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1.
Cancer Sci ; 114(10): 3806-3815, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37475576

RESUMO

The cGAS/STING pathway provides a key host defense mechanism by detecting the accumulation of cytoplasmic double-stranded DNA (dsDNA) and mediating innate and adaptive immune signaling. In addition to detecting pathogen-derived dsDNA, cGAS senses intrinsic dsDNA, such as those associated with defective cell cycle progression and mitophagy that has leaked from the nucleus or mitochondria, and subsequently evokes host immunity to eliminate pathogenic cells. In cancer cells, dysregulation of DNA repair and cell cycle caused at the DNA replication checkpoint and spindle assembly checkpoint results in aberrant cytoplasmic dsDNA accumulation, stimulating anti-tumor immunity. Therefore, the suppression of cGAS/STING signaling is beneficial for survival and frequently observed in cancer cells as a way to evade detection by the immune system, and is likely to be related to immune checkpoint blockade (ICB) resistance. Indeed, the mechanisms of ICB resistance overlap with those acquired in cancers during immunoediting to evade immune surveillance. This review highlights the current understanding of cGAS/STING suppression in cancer cells and discusses how to establish effective strategies to regenerate effective anti-tumor immunity through reactivation of the cGAS/STING pathway.

2.
Hepatology ; 74(4): 1971-1993, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33931882

RESUMO

BACKGROUND AND AIMS: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. APPROACH AND RESULTS: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)ß inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/ß phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. CONCLUSIONS: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Células Hep G2 , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/genética , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/genética , Camundongos , Transplante de Neoplasias , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Piridinas/uso terapêutico , Proteína do Retinoblastoma , Proteína Supressora de Tumor p53/genética , Proteínas de Xenopus
3.
Int J Mol Sci ; 21(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244804

RESUMO

The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls' malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy.


Assuntos
Ciclo Celular/genética , Neoplasias/genética , Proteína do Retinoblastoma/genética , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/genética , Citocinas/metabolismo , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteína do Retinoblastoma/metabolismo , Proteínas Supressoras de Tumor/metabolismo
4.
Semin Cell Dev Biol ; 58: 127-35, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27297136

RESUMO

While important strides have been made in cancer therapy by targeting certain oncogenes, KRAS, the most common among them, remains refractory to this approach. In recent years, a deeper understanding of the critical importance of inflammation in promoting KRAS-driven oncogenesis has emerged, and applies across the different contexts of lung, pancreatic, and colorectal tumorigenesis. Here we review why these tissue types are particularly prone to developing KRAS mutations, and how inflammation conspires with KRAS signaling to fuel carcinogenesis. We discuss multiple lines of evidence that have established NF-κB, STAT3, and certain cytokines as key transducers of these signals, and data to suggest that targeting these pathways has significant clinical potential. Furthermore, recent work has begun to uncover how inflammatory signaling interacts with other KRAS regulated survival pathways such as autophagy and MAPK signaling, and that co-targeting these multiple nodes may be required to achieve real benefit. In addition, the impact of KRAS associated inflammatory signaling on the greater tumor microenvironment has also become apparent, and taking advantage of this inflammation by incorporating approaches that harness T cell anti-tumor responses represents another promising therapeutic strategy. Finally, we highlight the likelihood that the genomic complexity of KRAS mutant tumors will ultimately require tailored application of these therapeutic approaches, and that targeting inflammation early in the course of tumor development could have the greatest impact on eradicating this deadly disease.


Assuntos
Carcinogênese/patologia , Inflamação/patologia , Proteínas ras/metabolismo , Animais , Autofagia , Humanos , Transdução de Sinais , Microambiente Tumoral/imunologia
5.
Cancer Sci ; 108(9): 1726-1731, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28865172

RESUMO

The Retinoblastoma (RB) tumor suppressor regulates G1 /S transition during cell cycle progression by modulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment-resistant cancers, it has become increasingly clear that, in the majority of cancers, somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene is often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates G1 /S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we reported that RB inactivation enhances pro-inflammatory signaling through stimulation of the interleukin-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling.


Assuntos
Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteína do Retinoblastoma/fisiologia , Animais , Transformação Celular Neoplásica/metabolismo , Citocinas/metabolismo , Progressão da Doença , Metabolismo Energético , Genes Supressores de Tumor , Humanos , Inflamação/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Transdução de Sinais
6.
Mol Carcinog ; 55(12): 1974-1989, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26621780

RESUMO

Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of genes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53-/- ; Rbf/f , Trp53-/- ; Ptenf/f , and Trp53-/- ; Rbf/f ; Ptenf/f prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53-/- prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. © 2015 Wiley Periodicals, Inc.


Assuntos
Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase/genética , Próstata/patologia , Neoplasias da Próstata/patologia , Proteína do Retinoblastoma/genética , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/genética , Células Cultivadas , Progressão da Doença , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Deleção de Genes , Masculino , Camundongos , Camundongos Knockout , Próstata/metabolismo , Neoplasias da Próstata/genética , Transdução de Sinais
7.
Stem Cells ; 33(5): 1657-69, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25694388

RESUMO

Retinoblastoma tumor suppressor protein (RB) is inactivated more frequently during tumor progression than during tumor initiation. However, its exact role in controlling the malignant features associated with tumor progression is poorly understood. We established in vivo and in vitro models to investigate the undifferentiated state induced by Rb inactivation. Rb heterozygous mice develop well-differentiated thyroid medullary carcinoma. We found that additional deletion of Trp53, without change in lineage, converted these Rb-deficient tumors to a poorly differentiated type associated with higher self-renewal activity. Freshly prepared mouse embryonic fibroblasts (MEFs) of Rb(-/-) ; Trp53(-/-) background formed stem cell-like spheres that expressed significant levels of embryonic genes despite of lacking the ability to form colonies on soft agar or tumors in immune-deficient mice. This suggested that Rb-p53 double inactivation resulted in an undifferentiated status but without carcinogenic conversion. We next established Rb(-/-) ; N-ras(-/-) MEFs that harbored a spontaneous carcinogenic mutation in Trp53. These cells (RN6), in an Rb-dependent manner, efficiently generated spheres that expressed very high levels of embryonic genes, and appeared to be carcinogenic. We then screened an FDA-approved drug library to search for agents that suppressed the spherogenic activity of RN6 cells. Data revealed that RN6 cells were sensitive to specific agents including ones those are effective against cancer stem cells. Taken together, all these findings suggest that the genetic interaction between Rb and p53 is a critical determinant of the undifferentiated state in normal and tumor cells.


Assuntos
Diferenciação Celular , Embrião de Mamíferos/citologia , Fibroblastos/citologia , Células Neuroendócrinas/citologia , Proteína do Retinoblastoma/metabolismo , Glândula Tireoide/citologia , Proteína Supressora de Tumor p53/metabolismo , Sequência de Aminoácidos , Animais , Comportamento Animal , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/metabolismo , Heterozigoto , Camundongos Knockout , Dados de Sequência Molecular , Mutação/genética , Fenótipo , Proteína do Retinoblastoma/deficiência , Esferoides Celulares/metabolismo , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteínas ras/metabolismo
8.
Cancer Discov ; 14(5): 752-765, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38227896

RESUMO

A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING-IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell-derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING-IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies. SIGNIFICANCE: STING-IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell-mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance. This article is featured in Selected Articles from This Issue, p. 695.


Assuntos
Exodesoxirribonucleases , Proteínas de Membrana , Fosfoproteínas , Transdução de Sinais , Exodesoxirribonucleases/genética , Camundongos , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Humanos , Animais , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/tratamento farmacológico , Interferons/metabolismo , Linhagem Celular Tumoral , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo
9.
Phys Chem Chem Phys ; 15(39): 16626-33, 2013 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-23963202

RESUMO

The composite material P(EO/EM)-Sa consisting of synthetic saponite (Sa) dispersed in poly[ethylene oxide-co-2-(2-methoxyethoxy)ethyl glycidyl ether] (P(EO/EM)) is studied by "in situ" measurements using broadband electrical spectroscopy (BES) under pressurized CO2 to characterize the dynamic behavior of conductivity and the dielectric relaxations of the ion host polymer matrix. It is revealed that there are three dielectric relaxation processes associated with: (I) the dipolar motions in the short oxyethylene side chains of P(EO/EM) (ß); and (II) the segmental motion of the main chains comprising the polyether components (αfast, αslow). αslow is attributed to the slow α-relaxation of P(EO/EM) macromolecules, which is hindered by the strong coordination interactions with the ions. Two conduction processes are observed, σDC and σID, which are attributed, respectively, to the bulk conductivity and the interdomain conductivity. The temperature dependence of conductivity and relaxation processes reveals that αfast and αslow are strongly correlated with σDC and σID. The "in situ" BES measurements under pressurized CO2 indicate a fast decrease in σDC at the initial CO2 treatment time resulting from the decrease in the concentration of polyether-M(n+) complexes, which is driven by the CO2 permeation. The relaxation frequency (fR) of αslow at the initial CO2 treatment time increases and shows a steep rise with time with the same behavior of the αfast mode. It is demonstrated that the interactions between polyether chains of P(EO/EM) and cations in the polymer electrolyte layers embedded in Sa are probably weakened by the low permittivity of CO2 (ε = 1.08). Thus, the formation of ion pairs in the polymer electrolyte domains of P(EO/EM)-Sa occurs, with a corresponding reduction in the concentration of ion carriers.

10.
Commun Biol ; 6(1): 65, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653474

RESUMO

Human cancers often re-express germline factors, yet their mechanistic role in oncogenesis and cancer progression remains unknown. Here we demonstrate that DEAD-box helicase 4 (DDX4), a germline factor and RNA helicase conserved in all multicellular organisms, contributes to increased cell motility and cisplatin-mediated drug resistance in small cell lung cancer (SCLC) cells. Proteomic analysis suggests that DDX4 expression upregulates proteins related to DNA repair and immune/inflammatory response. Consistent with these trends in cell lines, DDX4 depletion compromised in vivo tumor development while its overexpression enhanced tumor growth even after cisplatin treatment in nude mice. Further, the relatively higher DDX4 expression in SCLC patients correlates with decreased survival and shows increased expression of immune/inflammatory response markers. Taken together, we propose that DDX4 increases SCLC cell survival, by increasing the DNA damage and immune response pathways, especially under challenging conditions such as cisplatin treatment.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Camundongos , Animais , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos Nus , Proteômica , Células Germinativas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo
11.
Cancer Sci ; 103(7): 1182-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22448711

RESUMO

One-quarter of a century ago, identification of the human retinoblastoma gene (RB) loci proved Knudson's 'two-hit theory' that tumor suppressor genes exist. Since then, numerous works delineated crucial roles for the RB protein (pRB)-E2F transcription factor complex in G1-S phase transition. In addition, discovering the relationship between pRB and tissue-specific transcription factors enabled a better understanding of how cell cycle exit and terminal differentiation are coupled. Recent works provoked many exciting twists in views on pRB functions during cancer initiation and progression beyond its previously well-appreciated roles. Various mitogenic and cytostatic cellular signals appeared to modulate pRB functions and thus affect a wide variety of effector molecules. In addition, genetic studies in mice as well as other creatures incessantly force us to revise our views on pRB functions. This review will focus particularly on the roles of pRB in regulating intracellular signaling, cell metabolism, chromatin function, stem cells and cancer stem cells.


Assuntos
Mutação , Proteína do Retinoblastoma/genética , Transdução de Sinais/genética , Células-Tronco/metabolismo , Animais , Humanos , Redes e Vias Metabólicas/genética , Modelos Genéticos , Fosforilação , Retinoblastoma/genética , Retinoblastoma/metabolismo , Proteína do Retinoblastoma/metabolismo
12.
Cancer Res ; 82(21): 4079-4092, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36066413

RESUMO

Immunotherapy has shown limited efficacy in patients with EGFR-mutated lung cancer. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third-generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity (1). However, STING activation was restrained by ectonucleosidase CD73, which is induced in MET-amplified, EGFR-TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on coinduction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR-TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR-TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI-resistant EGFR-mutated lung cancers and promote immunogenicity. SIGNIFICANCE: MET amplification upregulates CD73 to suppress tumor cell STING induction and T-cell responsiveness in TKI-resistant, EGFR-mutated lung cancer, identifying a strategy to enhance immunogenicity and improve treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/metabolismo , Amplificação de Genes , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , 5'-Nucleotidase/metabolismo
13.
Cancer Cell ; 40(10): 1128-1144.e8, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36150391

RESUMO

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Decitabina , Genes ras , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
14.
Nat Neurosci ; 10(7): 838-45, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17558399

RESUMO

We report that during cortical development in the mouse embryo, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) critically regulates Notch signaling by antagonizing the ectodomain shedding of Notch ligands, which is mediated by a disintegrin and metalloproteinase domain 10 (ADAM10). In the embryonic brain, RECK is specifically expressed in Nestin-positive neural precursor cells (NPCs). Reck-deficient NPCs undergo precocious differentiation that is associated with downregulated Nestin expression, impaired Notch signaling and defective self-renewal. These phenotypes were substantially rescued either by enhancing Notch signaling or by suppressing endogenous ADAM10 activity. Consequently, we found that RECK regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10. This mechanism appeared to be essential for Notch ligands to properly induce Notch signaling in neighboring cells. These findings indicate that RECK is a physiological inhibitor of ADAM10, an upstream regulator of Notch signaling and a critical modulator of brain development.


Assuntos
Proteínas ADAM/fisiologia , Secretases da Proteína Precursora do Amiloide/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana/fisiologia , Neurônios/fisiologia , Receptores Notch/fisiologia , Transdução de Sinais/fisiologia , Proteína ADAM10 , Animais , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/metabolismo , Regulação para Baixo/fisiologia , Feminino , Imunofluorescência , Proteínas Ligadas por GPI , Immunoblotting , Imunoprecipitação , Ligantes , Luciferases/biossíntese , Luciferases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Plasmídeos/genética , Gravidez , Interferência de RNA , Proteínas Recombinantes/genética , Retroviridae/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Expert Opin Ther Targets ; 25(3): 167-174, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33703985

RESUMO

INTRODUCTION: KRAS mutations drive tumorigenesis by altering cell signaling and the tumor immune microenvironment. Recent studies have shown promise for KRAS-G12C covalent inhibitors, which are advancing rapidly through clinical trials. The sequencing and combination of these agents with other therapies including immune checkpoint blockade (ICB) will benefit from strategies that also address the immune microenvironment to improve durability of response. AREAS COVERED: This paper reviews KRAS signaling and discusses downstream effects on cytokine production and the tumor immune microenvironment. RAS targeted therapy is introduced and perspectives on therapeutic targeting of KRAS-G12C and its immunosuppressive tumor microenvironment are offered. EXPERT OPINION: The availability of KRAS-G12C covalent inhibitors raises hopes for targeting this pervasive oncogene and designing better therapeutic combinations to promote anti-tumor immunity. A comprehensive mechanistic understanding of KRAS immunosuppression is required in order to prioritize agents for clinical trials.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Desenho de Fármacos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade Inata , Terapia de Alvo Molecular , Mutação , Neoplasias/genética , Neoplasias/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral/imunologia
17.
J Clin Invest ; 131(2)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33151910

RESUMO

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.


Assuntos
Imunoterapia , Proteínas de Neoplasias , Neoplasias Experimentais , Receptor de Morte Celular Programada 1 , RNA-Seq , Análise de Célula Única , Esferoides Celulares , Animais , Linhagem Celular Tumoral , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Esferoides Celulares/imunologia , Esferoides Celulares/patologia
18.
Cancer Discov ; 11(8): 1952-1969, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33707236

RESUMO

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.This article is highlighted in the In This Issue feature, p. 1861.


Assuntos
Plasticidade Celular , Neoplasias Pulmonares/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Animais , Estudos de Coortes , Modelos Animais de Doenças , Registros Eletrônicos de Saúde , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Carcinoma de Pequenas Células do Pulmão/patologia
19.
Front Immunol ; 11: 2090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013881

RESUMO

Intratumoral recruitment of immune cells following innate immune activation is critical for anti-tumor immunity and involves cytosolic dsDNA sensing by the cGAS/STING pathway. We have previously shown that KRAS-LKB1 (KL) mutant lung cancer, which is resistant to PD-1 blockade, exhibits silencing of STING, impaired tumor cell production of immune chemoattractants, and T cell exclusion. Since the vasculature is also a critical gatekeeper of immune cell infiltration into tumors, we developed a novel microfluidic model to study KL tumor-vascular interactions. Notably, dsDNA priming of LKB1-reconstituted tumor cells activates the microvasculature, even when tumor cell STING is deleted. cGAS-driven extracellular export of 2'3' cGAMP by cancer cells activates STING signaling in endothelial cells and cooperates with type 1 interferon to increase vascular permeability and expression of E selectin, VCAM-1, and ICAM-1 and T cell adhesion to the endothelium. Thus, tumor cell cGAS-STING signaling not only produces T cell chemoattractants, but also primes tumor vasculature for immune cell escape.


Assuntos
Células Endoteliais/metabolismo , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica , Nucleotídeos Cíclicos/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Técnicas de Cocultura , Células Endoteliais/patologia , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Nucleotídeos Cíclicos/genética
20.
Cancer Discov ; 9(1): 34-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30297358

RESUMO

KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL)-mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS-mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape. SIGNIFICANCE: Oncogenic KRAS-mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype.See related commentary by Corte and Byers, p. 16.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Adenocarcinoma/genética , Deleção de Genes , Neoplasias Pulmonares/genética , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Quinases Proteína-Quinases Ativadas por AMP , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Regulador 3 de Interferon/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/genética , Mutação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT1/metabolismo
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