RESUMO
Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.
Assuntos
Fibrose/epidemiologia , Animais , População Negra , Citocinas/metabolismo , Doença/classificação , Fibrose/imunologia , Fibrose/metabolismo , Predisposição Genética para Doença , Helmintíase/genética , Helmintíase/imunologia , Humanos , Camundongos , PrevalênciaRESUMO
Women make up over one-half of all doctoral recipients in biology-related fields but are vastly underrepresented at the faculty level in the life sciences. To explore the current causes of women's underrepresentation in biology, we collected publicly accessible data from university directories and faculty websites about the composition of biology laboratories at leading academic institutions in the United States. We found that male faculty members tended to employ fewer female graduate students and postdoctoral researchers (postdocs) than female faculty members did. Furthermore, elite male faculty--those whose research was funded by the Howard Hughes Medical Institute, who had been elected to the National Academy of Sciences, or who had won a major career award--trained significantly fewer women than other male faculty members. In contrast, elite female faculty did not exhibit a gender bias in employment patterns. New assistant professors at the institutions that we surveyed were largely comprised of postdoctoral researchers from these prominent laboratories, and correspondingly, the laboratories that produced assistant professors had an overabundance of male postdocs. Thus, one cause of the leaky pipeline in biomedical research may be the exclusion of women, or their self-selected absence, from certain high-achieving laboratories.
Assuntos
Academias e Institutos , Disciplinas das Ciências Biológicas , Educação de Pós-Graduação , Docentes , National Academy of Sciences, U.S. , Mulheres Trabalhadoras , Feminino , Humanos , Masculino , Estados UnidosRESUMO
The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38ß, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.
Assuntos
Neoplasias Pulmonares , Proteína Quinase 14 Ativada por Mitógeno , Humanos , Receptores ErbB , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Mutação , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismoRESUMO
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses TP53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, specific aneuploidies play essential roles in tumorigenesis, raising the possibility that targeting these "aneuploidy addictions" could represent a novel approach for cancer treatment.
RESUMO
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these "aneuploidy addictions" could be targeted as a therapeutic strategy.
Assuntos
Proteínas de Ciclo Celular , Edição de Genes , Neoplasias , Oncogenes , Trissomia , Proteína Supressora de Tumor p53 , Humanos , Proteínas de Ciclo Celular/genética , Mutação , Neoplasias/genética , Neoplasias/terapia , Proteínas Proto-Oncogênicas/metabolismo , Edição de Genes/métodos , Proteína Supressora de Tumor p53/genética , Carcinogênese/genéticaRESUMO
Clinical decisions in cancer rely on precisely assessing patient risk. To improve our ability to identify the most aggressive malignancies, we constructed genome-wide survival models using gene expression, copy number, methylation, and mutation data from 10,884 patients. We identified more than 100,000 significant prognostic biomarkers and demonstrate that these genomic features can predict patient outcomes in clinically ambiguous situations. While adverse biomarkers are commonly believed to represent cancer driver genes and promising therapeutic targets, we show that cancer features associated with shorter survival times are not enriched for either oncogenes or for successful drug targets. Instead, the strongest adverse biomarkers represent widely expressed cell-cycle and housekeeping genes, and, correspondingly, nearly all therapies directed against these features have failed in clinical trials. In total, our analysis establishes a rich resource for prognostic biomarker analysis and clarifies the use of patient survival data in preclinical cancer research and therapeutic development.
Assuntos
Neoplasias , Oncogenes , Genômica , Humanos , Mutação/genética , Neoplasias/genética , PrognósticoRESUMO
Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.
Assuntos
Aneuploidia , Instabilidade Cromossômica/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Linhagem Celular Tumoral , Resistência a Medicamentos/efeitos dos fármacos , Meio Ambiente , Humanos , Neoplasias/genética , Resultado do TratamentoRESUMO
BACKGROUND: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. METHODS: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. FINDINGS: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. INTERPRETATION: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. FUNDING: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.
Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Ésteres/farmacologia , Guanidinas/farmacologia , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Células HEK293 , Humanos , Pulmão/patologia , Pulmão/virologia , Proteínas de Membrana/biossíntese , Simulação de Dinâmica Molecular , Serina Endopeptidases/biossíntese , Serina Proteases/biossíntese , Células Vero , Ativação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacosRESUMO
The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination.
Assuntos
Células Epiteliais Alveolares/metabolismo , Infecções por Coronavirus/epidemiologia , Interferons/metabolismo , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Mucosa Respiratória/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Fumar Tabaco/genética , Adulto , Idoso , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Células CACO-2 , Células Cultivadas , Feminino , Células HCT116 , Humanos , Interferons/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA-Seq , Ratos , Transdução de Sinais , Análise de Célula Única , Fumar Tabaco/epidemiologia , Fumar Tabaco/metabolismo , Regulação para CimaRESUMO
High levels of cancer aneuploidy are frequently associated with poor prognosis. To examine the relationship between aneuploidy and cancer progression, we analyzed a series of congenic cell lines that harbor single extra chromosomes. We found that across 13 different trisomic cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, we discovered that chromosomal instability activates cGAS/STING signaling but strongly suppresses invasiveness. By analyzing patient copy-number data, we demonstrate that specific aneuploidies are associated with distinct outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different aneuploidies can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, thereby linking genomic plasticity, phenotypic plasticity, and metastasis.
Assuntos
Aneuploidia , Movimento Celular , Instabilidade Cromossômica , Cromossomos Humanos Par 5/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Transição Epitelial-Mesenquimal , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/genética , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Antiviral therapy is urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The protease inhibitor camostat mesylate inhibits SARS-CoV-2 infection of lung cells by blocking the virus-activating host cell protease TMPRSS2. Camostat mesylate has been approved for treatment of pancreatitis in Japan and is currently being repurposed for COVID-19 treatment. However, potential mechanisms of viral resistance as well as camostat mesylate metabolization and antiviral activity of metabolites are unclear. Here, we show that SARS-CoV-2 can employ TMPRSS2-related host cell proteases for activation and that several of them are expressed in viral target cells. However, entry mediated by these proteases was blocked by camostat mesylate. The camostat metabolite GBPA inhibited the activity of recombinant TMPRSS2 with reduced efficiency as compared to camostat mesylate and was rapidly generated in the presence of serum. Importantly, the infection experiments in which camostat mesylate was identified as a SARS-CoV-2 inhibitor involved preincubation of target cells with camostat mesylate in the presence of serum for 2 h and thus allowed conversion of camostat mesylate into GBPA. Indeed, when the antiviral activities of GBPA and camostat mesylate were compared in this setting, no major differences were identified. Our results indicate that use of TMPRSS2-related proteases for entry into target cells will not render SARS-CoV-2 camostat mesylate resistant. Moreover, the present and previous findings suggest that the peak concentrations of GBPA established after the clinically approved camostat mesylate dose (600 mg/day) will result in antiviral activity.
RESUMO
Successful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed the genomic profiles of 17,879 tumors from patients with known outcomes. We find that mutations in almost all cancer driver genes contain remarkably little information on patient prognosis. However, CNAs in these same driver genes harbor significant prognostic power. Focal CNAs are associated with worse outcomes than broad alterations, and CNAs in many driver genes remain prognostic when controlling for stage, grade, TP53 status, and total aneuploidy. By performing a meta-analysis across independent patient cohorts, we identify robust prognostic biomarkers in specific cancer types, and we demonstrate that a subset of these alterations also confer specific therapeutic vulnerabilities. In total, our analysis establishes a comprehensive resource for cancer biomarker identification and underscores the importance of gene copy number profiling in assessing clinical risk.
Assuntos
Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Mutação , Proteínas de Neoplasias/genética , Neoplasias/genética , Oncogenes , Aneuploidia , Antineoplásicos/uso terapêutico , Feminino , Dosagem de Genes , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/terapia , Prognóstico , Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (
Assuntos
Carcinogênese , Expressão Gênica , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Inativação de Genes , Humanos , Camundongos NusRESUMO
The incidence of familial adenomatous polyposis (FAP) is one in 7,000 to 12,000 live births. Virtually, all surgically untreated patients with FAP inevitably develop colorectal-cancer in their lifetime because they carry the adenomatous polyposis coli gene. Thus prophylactic proctocolectomy is indicated. Surgical treatment of FAP is still controversial. There are however, four surgical options: ileorectal anastomosis, restorative proctocolectomy with ileal pouch-anal anastomosis, proctocolectomy with ileostomy, and proctocolectomy with continent-ileostomy. Conventional proctocolectomy options largely lie between colectomy with ileorectal anastomosis or ileal pouch-anal anastomosis. Detractors of ileal pouch-anal anastomosis prefer ileorectal anastomosis because of better functional results and quality of life. The functional outcome of total colectomy with ileorectal anastomosis is undoubtedly far superior to that of the ileoanal pouch; however, the risk for rectal cancer is increased by 30%. Even after mucosectomy, inadvertent small mucosal residual islands remain. These residual islands carry the potential for the development of subsequent malignancy. We reviewed the literature (1975-2012) on the incidence, nature, and possible etiology of subsequent ileal-pouch and anal transit zone adenocarcinoma after prophylactic surgery procedure for FAP. To date there are 24 studies reporting 92 pouch-related cancers; 15 case reports, 4 prospective and 5 retrospective studies. Twenty three of 92 cancers (25%) developed in the pouch mucosa and 69 (75%) in anal transit zone (ATZ). Current recommendation for pouch surveillance and treatment are presented. Data suggest lifetime surveillance of these patients.
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Biologia , Pesquisa Biomédica , Razão de Masculinidade , Sexismo , Mulheres , Docentes , Características da Família , Feminino , Humanos , Masculino , Homens , Recursos HumanosRESUMO
Keloids are benign tumors of the dermis that form during a protracted wound healing process. Susceptibility to keloid formation occurs predominantly in people of African and Asian descent. The key alteration(s) responsible for keloid formation has not been identified and there is no satisfactory treatment for this disorder. The altered regulatory mechanism is limited to dermal wound healing, although several diseases characterized by an exaggerated response to injury are prevalent in individuals of African ancestry. We have observed a complex pattern of phenotypic differences in keloid fibroblasts grown in standard culture medium or induced by hydrocortisone (HC). In this study Affymetrix-based microarray was performed on RNA obtained from fibroblasts cultured from normal scars and keloids grown in the absence and presence of HC. We observed differential regulation of approximately 500 genes of the 38,000 represented on the Affymetrix chip. Of particular interest was increased expression of several IGF-binding and IGF-binding-related proteins and decreased expression of a subset of Wnt pathway inhibitors and multiple IL-1-inducible genes. Increased expression of connective tissue growth factor and insulin-like growth factor binding protein-3 was observed in keloid fibroblasts only in the presence of HC. These findings support a role for multiple fibrosis-related pathways in the pathogenesis of keloids.