RESUMEN
The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.
Asunto(s)
Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fenotipo , Línea Celular Tumoral , Reparación del ADN , Resistencia a Antineoplásicos , Femenino , Heterogeneidad Genética , Humanos , Mutación , Análisis de Secuencia de ARN , TranscriptomaRESUMEN
Cancer cell phenotypes evolve during a tumor's treatment. In some cases, tumor cells acquire cancer stem cell-like (CSL) traits such as resistance to chemotherapy and diminished differentiation; therefore, targeting these cells may be therapeutically beneficial. In this study we show that in progressive estrogen receptor positive (ER+) metastatic breast cancer tumors, resistant subclones that emerge following chemotherapy have increased CSL abundance. Further, in vitro organoid growth of ER+ patient cancer cells also shows that chemotherapy treatment leads to increased abundance of ALDH+/CD44+ CSL cells. Chemotherapy induced CSL abundance is blocked by treatment with a pan-HDAC inhibitor, belinostat. Belinostat treatment diminished both mammosphere formation and size following chemotherapy, indicating a decrease in progenitor CSL traits. HDAC inhibitors specific to class IIa (HDAC4, HDAC5) and IIb (HDAC6) were shown to primarily reverse the chemo-resistant CSL state. Single-cell RNA sequencing analysis with patient samples showed that HDAC targets and MYC signaling were promoted by chemotherapy and inhibited upon HDAC inhibitor treatment. In summary, HDAC inhibition can block chemotherapy-induced drug resistant phenotypes with 'one-two punch' strategy in refractory breast cancer cells.
RESUMEN
Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Initial studies showed its deletion and loss of expression in a variety of tumors but the role of this gene in tumor development is not completely understood. Here, we examined the role of DMBT1 in gastric precancerous lesions in Caucasian, African American and Hispanic individuals as well as in the development of gastric pathology in a mouse model of H. pylori infection. We found that in 3 different populations, mucosal DMBT1 expression was significantly increased (2.5 fold) in individuals with dysplasia compared to multifocal atrophic gastritis without intestinal metaplasia; the increase was also observed in individuals with advanced gastritis and positive H. pylori infection. In our animal model, H. pylori infection of Dmbt1-/- mice resulted in significantly higher levels of gastritis, more extensive mucous metaplasia and reduced Il33 expression levels in the gastric mucosa compared to H. pylori-infected wild type mice. Our data in the animal model suggest that in response to H. pylori infection DMBT1 may mediate mucosal protection reducing the risk of developing gastric precancerous lesions. However, the increased expression in human gastric precancerous lesions points to a more complex role of DMBT1 in gastric carcinogenesis.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Lesiones Precancerosas/genética , Receptores de Superficie Celular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Animales , Proteínas de Unión al Calcio , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Etnicidad/genética , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Infecciones por Helicobacter/complicaciones , Humanos , Ratones , Ratones Noqueados , Estadificación de Neoplasias , Proteínas Supresoras de TumorRESUMEN
Single-nucleotide polymorphisms (SNPs) in cytokine genes can affect gene expression and thereby modulate inflammation and carcinogenesis. However, the data on the association between SNPs in the interleukin 1 beta gene (IL1B) and colorectal cancer (CRC) are conflicting. We found an association between a 4-SNP haplotype block of the IL1B (-3737C/-1464G/-511T/-31C) and CRC risk, and this association was exclusively observed in individuals with a higher proportion of African ancestry, such as individuals from the Coastal Colombian region (odds ratio, OR 2.06; 95% CI 1.31-3.25; p < 0.01). Moreover, a significant interaction between this CRC risk haplotype and local African ancestry dosage was identified in locus 2q14 (p = 0.03). We conclude that Colombian individuals with high African ancestry proportions at locus 2q14 harbour more IL1B-CGTC copies and are consequently at an increased risk of CRC. This haplotype has been previously found to increase the IL1B promoter activity and is the most frequent haplotype in African Americans. Despite of limitations in the number of samples and the lack of functional analysis to examine the effect of these haplotypes on CRC cell lines, our results suggest that inflammation and ethnicity play a major role in the modulation of CRC risk.
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Neoplasias Colorrectales/genética , Interleucina-1beta/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Población Negra/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 2/genética , Colombia , Neoplasias Colorrectales/etnología , Femenino , Sitios Genéticos , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.
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Mucosa Gástrica/metabolismo , Gastritis Atrófica/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/patogenicidad , Receptores de Hialuranos/metabolismo , Lesiones Precancerosas/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Antígenos Ly/metabolismo , Células Cultivadas , Quimiotaxis de Leucocito , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis Atrófica/diagnóstico , Gastritis Atrófica/genética , Gastritis Atrófica/inmunología , Gastritis Atrófica/microbiología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/inmunología , Interferón gamma/metabolismo , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/inmunología , Neutrófilos/metabolismo , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/microbiología , Transducción de Señal , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/microbiología , Factores de TiempoRESUMEN
A new trend was developed for the formation of a complex between vanadium and flavonoid derivatives in order to increase the intestinal absorption and to reduce the toxicity of vanadium compounds. The vanadium-rutin complex was characterized by several spectroscopic techniques like ultraviolet (UV)-visible, Fourier transform infrared (FTIR), NMR, mass spectrometry, and microscopic evaluation by scanning electron microscopy. The mononuclear complex was formed by the interaction between vanadium and rutin with 1:2 metal to ligand stoichiometry. Antioxidant activity of the complex was evaluated by 1,1-diphenyl-2 picrylhydrazyl, ferric-reducing power, and 2,2'-azin-obis 3-ethylbenzothiazoline-6-sulphonic acid methods. It was shown that radical scavenging activity and ferric-reducing potential of free rutin was lower as compared with vanadium-rutin complex. The study was also investigated for oral acute toxicity and 28 days repeated oral subacute toxicity study of vanadium-rutin complex in balb/c mice. The vanadium-rutin complex showed mortality at a dose of 120 mg/kg in the balb/c mice. In 28 days repeated oral toxicity study, vanadium-rutin complex was administered to both sex of balb/c mice at dose levels of 90, 45, and 20 ppm, respectively. In addition, subacute toxicity study of vanadium-rutin complex (at 90 ppm dose level) showed increase levels of white blood cell (WBC), total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen and decrease level of total protein (TP) as compared with control group. Histopathological study of vanadium-rutin showed structural alteration in the liver, kidney, and stomach at 90 ppm dose level. No observed toxic level of vanadium-rutin complex at 20 ppm dose level could be good for further study.
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Antioxidantes/metabolismo , Rutina/química , Compuestos de Vanadio/toxicidad , Vanadio/química , Animales , Mucosa Gástrica/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Estómago/efectos de los fármacos , Compuestos de Vanadio/síntesis química , Compuestos de Vanadio/químicaRESUMEN
The complex formation between luteolin (L) and vanadium(IV) oxide sulphate monohydrate (VOSO4·H2O) was examined under UV-visible, infra-red spectroscopy, mass spectroscopy and NMR techniques. The spectroscopic data indicated that luteolin reacts with vanadium oxide cation (VO(+2)) through 4-carbonyl-5-hydroxy chelation site in the two luteolin molecule. The free radical antioxidant activity of the complex with respect to the parent molecule was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and 2,2'-azinobis 3-ethylbenzothiazoline-6-sulphonic acid diammonium salt (ABTS) methods. It was observed that the free radical scavenging activity and ferric ion reducing potential of luteolin was increased after the formation of complex with vanadium oxide (VO(+2)) cation.
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Antioxidantes/química , Luteolina/síntesis química , Óxidos/química , Compuestos de Vanadio/química , Benzotiazoles/química , Compuestos de Bifenilo/química , Radicales Libres/química , Espectroscopía de Resonancia Magnética , Picratos/química , Extractos Vegetales , Espectrofotometría Infrarroja , Ácidos Sulfónicos/químicaRESUMEN
The speckle-type POZ protein (SPOP) is a tumor suppressor in prostate cancer (PCa). SPOP somatic mutations have been reported in up to 15% of PCa of those of European descent. However, the genetic roles of SPOP in African American (AA)-PCa are currently unknown. We sequenced the SPOP gene to identify somatic mutations in 49 AA prostate tumors and identified three missense mutations (p.Y87C, p.F102S, and p.G111E) in five AA prostate tumors (10%) and one synonymous variant (p.I106I) in one tumor. Intriguingly, all of mutations and variants clustered in exon six, and all of the mutations altered conserved amino acids. Moreover, two mutations (p.F102S and p.G111E) have only been identified in AA-PCa to date. Quantitative real-time polymerase chain reaction analysis showed a lower level of SPOP expression in tumors carrying SPOP mutations than their matched normal prostate tissues. In addition, SPOP mutations and novel variants were detected in 5 of 27 aggressive PCa and one of 22 less aggressive PCa (P < 0.05). Further studies with increased sample size are needed to validate the clinicopathological significance of these SPOP mutations in AA-PCa.