimerasas Dirigidas por ADN/metabolismo , Evasión Inmune , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo
3.
Cell Death Differ ; 30(7): 1710-1725, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37202505

RESUMEN

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Pulmonares , Ratones , Animales , Humanos , Ácido Mevalónico/metabolismo , Neoplasias Pulmonares/genética , Carcinoma de Células Escamosas/genética , Ubiquitina Tiolesterasa/metabolismo
4.
Cancer Res ; 81(16): 4242-4256, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34145038

RESUMEN

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. SIGNIFICANCE: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.


Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Evasión Inmune , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Bicatenario , Adenocarcinoma/inmunología , Animales , Transporte Biológico , Carcinoma Ductal Pancreático/inmunología , Núcleo Celular/metabolismo , Eliminación de Gen , Células HEK293 , Humanos , Sistema Inmunológico , Intrones , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Desnudos , Neoplasias Pancreáticas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/metabolismo
5.
Nat Commun ; 10(1): 5387, 2019 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-31772172

RESUMEN

T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (VL) or variable heavy (VH) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies.


Asunto(s)
Anticuerpos/farmacología , Antineoplásicos Inmunológicos/farmacología , Complejo CD3/metabolismo , Inmunoterapia/métodos , Linfocitos T/inmunología , Animales , Anticuerpos/genética , Antineoplásicos Inmunológicos/inmunología , Sitios de Unión , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Efecto Espectador , Línea Celular Tumoral , Femenino , Antígeno HLA-A2/genética , Antígeno HLA-A2/inmunología , Humanos , Activación de Linfocitos , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Medicina de Precisión/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
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