RESUMEN
Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.
Asunto(s)
Carcinogénesis/genética , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/fisiopatología , Factores de Transcripción/metabolismo , Humanos , Unión Proteica , Neoplasias PancreáticasRESUMEN
BACKGROUND: Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS. METHODS: We conducted a systematic review to identify CS cases to create a retrospective cohort. We tested genotype-phenotype correlations and calculated cumulative incidence and hazard rates (HR) for cancer and cancer-free death, standardised incidence rates (SIR) and survival after cancer. RESULTS: This study includes 234 publications reporting 621 patients from 35 countries. Over nine percent had cancer, including rhabdomyosarcoma, bladder, and neuroblastoma. The rate of cancer and death associated with p.Gly12Ser were lower when compared to all other variants (P < 0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P < 0.05). Cumulative incidence by age 20 was 13% (cancer) and 11% (cancer-free death). HR (death) was 3-4% until age 3. Statistically significant SIRs were found for rhabdomyosarcoma (SIR = 1240), bladder (SIR = 1971), and neuroblastoma (SIR = 60). Survival after cancer appeared reduced. CONCLUSIONS: This is the largest investigation of cancer in CS to date. The high incidence and SIR values found to highlight the need for rigorous surveillance and evidence-based guidelines for this high-risk population.
Asunto(s)
Síndrome de Costello , Neuroblastoma , Rabdomiosarcoma , Humanos , Síndrome de Costello/genética , Síndrome de Costello/patología , Estudios Retrospectivos , GenotipoRESUMEN
The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of ß-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.
Asunto(s)
Carcinoma Ductal Pancreático/fisiopatología , Neoplasias Pancreáticas/fisiopatología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/metabolismo , Animales , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Receptores de Hialuranos/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Transgénicos , Invasividad Neoplásica/genética , Neoplasias Pancreáticas/enzimología , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , beta Catenina/metabolismoRESUMEN
Induction of DNA damage by ionizing radiation (IR) and/or cytotoxic chemotherapy is an essential component of cancer therapy. The ataxia telangiectasia group D complementing gene (ATDC, also called TRIM29) is highly expressed in many malignancies. It participates in the DNA damage response downstream of ataxia telangiectasia-mutated (ATM) and p38/MK2 and promotes cell survival after IR. To elucidate the downstream mechanisms of ATDC-induced IR protection, we performed a mass spectrometry screen to identify ATDC binding partners. We identified a direct physical interaction between ATDC and the E3 ubiquitin ligase and DNA damage response protein, RNF8, which is required for ATDC-induced radioresistance. This interaction was refined to the C-terminal portion (amino acids 348-588) of ATDC and the RING domain of RNF8 and was disrupted by mutation of ATDC Ser-550 to alanine. Mutations disrupting this interaction abrogated ATDC-induced radioresistance. The interaction between RNF8 and ATDC, which was increased by IR, also promoted downstream DNA damage responses such as IR-induced γ-H2AX ubiquitination, 53BP1 phosphorylation, and subsequent resolution of the DNA damage foci. These studies define a novel function for ATDC in the RNF8-mediated DNA damage response and implicate RNF8 binding as a key determinant of the radioprotective function of ATDC.
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Proteínas de Unión al ADN/metabolismo , Tolerancia a Radiación/fisiología , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Transporte Activo de Núcleo Celular/efectos de la radiación , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Proteína BRCA1/metabolismo , Línea Celular Tumoral , Roturas del ADN de Doble Cadena , Daño del ADN , Reparación del ADN , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Células HEK293 , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Fosforilación , Unión Proteica/efectos de la radiación , Dominios y Motivos de Interacción de Proteínas , Tolerancia a Radiación/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Proteína 1 de Unión al Supresor Tumoral P53 , UbiquitinaciónRESUMEN
PURPOSE: To determine the cancer risk and spectrum in patients with multi-lineage mosaic RASopathies with pathogenic variants (PV) in HRAS or KRAS. METHODS: We conducted a systematic literature review to identify multi-lineage mosaic RASopathy cases with a PV in HRAS or KRAS to create a retrospective cohort. We calculated cumulative incidence, cancer-free survival and hazard rates (HR) for cancer and standardized incidence rates (SIR). RESULTS: This study identified 69 patients. Seventeen percent had cancer, including rhabdomyosarcoma located in the urogenital region (n=7), skin cancer (n=3), Wilms tumor (n=1), and bladder cancer (n=1). Cumulative cancer incidence by age 20 was 20% (95% CI, 4 to 37%). The annual cancer HR peaked at 14% within the first two years of life. The highest SIR was found for rhabdomyosarcoma (SIR = 800, 95% CI, 300 to 1648). CONCLUSIONS: This is the first investigation of cancer risk in KRAS or HRAS PV-positive mosaic RASopathies to date. The high incidence and SIR values found highlight the need for rigorous rhabdomyosarcoma surveillance in young children and skin cancer surveillance in adults with this high-risk condition.
RESUMEN
Background: Cardiofaciocutaneous syndrome (CFC) is a rare disorder with multiple congenital anomalies including macrocephaly, failure to thrive, and neurocognitive delay. CFC is part "RASopathy" syndromes caused by pathogenic germline variants in BRAF, KRAS, MAP2K1, and MAP2K2. To estimate cancer risk in CFC we conducted a systematic review using case reports and series. Methods: We reviewed articles and abstracted CFC cases to form a retrospective cohort based on PRISMA guidelines. Genotype-pphenotype (cancer) correlations, standardized incidence ratios (SIR), cumulative incidence and cause-specific hazard rates for cancer and cancer-free in CFC were calculated. Results: This study includes 198 publications reporting 690 patients. Only 1.6% (11) had cancer, including acute lymphoblastic leukemia (ALL). Six cancer patients harbored pathogenic variants within BRAF, MAP2K1 , and MAP2K2 . Cumulative incidence by age 10 was 5% for cancer or cancer-free death. Hazard Ratio (death) was 1-2% until age 3 and declined thereafter. Significant SIRs were found for all sites (SIR=4.96) and ALL (SIR=24.23). Conclusions: This is the largest investigation of cancer in CFC to date. Cancer risk in the CFC population is elevated but appears limited to earlier childhood. Modest case and cancer numbers could pose limitations to accurately assess cancer risk in CFC and more studies are needed. Systematic Review Registration: The review was registered using PROSPERO under the identification tag CRD42023405823 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=405823 ).
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Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes, grouped as RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together, RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the past decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multidisciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other health care professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.
Asunto(s)
Síndrome de Costello , Neurofibromatosis 1 , Síndrome de Noonan , Humanos , Síndrome de Noonan/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/epidemiología , Neurofibromatosis 1/genética , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/terapia , Síndrome de Costello/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/terapia , Niño , Neoplasias/genética , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/etiología , Predisposición Genética a la Enfermedad , Proteínas ras/genéticaRESUMEN
Leukemic relapse is believed to be driven by transformed hematopoietic stem cells (HSC) that harbor oncogenic mutations or have lost tumor suppressor function. Recent comprehensive sequencing studies have shown that mutations predicted to activate Ras signaling are highly prevalent in hematologic malignancies and, notably, in refractory and relapsed cases. To better understand what drives this clinical phenomenon, we expressed oncogenic NrasG12D within the hematopoietic system in mice and interrogated its effects on HSC survival. N-RasG12D conferred a survival benefit to HSCs and progenitors following metabolic and genotoxic stress. This effect was limited to HSCs and early progenitors and was independent of autophagy and cell proliferation. N-RasG12D-mediated HSC survival was not affected by inhibition of canonical Ras effectors such as MEK and PI3K. However, inhibition of the noncanonical Ras effector pathway protein kinase C (PKC) ameliorated the protective effects of N-RasG12D. Mechanistically, N-RasG12D lowered levels of reactive oxygen species (ROS), which correlated with reduced mitochondrial membrane potential and ATP levels. Inhibition of PKC restored the levels of ROS to that of control HSCs and abrogated the protective effects granted by N-RasG12D. Thus, N-RasG12D activation within HSCs promotes cell survival through the mitigation of ROS, and targeting this mechanism may represent a viable strategy to induce apoptosis during malignant transformation of HSCs. SIGNIFICANCE: Targeting oncogenic N-Ras-mediated reduction of ROS in hematopoietic stem cells through inhibition of the noncanonical Ras effector PKC may serve as a novel strategy for treatment of leukemia and other Ras-mutated cancers.
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Apoptosis/fisiología , Genes ras/genética , Células Madre Hematopoyéticas/fisiología , Estrés Oxidativo/fisiología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Autofagia/fisiología , Supervivencia Celular/genética , Células Cultivadas , Femenino , Fluorouracilo/efectos adversos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Células Madre Hematopoyéticas/efectos de la radiación , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Radiación Ionizante , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismoRESUMEN
As genomic sequencing has become more widely available, the high prevalence of Ras pathway mutations in pediatric diseases has begun to emerge. Germline Ras-activating mutations have been known to contribute to cancer predisposition in a group of disorders known as the RASopathies, and now large pediatric sequencing studies have identified frequent somatic Ras pathway alterations across a diverse group of pediatric malignancies. These include glial brain tumors, relapsed high-risk neuroblastoma, embryonal rhabdomyosarcoma, acute myeloid leukemia, and relapsed acute lymphoblastic leukemia, and their prognostic impact is becoming increasingly better understood. Clinically, there has been success in targeting the Ras pathway in pediatric diseases, including the use of MEK inhibitors in plexiform neurofibromas associated with neurofibromatosis type 1 and the use of Ras pathway inhibitors in low-grade gliomas. Given the importance of this pathway in pediatric cancer, it is imperative that future studies strive to better understand the functional significance of these mutations, including their role in tumor growth and treatment resistance and how they can be better targeted to improve outcomes.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/metabolismo , Proteínas ras/metabolismo , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Humanos , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/metabolismo , Transducción de Señal , Proteínas ras/genéticaRESUMEN
BACKGROUND: Cancer remains the number one cause of disease-related mortality in children, and despite advances in the molecular understanding of leukemia and targeted therapies, refractory leukemia remains a leading cause of death. It therefore is essential to further define features, e.g., FLT3 alterations and KMT2A rearrangements, associated with inferior survival early to augment or alter therapeutic strategies to improve outcomes. METHODS: To gain insights into the genetic drivers predictive of aggressive clinical behavior among pediatric leukemia patients, we performed comprehensive integrative clinical sequencing (ICS), including paired tumor/normal DNA sequencing and RNA-seq, for pediatric patients who presented at our institution over a period of five years with acute lymphoblastic or myelogenous leukemia (ALL and AML; n=43) and high-risk clinical features (high white blood cell count, extramedullary disease, or refractory and/or relapsed disease). RESULTS: We found that RAS- and Ras-pathway aberrations, including N-RAS, NF1 and PTPN11, are frequent somatic mutations and, importantly, associated with decreased event free and overall survival (OS) (P=0.04, median event free survival 22.8 vs. 5.6 months; P=0.04, median OS 124 vs. 22.5 months). CONCLUSIONS: We thus propose that hyperactive Ras signaling confers inferior survival in high-risk pediatric acute leukemia and that Ras pathways should be molecularly characterized to inform clinical decision making and to identify patients for experimental clinical trials and RAS-targeted therapy.
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Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F(1)F(o)-ATPase. Bz-423 inhibits F(1)F(o)-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful.
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Linfocitos B/efectos de los fármacos , Benzodiazepinas/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Poliaminas Biogénicas/metabolismo , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Proteínas de Ciclo Celular/biosíntesis , Procesos de Crecimiento Celular/efectos de los fármacos , Humanos , Activación de Linfocitos/efectos de los fármacos , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas c-myc/inmunología , Superóxidos/metabolismoAsunto(s)
Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/genética , Transporte de Electrón , Humanos , Paraganglioma/epidemiología , Paraganglioma/genética , Feocromocitoma/epidemiología , Feocromocitoma/genéticaRESUMEN
Bladder cancer is a common and deadly malignancy but its treatment has advanced little due to poor understanding of the factors and pathways that promote disease. ATDC/TRIM29 is a highly expressed gene in several lethal tumor types, including bladder tumors, but its role as a pathogenic driver has not been established. Here we show that overexpression of ATDC in vivo is sufficient to drive both noninvasive and invasive bladder carcinoma development in transgenic mice. ATDC-driven bladder tumors were indistinguishable from human bladder cancers, which displayed similar gene expression signatures. Clinically, ATDC was highly expressed in bladder tumors in a manner associated with invasive growth behaviors. Mechanistically, ATDC exerted its oncogenic effects by suppressing miR-29 and subsequent upregulation of DNMT3A, leading to DNA methylation and silencing of the tumor suppressor PTEN. Taken together, our findings established a role for ATDC as a robust pathogenic driver of bladder cancer development, identified downstream effector pathways, and implicated ATDC as a candidate biomarker and therapeutic target.