RESUMEN
Cholangiocarcinoma (CCA) and other liver cancer subtypes often develop in damaged organs. Physiological agents or extrinsic factors, like toxins, can induce cell death in such tissues, triggering compensatory proliferation and inflammation. Depending on extracellular and intracellular factors, different mechanisms, like apoptosis, necroptosis, ferroptosis, or autophagy, can be triggered. Each of them can lead to protumorigenic or anti-tumorigenic events within a cell or through regulation of the microenvironment. However, the exact role of each cell death mechanism in CCA onset, progression, and treatment is not well known. Here, we summarize current knowledge of different cell death mechanisms in patients with CCA and preclinical CCA research. We discuss cell death-related drugs with relevance to CCA treatment and how they could be used in the future to improve targeted CCA therapy.
RESUMEN
Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
Asunto(s)
Apoptosis , Carcinoma Hepatocelular/patología , Linaje de la Célula , Colangiocarcinoma/patología , Neoplasias Hepáticas/patología , Necrosis , Microambiente Tumoral , Animales , Apoptosis/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Diferenciación Celular , Linaje de la Célula/genética , Colangiocarcinoma/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Citocinas/metabolismo , Elementos Transponibles de ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Epigénesis Genética/genética , Femenino , Perfilación de la Expresión Génica , Genes myc , Genes ras , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones , Mosaicismo , Necrosis/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In this Article, the pCaMIN construct consisted of 'mouse MYC and mouse NrasG12V' instead of 'mouse Myc and human NRASG12V; and the pCAMIA construct consisted of 'mouse Myc and human AKT1' instead of 'mouse Myc and Akt1' this has been corrected online.
RESUMEN
BACKGROUND & AIMS: Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their tumour biology and responses to cancer therapies. Liver cells harbour a high degree of cellular plasticity and can give rise to either HCC or iCCA. However, little is known about the cell-intrinsic mechanisms directing an oncogenically transformed liver cell to either HCC or iCCA. The scope of this study was to identify cell-intrinsic factors determining lineage commitment in PLC. METHODS: Cross-species transcriptomic and epigenetic profiling was applied to murine HCCs and iCCAs and to two human PLC cohorts. Integrative data analysis comprised epigenetic Landscape In Silico deletion Analysis (LISA) of transcriptomic data and Hypergeometric Optimization of Motif EnRichment (HOMER) analysis of chromatin accessibility data. Identified candidate genes were subjected to functional genetic testing in non-germline genetically engineered PLC mouse models (shRNAmir knockdown or overexpression of full-length cDNAs). RESULTS: Integrative bioinformatic analyses of transcriptomic and epigenetic data pinpointed the Forkhead-family transcription factors FOXA1 and FOXA2 as MYC-dependent determination factors of the HCC lineage. Conversely, the ETS family transcription factor ETS1 was identified as a determinant of the iCCA lineage, which was found to be suppressed by MYC during HCC development. Strikingly, shRNA-mediated suppression of FOXA1 and FOXA2 with concomitant ETS1 expression fully switched HCC to iCCA development in PLC mouse models. CONCLUSIONS: The herein reported data establish MYC as a key determinant of lineage commitment in PLC and provide a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. IMPACT AND IMPLICATIONS: Liver cancer is a major health problem and comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their morphology, tumour biology, and responses to cancer therapies. We identified the transcription factor and oncogenic master regulator MYC as a switch between HCC and iCCA development. When MYC levels are high at the time point when a hepatocyte becomes a tumour cell, an HCC is growing out. Conversely, if MYC levels are low at this time point, the result is the outgrowth of an iCCA. Our study provides a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. Furthermore, our data harbour potential for the development of better PLC therapies.
Asunto(s)
Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Hígado Graso , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Factores de Transcripción/metabolismo , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/patologíaRESUMEN
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.
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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/metabolismoRESUMEN
The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids. Raf-1 was found to bind and activate SCD1, and conformation-changing DFG-out Raf inhibitors could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity. Studies in genetically engineered and nonalcoholic steatohepatitis-induced HCC mouse models and xenograft models of human HCC revealed that therapies comprising LXR agonists and Raf inhibitors were well tolerated and capable of overcoming therapy resistance in HCC. Conceptually, our study suggests pharmacologically induced lipotoxicity as a new mode for metabolic targeting of liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Prognosis of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma, a type of primary liver cancer comprising areas with HCC and ICC histopathology, is dismal, and it is unclear if such tumors develop clonally and how they should be treated. In this issue of Cancer Cell, Xue et al. (2019) provide answers to these questions.
Asunto(s)
Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Genómica , Humanos , Pronóstico , TranscriptomaRESUMEN
Although it is well established that TNFα contributes to hepatitis, liver failure and associated hepatocarcinogenesis via the regulation of inflammation, its pro-apoptotic role in the liver has remained enigmatic. On its own, TNFα is unable to trigger apoptosis. However, when combined with the transcriptional inhibitor GaLN, it can cause hepatocyte apoptosis and liver failure in mice. Moreover, along with others, we have shown that TNFα is capable of sensitizing cells to FasL- or drug-induced cell death via c-Jun N-terminal kinase (JNK) activation and phosphorylation/activation of the BH3-only protein Bim. In this context, TNFα could exacerbate hepatocyte cell death during simultaneous inflammatory and T-cell-mediated immune responses in the liver. Here we show that TNFα sensitizes primary hepatocytes, established hepatocyte cell lines and mouse embryo fibroblasts to FasL-induced apoptosis by the transcriptional induction and higher surface expression of Fas via the NFκB pathway. Genetic deletion, diminished expression or dominant-negative inhibition of the NFκB subunit p65 resulted in lower Fas expression and inhibited TNFα-induced Fas upregulation and sensitization to FasL-induced cell death. By hydrodynamic injection of p65 shRNA into the tail vein of mice, we confirm that Fas upregulation by TNFα is also NFκB-mediated in the liver. In conclusion, TNFα sensitization of FasL-induced apoptosis in the liver proceeds via two parallel signaling pathways, activation of JNK and Bim phosphorylation and NFκB-mediated Fas upregulation.
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Apoptosis/fisiología , Proteína Ligando Fas/metabolismo , Hepatocitos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/fisiología , Receptor fas/metabolismo , Células 3T3 , Animales , Línea Celular , Línea Celular Tumoral , Células HEK293 , Células Hep G2 , Humanos , Hígado/metabolismo , Ratones , Transducción de Señal/fisiología , Factor de Transcripción ReIA/metabolismo , Activación Transcripcional/fisiologíaRESUMEN
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.
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Transformación Celular Neoplásica/metabolismo , Senescencia Celular , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Inflamación/metabolismo , Neoplasias/metabolismo , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Empalme Alternativo , Animales , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteínas Nucleares Heterogéneas/genética , Humanos , Inflamación/genética , Inflamación/patología , Inflamación/terapia , Células MCF-7 , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias/genética , Neoplasias/patología , Neoplasias/prevención & control , Comunicación Paracrina , Fenotipo , Proteína de Unión al Tracto de Polipirimidina/genética , Interferencia de ARN , Transducción de Señal , Carga Tumoral , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provides a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in Eµ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to oncogenic Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but instead relied on the activity of the ARF-p53 pathway. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors.
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Linfocitos B/metabolismo , Proliferación Celular/genética , Linfoma/genética , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Células Cultivadas , Embrión de Mamíferos/citología , Fibroblastos/metabolismo , Perfilación de la Expresión Génica/métodos , Linfoma/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARNRESUMEN
A precise balance between quiescence and proliferation is crucial for the lifelong function of hematopoietic stem cells (HSCs). Cyclins E1 and E2 regulate exit from quiescence in fibroblasts, but their role in HSCs remains unknown. Here, we report a non-redundant role for cyclin E1 in mouse HSCs. A long-term culture-initiating cell (LTC-IC) assay indicated that the loss of cyclin E1, but not E2, compromised the colony-forming activity of primitive hematopoietic progenitors. Ccne1(-/-) mice showed normal hematopoiesis in vivo under homeostatic conditions but a severe impairment following myeloablative stress induced by 5-fluorouracil (5-FU). Under these conditions, Ccne1(-/-) HSCs were less efficient in entering the cell cycle, resulting in decreased hematopoiesis and reduced survival of mutant mice upon weekly 5-FU treatment. The role of cyclin E1 in homeostatic conditions became apparent in aged mice, where HSC quiescence was increased in Ccne1(-/-) animals. On the other hand, loss of cyclin E1 provided HSCs with a competitive advantage in bone marrow serial transplantation assays, suggesting that a partial impairment of cell cycle entry may exert a protective role by preventing premature depletion of the HSC compartment. Our data support a role for cyclin E1 in controlling the exit from quiescence in HSCs. This activity, depending on the physiological context, can either jeopardize or protect the maintenance of hematopoiesis.