RESUMEN
Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway, rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.
Asunto(s)
Páncreas Exocrino , Animales , Ratones , Páncreas Exocrino/metabolismo , Interferones/genética , Interferones/metabolismo , Fenotipo , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismoRESUMEN
Conventional genetically engineered mouse models (GEMM) are time-consuming, laborious, and offer limited spatiotemporal control. Here, we describe the development of a streamlined platform for in vivo gene activation using CRISPR activation (CRISPRa) technology. Unlike conventional GEMMs, this model system allows for flexible, sustained, and timed activation of one or more target genes using single or pooled lentiviral guides. Myc and Yap1 were used as model oncogenes to demonstrate gene activation in primary pancreatic organoid cultures in vitro and enhanced tumorigenic potential in Myc-activated organoids when transplanted orthotopically in vivo. Implementation of this model as an autochthonous lung cancer model showed that transduction-mediated activation of Myc led to accelerated tumor progression and significantly reduced overall survival relative to nontargeted tumor controls. Furthermore, Myc activation led to the acquisition of an immune suppressive, "cold" tumor microenvironment. Cross-species validation of these results using publicly available RNA/DNA-seq datasets linked MYC to a previously described immunosuppressive molecular subtype in patient tumors, thus identifying a patient cohort that may benefit from combined MYC- and immune-targeted therapies. Overall, this work demonstrates how CRISPRa can be used for rapid functional validation of putative oncogenes and may allow for the identification and evaluation of potential metastatic and oncogenic drivers through competitive screening. SIGNIFICANCE: A streamlined platform for programmable CRISPR gene activation enables rapid evaluation and functional validation of putative oncogenes in vivo.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-myc , Adenocarcinoma del Pulmón/genética , Animales , Carcinogénesis/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Oncogenes/genética , Proteínas Proto-Oncogénicas c-myc/genética , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Early detection of pancreatic ductal adenocarcinoma (PDA) may improve survival. We previously developed a clinical prediction model among patients with new-onset diabetes to help identify PDAs 6 months prior to the clinical diagnosis of the cancer. We developed and internally validated a new model to predict PDA risk among those newly diagnosed with impaired fasting glucose (IFG). METHODS: We conducted a retrospective cohort study in The Health Improvement Network (THIN) (1995-2013) from the UK. Eligible study patients had newly diagnosed IFG during follow-up in THIN. The outcome was incident PDA diagnosed within 3 years of IFG diagnosis. Candidate predictors were factors associated with PDA, glucose metabolism or both. RESULTS: Among the 138 232 eligible patients with initial IFG diagnosis, 245 (0.2%) were diagnosed with PDA within 3 years. The median time from IFG diagnosis to clinical PDA diagnosis was 326 days (IQR 120-588). The final prediction model included age, BMI, proton pump inhibitor use, total cholesterol, low-density lipoprotein, alanine aminotransferase and alkaline phosphatase. The model achieved good discrimination [area under the curve 0.71 (95% CI, 0.67-0.75)] and calibration (Hosmer and Lemeshow goodness-of-fit test P > 0.05 in 17 of the 20 imputed data sets) with optimism of 0.0012662 (95% CI, -0.00932 to 0.0108771). CONCLUSIONS: We developed and internally validated a sequential PDA prediction model based on clinical information routinely available at the initial appearance of IFG. If externally validated, this model could significantly extend our ability to detect PDAs at an earlier stage.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Estado Prediabético , Glucemia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/epidemiología , Humanos , Modelos Estadísticos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Estado Prediabético/diagnóstico , Estado Prediabético/epidemiología , Pronóstico , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
INTRODUCTION: Chronic pancreatitis is associated with an increased risk of developing pancreatic cancer, and patients with inherited forms of pancreatitis are at greatest risk. We investigated whether clinical severity of pancreatitis could also be an indicator of cancer risk independent of etiology by performing targeted DNA sequencing to assess the mutational burden in 55 cancer-associated genes. METHODS: Using picodroplet digital polymerase chain reaction and next-generation sequencing, we reported the genomic profiles of pancreases from severe clinical cases of chronic pancreatitis that necessitated palliative total pancreatectomy with islet autotransplantation. RESULTS: We assessed 57 tissue samples from 39 patients with genetic and idiopathic etiologies and found that despite the clinical severity of disease, there was no corresponding increase in mutational burden. The average allele frequency of somatic variants was 1.19% (range 1.00%-5.97%), and distinct regions from the same patient displayed genomic heterogeneity, suggesting that these variants are subclonal. Few oncogenic KRAS mutations were discovered (7% of all samples), although we detected evidence of frequent cancer-related variants in other genes such as TP53, CDKN2A, and SMAD4. Of note, tissue samples with oncogenic KRAS mutations and samples from patients with PRSS1 mutations harbored an increased total number of somatic variants, suggesting that these patients may have increased genomic instability and could be at an increased risk of developing pancreatic cancer. DISCUSSION: Overall, we showed that even in those patients with chronic pancreatitis severe enough to warrant total pancreatectomy with islet autotransplantation, pancreatic cancer-related mutational burden is not appreciably increased.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Mutación , Neoplasias Pancreáticas/genética , Pancreatitis Crónica/genética , Adulto , Edad de Inicio , Niño , Femenino , Humanos , Trasplante de Islotes Pancreáticos , Masculino , Pancreatectomía , Pancreatitis Crónica/complicaciones , Pancreatitis Crónica/cirugía , Gravedad del Paciente , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas p21(ras)/genética , Tripsina/genéticaRESUMEN
Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.
Asunto(s)
Células Acinares/patología , Carcinogénesis , Carcinoma Ductal Pancreático/patología , Genes ras , Páncreas/patología , Pancreatitis/fisiopatología , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/fisiopatología , Transformación Celular Neoplásica , Células Cultivadas , Reprogramación Celular , Cromatina/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Precursores Enzimáticos/metabolismo , Epigénesis Genética , Células Epiteliales/patología , Células Epiteliales/fisiología , Femenino , Sistema de Señalización de MAP Quinasas , Masculino , Metaplasia , Ratones , Mutación , Páncreas/metabolismo , Pancreatitis/genética , Pancreatitis/inmunología , Esferoides Celulares , TranscriptomaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is therapeutically recalcitrant and metastatic. Partial epithelial to mesenchymal transition (EMT) is associated with metastasis; however, a causal connection needs further unraveling. Here, we use single-cell RNA sequencing and genetic mouse models to identify the functional roles of partial EMT and epithelial stabilization in PDAC growth and metastasis. A global EMT expression signature identifies â¼50 cancer cell clusters spanning the epithelial-mesenchymal continuum in both human and murine PDACs. The combined genetic suppression of Snail and Twist results in PDAC epithelial stabilization and increased liver metastasis. Genetic deletion of Zeb1 in PDAC cells also leads to liver metastasis associated with cancer cell epithelial stabilization. We demonstrate that epithelial stabilization leads to the enhanced collective migration of cancer cells and modulation of the immune microenvironment, which likely contribute to efficient liver colonization. Our study provides insights into the diverse mechanisms of metastasis in pancreatic cancer and potential therapeutic targets.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Transición Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Factores de Transcripción de la Familia Snail/genética , Proteína 1 Relacionada con Twist/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/secundario , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Ratones , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Análisis de la Célula Individual , Factores de Transcripción de la Familia Snail/metabolismo , Análisis de Supervivencia , Microambiente Tumoral/genética , Proteína 1 Relacionada con Twist/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/deficienciaRESUMEN
Despite efforts in understanding its underlying mechanisms, the etiology of chromosomal instability (CIN) remains unclear for many tumor types. Here, we identify CIN initiation as a previously undescribed function for APOBEC3A (A3A), a cytidine deaminase upregulated across cancer types. Using genetic mouse models of pancreatic ductal adenocarcinoma (PDA) and genomics analyses in human tumor cells we show that A3A-induced CIN leads to aggressive tumors characterized by enhanced early dissemination and metastasis in a STING-dependent manner and independently of the canonical deaminase functions of A3A. We show that A3A upregulation recapitulates numerous copy number alterations commonly observed in patients with PDA, including co-deletions in DNA repair pathway genes, which in turn render these tumors susceptible to poly (ADP-ribose) polymerase inhibition. Overall, our results demonstrate that A3A plays an unexpected role in PDA as a specific driver of CIN, with significant effects on disease progression and treatment.
Asunto(s)
Citidina Desaminasa , Neoplasias Pancreáticas , Animales , Inestabilidad Cromosómica/genética , Citidina Desaminasa/genética , Humanos , Ratones , Neoplasias Pancreáticas/genética , Proteínas/genética , Neoplasias PancreáticasRESUMEN
Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar-ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of ß-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.
Asunto(s)
Carcinogénesis , Carcinoma Ductal Pancreático/fisiopatología , Neoplasias Pancreáticas/fisiopatología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/fisiología , Células Acinares/metabolismo , Células Acinares/patología , Animales , Carcinoma in Situ/patología , Carcinoma in Situ/fisiopatología , Carcinoma Ductal Pancreático/patología , Transdiferenciación Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Humanos , Metaplasia , Ratones , Ratones Transgénicos , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Physical activity is associated with a lower risk of disease recurrence among colon cancer patients. Circulating tumor cells (CTC) are prognostic of disease recurrence among stage I-III colon cancer patients. The pathways through which physical activity may alter disease outcomes are unknown, but may be mediated by changes in CTCs. METHODS: Participants included 23 stage I-III colon cancer patients randomized into one of three groups: usual-care control, 150 minâwk-1 of aerobic exercise (low-dose), and 300 minâwk-1 of aerobic exercise (high-dose) for six months. CTCs from venous blood were quantified in a blinded fashion using an established microfluidic antibody-mediated capture device. Poisson regression models estimated the logarithmic counts of CTCs. RESULTS: At baseline, 78% (18/23) of patients had ≥1 CTC. At baseline, older age (-0.12±0.06; P = 0.04), lymphovascular invasion (0.63±0.25; P = 0.012), moderate/poor histology (1.09±0.34; P = 0.001), body mass index (0.07±0.02; P = 0.001), visceral adipose tissue (0.08±0.04; P = 0.036), insulin (0.06±0.02; P = 0.011), sICAM-1 (0.04±0.02; P = 0.037), and sVCAM-1 (0.06±0.03; P = 0.045) were associated with CTCs. Over six months, significant decreases in CTCs were observed in the low-dose (-1.34±0.34; P<0.001) and high-dose (-1.18±0.40; P = 0.004) exercise groups, whereas no significant change was observed in the control group (-0.59±0.56; P = 0.292). Over six months, reductions in body mass index (-0.07±0.02; P = 0.007), insulin (-0.08±0.03; P = 0.014), and sICAM-1 (-0.07±0.03; P = 0.005) were associated with reductions in CTCs. The main limitations of this proof-of-concept study are the small sample size, heterogenous population, and per-protocol statistical analysis. CONCLUSION: Exercise may reduce CTCs among stage I-III colon cancer patients. Changes in host factors correlated with changes in CTCs. Exercise may have a direct effect on CTCs and indirect effects through alterations in host factors. This hypothesis-generating observation derived from a small pilot study warrants further investigation and replication.
Asunto(s)
Neoplasias del Colon/rehabilitación , Terapia por Ejercicio/métodos , Células Neoplásicas Circulantes/patología , Anciano , Recuento de Células , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cooperación del Paciente , Proyectos Piloto , Distribución de Poisson , Distribución AleatoriaRESUMEN
The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates KrasG12D-driven pancreatic cancer formation and liver metastasis. Importantly, one p120ctn allele is sufficient for E-CADHERIN-mediated cell adhesion. By contrast, cells with bi-allelic p120ctn loss demonstrate marked lung organotropism; however, rescue with p120ctn isoform 1A restores liver metastasis. In a p120ctn-independent PDAC model, mosaic loss of E-CADHERIN expression reveals selective pressure for E-CADHERIN-positive liver metastasis and E-CADHERIN-negative lung metastasis. Furthermore, human PDAC and liver metastases support the premise that liver metastases exhibit predominantly epithelial characteristics. RNA-seq demonstrates differential induction of pathways associated with metastasis and epithelial-to-mesenchymal transition in p120ctn-deficient versus p120ctn-wild-type cells. Taken together, P120CTN and E-CADHERIN mediated epithelial plasticity is an addition to the conceptual framework underlying metastatic organotropism in pancreatic cancer.
Asunto(s)
Cateninas/metabolismo , Plasticidad de la Célula/fisiología , Neoplasias Pancreáticas/patología , Animales , Cadherinas/metabolismo , Adhesión Celular , Línea Celular Tumoral , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/genética , Ratones , Metástasis de la Neoplasia/fisiopatología , Conductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/metabolismo , Fosfoproteínas/metabolismo , Isoformas de Proteínas/metabolismo , Catenina deltaRESUMEN
OBJECTIVE: To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors. METHODS: Thirty-nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min·wk-1 of aerobic exercise (low-dose) and 300 min·wk-1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. RESULTS: Over 6 months, the low-dose group completed 141 ± 10 min·wk-1 of aerobic exercise, and the high-dose group completed 247 ± 11 min·wk-1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (Ptrend = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (Ptrend = 0.025), the Pittsburgh Sleep Quality Index (Ptrend = 0.049), and the Fatigue Symptom Inventory (Ptrend = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. CONCLUSION: Higher doses of aerobic exercise, up to 300 min·wk-1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors.
Asunto(s)
Supervivientes de Cáncer/psicología , Neoplasias del Colon/psicología , Terapia por Ejercicio/métodos , Ejercicio Físico/psicología , Calidad de Vida , Neoplasias del Colon/fisiopatología , Neoplasias del Colon/rehabilitación , Ejercicio Físico/fisiología , Fatiga/fisiopatología , Fatiga/psicología , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el PacienteRESUMEN
Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may include changes in metabolic growth factors, such as insulin. Between January 2015 and August 2015, 39 stage I-III colon cancer survivors were randomized to one of the three groups: usual care control, 150 min/week of aerobic exercise (low-dose) and 300 min/week of aerobic exercise (high-dose) for six months. The pre-specified key metabolic growth factor outcome was fasting insulin. Insulin resistance was quantified using the homeostatic model assessment. Mean age was 56.5 ± 10.0 years, 51% had stage III disease, 72% were treated with chemotherapy and the mean time since finishing treatment was 10.9 ± 6.1 months. Over six months, the low-dose group completed 141.5 ± 9.9 min/week of aerobic exercise, and the high-dose group completed 247.2 ± 10.7 min/week of aerobic exercise. Fasting insulin concentrations decreased 7.4 ± 9.4 pmol/L in the control group, 28.0 ± 8.3 pmol/L in the low-dose group and 20.7 ± 9.3 pmol/L in the high-dose group (nonlinear Ptrend = 0.042). Insulin resistance decreased 0.11 ± 0.20 in the control group, 0.63 ± 0.17 in the low-dose group and 0.43 ± 0.19 in the high-dose group (nonlinear Ptrend = 0.012). Aerobic exercise reduces insulin concentrations and insulin resistance among patients with stage I-III colon cancer. Prescribing 150 min/week of aerobic exercise may be sufficient for reducing insulin concentrations and insulin resistance, which may partially mediate the relationship between physical activity and colon cancer prognosis.
Asunto(s)
Supervivientes de Cáncer , Neoplasias del Colon/sangre , Neoplasias del Colon/terapia , Ejercicio Físico , Insulina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Composición Corporal , Neoplasias del Colon/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND: Observational studies suggest that higher volumes of physical activity are associated with a lower risk of disease recurrence among survivors of colon cancer. However, the feasibility and safety of prescribing higher volumes of physical activity to survivors of colon cancer are unknown. Furthermore, the pathways through which exercise may reduce disease recurrence are unknown. PATIENTS AND METHODS: Survivors of stage I to III colon cancer were randomized to usual-care control, 150 minutes per week of aerobic exercise (low-dose), or 300 minutes per week of aerobic exercise (high-dose). Changes in soluble intercellular adhesion molecule-1 and vascular adhesion molecule-1 prognostic biomarkers were examined. RESULTS: From January 2015 to February 2016, 39 patients were enrolled (n = 13 usual-care control; n = 14 low-dose; n = 12 high-dose), and 38 participants completed the study (97% follow-up). Over 6 months, the low-dose group completed 142 minutes per week (92.8% adherence), and the high-dose group completed 247 minutes per week (89.0% adherence) of exercise. Compared with the control group, changes in soluble intercellular adhesion molecule-1 were -134.9 ng/mL (95% confidence interval, -238.1 to -31.6 ng/mL) in the low-dose group and -114.8 ng/mL (95% confidence interval, -222.5 to -7.1 ng/mL) in the high-dose group (linear Ptrend = .023; nonlinear Ptrend = .044). No changes were observed for soluable vascular adhesion molecule-1 (linear Ptrend = .791; nonlinear Ptrend = .604). Non-serious adverse events occurred at similar rates among randomized groups. No serious adverse events occurred. CONCLUSION: Higher volumes of moderate-intensity aerobic exercise, up to 300 minutes per week, are feasible, safe, and elicit favorable changes in prognostic biomarkers among patients recently treated for stage I to III colon cancer. These data can be used to guide clinical recommendations for patients, and inform future trials.
Asunto(s)
Supervivientes de Cáncer , Neoplasias del Colon , Terapia por Ejercicio/métodos , Adulto , Anciano , Amina Oxidasa (conteniendo Cobre)/sangre , Biomarcadores de Tumor/análisis , Moléculas de Adhesión Celular/sangre , Ejercicio Físico , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & controlRESUMEN
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasias (IPMNs) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression. METHODS: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreERT2;Ptenflox/flox;R26RYFP or PtenΔDuct/ΔDuct mice) and used PtenΔDuct/+ and Pten+/+ mice as controls. We also generated KrasG12D;PtenΔDuct/ΔDuct and KrasG12D;PtenΔDuct/+ mice. Pancreata were collected when mice were 28 weeks to 14.5 months old and analyzed by histology, immunohistochemistry, and electron microscopy. We performed multiplexed droplet digital polymerase chain reaction to detect spontaneous Kras mutations in PtenΔDuct/ΔDuct mice and study the effects of Ras pathway activation on initiation and progression of IPMNs. We obtained 2 pancreatic sections from a patient with an invasive pancreatobiliary IPMN and analyzed the regions with and without the invasive IPMN (control tissue) by immunohistochemistry. RESULTS: Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions with histologic and molecular features of human IPMNs. PtenΔDuct/ΔDuct mice developed IPMNs of several subtypes. In PtenΔDuct/ΔDuct mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. KrasG12D;PtenΔDuct/ΔDuct mice all developed invasive IPMNs within 1 month. In KrasG12D;PtenΔDuct/+ mice, 70% developed IPMN, predominately of the pancreatobiliary subtype, and 63.3% developed PDAC. In all models, IPMNs and PDAC expressed the duct-specific lineage tracing marker yellow fluorescent protein. In immunohistochemical analyses, we found that the invasive human pancreatobiliary IPMN tissue had lower levels of PTEN and increased levels of phosphorylated (activated) ERK compared with healthy pancreatic tissue. CONCLUSIONS: In analyses of mice with ductal cell-specific disruption of Pten, with or without activated Kras, we found evidence for a ductal cell origin of IPMNs. We also showed that PTEN loss and activated Kras have synergistic effects in promoting development of IPMN and progression to PDAC.
Asunto(s)
Carcinoma Ductal Pancreático/enzimología , Transformación Celular Neoplásica/metabolismo , Neoplasias Quísticas, Mucinosas y Serosas/enzimología , Fosfohidrolasa PTEN/deficiencia , Conductos Pancreáticos/enzimología , Neoplasias Pancreáticas/enzimología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Linaje de la Célula , Movimiento Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Invasividad Neoplásica , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Quísticas, Mucinosas y Serosas/patología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Fenotipo , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal , Factores de TiempoRESUMEN
Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.
Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Antineoplásicos/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Diferenciación Celular , Línea Celular Tumoral , Linaje de la Célula , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Xenoinjertos , Humanos , Queratinas/metabolismo , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Trasplante de Neoplasias , Células Neuroendocrinas/metabolismo , Células Neuroendocrinas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Pronóstico , Sinaptofisina/metabolismo , GemcitabinaRESUMEN
BACKGROUND: Physical activity is associated with a lower risk of disease recurrence among colon cancer survivors. Excess visceral adipose tissue is associated with a higher risk of disease recurrence among colon cancer survivors. The pathways through which physical activity may alter disease outcomes are unknown, but may be mediated by changes in visceral adipose tissue. METHODS: Thirty-nine stage I-III colon cancer survivors were randomised to one of three groups: usual-care control, 150 min wk-1 of aerobic exercise (low dose) and 300 min wk-1 of aerobic exercise (high dose) for 6 months. The prespecified key body composition outcome was visceral adipose tissue quantified using dual energy X-ray absorptiometry. RESULTS: Exercise reduced visceral adipose tissue in dose-response fashion (Ptrend=0.008). Compared with the control group, the low- and high-dose exercise groups lost 9.5 cm2 (95% CI: -22.4, 3.5) and 13.6 cm2 (95% CI: -27.0, -0.1) in visceral adipose tissue, respectively. Each 60 min wk-1 increase in exercise predicted a 2.7 cm2 (95% CI: -5.4, -0.1) reduction in visceral adipose tissue. CONCLUSIONS: Aerobic exercise reduces visceral adipose tissue in dose-response fashion among patients with stage I-III colon cancer. Visceral adipose tissue may be a mechanism through which exercise reduces the risk of disease recurrence among colon cancer survivors.
Asunto(s)
Composición Corporal , Supervivientes de Cáncer , Neoplasias del Colon/metabolismo , Neoplasias del Colon/mortalidad , Ejercicio Físico , Adulto , Anciano , Femenino , Humanos , Grasa Intraabdominal/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & controlRESUMEN
Acute myelogenous leukemia (AML) frequently relapses after complete remission (CR), necessitating improved detection and phenotypic characterization of treatment-resistant residual disease. In this work, we have optimized droplet digital PCR to broadly measure mutated alleles of recurrently mutated genes in CR marrows of AML patients at levels as low as 0.002% variant allele frequency. Most gene mutations persisted in CR, albeit at highly variable and gene-dependent levels. The majority of AML cases demonstrated residual aberrant oligoclonal hematopoiesis. Importantly, we detected very rare cells (as few as 1 in 15,000) that were genomically similar to the dominant blast populations at diagnosis and were fully clonally represented at relapse, identifying these rare cells as one common source of AML relapse. Clinically, the mutant allele burden was associated with overall survival in AML, and our findings narrow the repertoire of gene mutations useful in minimal residual disease-based prognostication in AML. Overall, this work delineates rare cell populations that cause AML relapse, with direct implications for AML research directions and strategies to improve AML therapies and outcome.
Asunto(s)
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Recurrencia Local de Neoplasia , Neoplasia Residual/genética , Adulto , Anciano , Alelos , Antraciclinas/administración & dosificación , Médula Ósea/patología , Citarabina/administración & dosificación , Exoma , Femenino , Hematopoyesis , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Inducción de Remisión , Trasplante de Células Madre , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
The primary treatment of pancreatic cancer was the topic of the 3rd St. Gallen Conference 2016. A multidisciplinary panel reviewed the current evidence and discussed controversial issues in a moderated consensus session. Here we report on the key expert recommendations. It was generally accepted that radical surgical resection followed by adjuvant chemotherapy offers the only evidence-based treatment with a chance for cure. Initial staging should classify localised tumours as resectable or unresectable (i.e. locally advanced pancreatic cancer) although there remains a large grey-zone of potentially resectable disease between these two categories which has recently been named as borderline resectable, a concept which was generally accepted by the panel members. However, the definition of these borderline-resectable (BR) tumours varies between classifications due to their focus on either (i) technical hurdles (e.g. the feasibility of vascular resection) or (ii) oncological outcome (e.g. predicting the risk of a R1 resection and/or occult metastases). The resulting expert discussion focussed on imaging standards as well as the value of pretherapeutic laparoscopy. Indications for biliary drainage were seen especially before neoadjuvant therapy. Following standard resection, the panel unanimously voted for the use of adjuvant chemotherapy after R0 resection and considered it as a reasonable standard of care after R1 resection, even though the optimal pathologic evaluation and the definition of R0/R1 was the issue of an ongoing debate. The general concept of BR tumours was considered as a good basis to select patients for preoperative therapy, albeit its current impact on the therapeutic strategy was far less clear. Main focus of the conference was to discuss the limits of surgical resection and to identify ways to standardise procedures and to improve curative outcome, including adjuvant and perioperative treatment.