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1.
Clin Cancer Res ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33172898

RESUMO

PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard of care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications. EXPERIMENTAL DESIGN: RNA/DNA sequencing of 54 flash-frozen salivary ACC and reverse-phase protein array (RPPA) in 38 specimens were performed, with validation by western blot and/or immunohistochemistry. Three independent ACC cohorts were used for validation. RESULTS: Both unbiased RNA-seq and RPPA analysis revealed two molecular subtypes; ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH activating mutations and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, EGFR), and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNAseq. Furthermore, immunohistochemical staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggests a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II producing unique therapeutic vulnerabilities for each subtype. CONCLUSIONS: Co-occurrence of multiple actionable protein/pathways alterations in each subtype indicate unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.

2.
Nucleic Acids Res ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33211847

RESUMO

Understanding the functional impact of cancer somatic mutations represents a critical knowledge gap for implementing precision oncology. It has been increasingly appreciated that the interaction profile mediated by a genomic mutation provides a fundamental link between genotype and phenotype. However, specific effects on biological signaling networks for the majority of mutations are largely unknown by experimental approaches. To resolve this challenge, we developed e-MutPath (edgetic Mutation-mediated Pathway perturbations), a network-based computational method to identify candidate 'edgetic' mutations that perturb functional pathways. e-MutPath identifies informative paths that could be used to distinguish disease risk factors from neutral elements and to stratify disease subtypes with clinical relevance. The predicted targets are enriched in cancer vulnerability genes, known drug targets but depleted for proteins associated with side effects, demonstrating the power of network-based strategies to investigate the functional impact and perturbation profiles of genomic mutations. Together, e-MutPath represents a robust computational tool to systematically assign functions to genetic mutations, especially in the context of their specific pathway perturbation effect.

3.
J Thorac Oncol ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096269

RESUMO

INTRODUCTION: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. METHODS: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). RESULTS: NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3- tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. CONCLUSIONS: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.

4.
Sci Rep ; 10(1): 18377, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110184

RESUMO

The Bacillus Calmette-Guerin (BCG) vaccine provides protection against tuberculosis (TB), and is thought to provide protection against non-TB infectious diseases. BCG vaccination has recently been proposed as a strategy to prevent infection with SARS-CoV-2 (CoV-2) to combat the COVID-19 outbreak, supported by its potential to boost innate immunity and initial epidemiological analyses which observed reduced severity of COVID-19 in countries with universal BCG vaccination policies. Seventeen clinical trials are currently registered to inform on the benefits of BCG vaccinations upon exposure to CoV-2. Numerous epidemiological analyses showed a correlation between incidence of COVID-19 and BCG vaccination policies. These studies were not systematically corrected for confounding variables. We observed that after correction for confounding variables, most notably testing rates, there was no association between BCG vaccination policy and COVD-19 spread rate or percent mortality. Moreover, we found variables describing co-morbidities, including cardiovascular death rate and smoking prevalence, were significantly associated COVID-19 spread rate and percent mortality, respectively. While reporting biases may confound our observations, our epidemiological findings do not provide evidence to correlate overall BCG vaccination policy with the spread of CoV-2 and its associated mortality.


Assuntos
Vacina BCG/administração & dosagem , Infecções por Coronavirus/epidemiologia , Vacinação em Massa/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Tuberculose/prevenção & controle , Vacina BCG/uso terapêutico , Correlação de Dados , Política de Saúde , Humanos , Pandemias
5.
Cancer Res ; 80(21): 4854-4867, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32855206

RESUMO

Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output across cancer types is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in patients with cancer. To do so, we developed a Network-based Integrative model to Prioritize Potential immune respondER genes (NIPPER). Identified mutations were enriched in essential protein domains and genes identified by NIPPER were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a resource for future functional studies and targeted therapeutics. SIGNIFICANCE: This study demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics.

6.
PLoS One ; 15(7): e0236619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730356

RESUMO

The outbreak the SARS-CoV-2 (CoV-2) virus has resulted in over 6.5 million cases of COVID19, greatly stressing global healthcare infrastructure. Lacking medical prophylactic measures to combat disease spread, many nations have adopted social distancing policies in order to mitigate transmission of CoV-2. While mathematical models have suggested the efficacy of social distancing to curb the spread of CoV-2, there is a lack of systematic studies to quantify the real-world efficacy of these approaches. Here, we first demonstrate that implementation of social distancing policies in US states corresponded with a reduction in COVID19 spread rates, and that the reduction in spread rate is proportional to the average change in mobility. We validate this observation on a worldwide scale by analyzing COVID19 spread rate in 134 nations with varying social distancing policies. Globally, we find that social distancing policies significantly reduced the COVID19 spread rate, with resulting in an estimated 65% reduction (95% CI = 39-80%) in new COVID19 cases over a two week time period. These data suggest that social distancing policies may be a powerful tool to prevent spread of COVID19 in real-world scenarios.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Modelos Teóricos , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Quarentena/métodos , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Humanos , Regulamento Sanitário Internacional , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Quarentena/economia , Estados Unidos/epidemiologia
7.
Nat Commun ; 11(1): 2135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358509

RESUMO

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/microbiologia , Fatores de Transcrição/metabolismo , Animais , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/metabolismo , Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Análise Serial de Tecidos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcriptoma/genética
8.
Mol Cancer Res ; 18(5): 723-734, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32051231

RESUMO

Hepatocellular carcinomas (HCC) are adapted to survive extreme genomic stress conditions imposed by hyperactive DNA replication and genotoxic drug treatment. The underlying mechanisms remain unclear, but may involve intensified DNA damage response/repair programs. Here, we investigate a new role of nucleostemin (NS) in allowing HCC to survive its own malignancy, as NS was previously shown to promote liver regeneration via a damage repair mechanism. We first established that a higher NS transcript level correlates with high-HCC grades and poor prognostic signatures, and is an independent predictor of shorter overall and progression-free survival specifically for HCC and kidney cancer but not for others. Immunostaining confirmed that NS is most abundantly expressed in high-grade and metastatic HCCs. Genome-wide analyses revealed that NS is coenriched with MYC target and homologous recombination (HR) repair genes in human HCC samples and functionally intersects with those involved in replication stress response and HR repair in yeasts. In support, NS-high HCCs are more reliant on the replicative/oxidative stress response pathways, whereas NS-low HCCs depend more on the mTOR pathway. Perturbation studies showed NS function in protecting human HCC cells from replication- and drug-induced DNA damage. Notably, NS depletion in HCC cells increases the amounts of physical DNA damage and cytosolic double-stranded DNA, leading to a reactive increase of cytokines and PD-L1. This study shows that NS provides an essential mechanism for HCC to adapt to high genomic stress for oncogenic maintenance and propagation. NS deficiency sensitizes HCC cells to chemotherapy but also triggers tumor immune responses. IMPLICATIONS: HCC employs a novel, nucleostemin (NS)-mediated-mediated adaptive mechanism to survive high genomic stress conditions, a deficiency of which sensitizes HCC cells to chemotherapy but also triggers tumor immune responses.

9.
Cancer Cell ; 37(3): 371-386.e12, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32109374

RESUMO

Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.


Assuntos
Ciclopentanos/farmacologia , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/tratamento farmacológico , Proteoma/genética , Pirimidinas/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Feminino , Células HCT116 , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Instabilidade de Microssatélites , Mutação , Proteína NEDD8/antagonistas & inibidores , Proteína NEDD8/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Estabilidade Proteica , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Semin Cell Dev Biol ; 99: 3-11, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-29738884

RESUMO

Genes and gene products interact with each other to form signal transduction networks in the cell. The interactome networks are under intricate regulation in physiological conditions, but could go awry upon genome instability caused by genetic mutations. In the past decade with next-generation sequencing technologies, an increasing number of genomic mutations have been identified in a variety of disease patients and healthy individuals. As functional and systematic studies on these mutations leap forward, they begin to reveal insights into cellular homeostasis and disease mechanisms. In this review, we discuss recent advances in the field of network biology and signaling pathway perturbations upon genomic changes, and highlight the success of various omics datasets in unraveling genotype-to-phenotype relationships.

11.
Cancer Cell ; 35(6): 851-867.e7, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185210

RESUMO

We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Esquema de Medicação , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos SCID , Mitose/efeitos dos fármacos , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos
12.
Oncogene ; 38(20): 3919-3931, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30692636

RESUMO

A defective homologous recombination (HR) repair program increases tumor incidence as well as providing a survival advantage in patients with breast and ovarian cancers. Here we hypothesize that the tumor-promoting side of genome maintenance programs may be contributed by a self-renewal protein, nucleostemin (NS). To address this issue, we established its functional importance in mammary tumor progression in mice and showed that mammary tumor cells become highly susceptible to replicative DNA damage following NS depletion and are protected from hydroxyurea-induced damage by NS overexpression. Breast cancer cells with basal-like characters display more reliance on NS for genome maintenance than those with luminal characters. Mechanistically, NS-deficient cells demonstrate a significantly reduced HR repair activity. TCGA analyses of human breast cancers revealed that NS is co-enriched positively with HR repair proteins and that high NS expression correlates with low HR defects and predicts poor progression-free survival and resistance to knockdown of cell-cycle checkpoint genes in triple-negative/basal-like breast cancers. This work indicates that NS constitutes a tumor-promoting genome maintenance program required for mammary tumor progression.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/genética , Proteínas de Ligação ao GTP/genética , Recombinação Homóloga , Neoplasias Mamárias Animais/genética , Proteínas Nucleares/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Transporte/metabolismo , Dano ao DNA , Intervalo Livre de Doença , Feminino , Proteínas de Ligação ao GTP/metabolismo , Regulação Neoplásica da Expressão Gênica , Genoma , Humanos , Hidroxiureia/farmacologia , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos Nus , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA , Células Tumorais Cultivadas
13.
Int J Cancer ; 144(5): 1092-1103, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30152517

RESUMO

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise in the treatment of patients with deficiencies in homologous recombination (HR) DNA repair, such as those with loss of BRCA1 or BRCA2 function. However, emerging studies suggest that PARP inhibition can also target HR-competent cancers, such as non-small-cell lung cancer (NSCLC), and that the therapeutic effect of PARP inhibition may be improved by combination with chemotherapy agents. In our study, it was found that PARP inhibitors talazoparib (BMN-673) and olaparib (AZD-2281) both had synergistic activity with the common first-line chemotherapeutic gemcitabine in a panel of lung cancer cell lines. Furthermore, the combination demonstrated significant in vivo antitumor activity in an H23 xenograft model of NSCLC compared to either agent as monotherapy. This synergism occurred without loss of HR repair efficiency. Instead, the combination induced synergistic single-strand DNA breaks, leading to accumulation of toxic double-strand DNA lesions in vitro and in vivo. Our study elucidates the underlying mechanisms of synergistic activity of PARP inhibitors and gemcitabine, providing a strong motivation to pursue this combination as an improved therapeutic regimen.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , Ftalazinas/farmacologia , Piperazinas/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
14.
Hepatology ; 70(2): 532-546, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30153342

RESUMO

The interaction between RNA-binding proteins (RBPs) and RNA plays an important role in regulating cellular function. However, decoding genome-wide protein-RNA regulatory networks as well as how cancer-related mutations impair RNA regulatory activities in hepatocellular carcinoma (HCC) remains mostly undetermined. We explored the genetic alteration patterns of RBPs and found that deleterious mutations are likely to occur on the surface of RBPs. We then constructed protein-RNA interactome networks by integration of target binding screens and expression profiles. Network analysis highlights regulatory principles among interacting RBPs. In addition, somatic mutations selectively target functionally important genes (cancer genes, core fitness genes, or conserved genes) and perturb the RBP-gene regulatory networks in cancer. These regulatory patterns were further validated using independent data. A computational method (Mutational Effect on RNA Interactome Topology) and a web-based, user-friendly resource were further proposed to analyze the RBP-gene regulatory networks across cancer types. Pan-cancer analysis also suggests that cancer cells selectively target "vulnerability" genes to perturb protein-RNA interactome that is involved in cancer hallmark-related functions. Specifically, we experimentally validated four pairs of RBP-gene interactions perturbed by mutations in HCC, which play critical roles in cell proliferation. Based on the expression of perturbed RBP and target genes, we identified three subtypes of HCC with different survival rates. Conclusion: Our results provide a valuable resource for characterizing somatic mutation-perturbed protein-RNA regulatory networks in HCC, yielding valuable insights into the genotype-phenotype relationships underlying human cancer, and potential biomarkers for precision medicine.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mutação , Proteínas de Ligação a RNA/genética , RNA/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Proliferação de Células , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Mapas de Interação de Proteínas , Taxa de Sobrevida
15.
Trends Biochem Sci ; 43(8): 576-592, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29941230

RESUMO

Gene regulatory networks underlie biological function and cellular physiology. Alternative splicing (AS) is a fundamental step in gene regulatory networks and plays a key role in development and disease. In addition to the identification of aberrant AS events, an increasing number of studies are focusing on molecular determinants of AS, including genetic and epigenetic regulators. We review here recent efforts to identify various deregulated AS events as well as their molecular determinants that alter biological functions, and discuss clinical features of AS and their druggable potential.


Assuntos
Epigênese Genética , Redes Reguladoras de Genes , Variação Genética , Processamento Alternativo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
16.
Am J Cancer Res ; 8(5): 903-914, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29888111

RESUMO

Endometrial cancer is one of the most common cancers of the female reproductive system. CHD4, a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex, is frequently mutated in these patients. However the role it plays in promoting endometrial tumorigenesis is poorly understood. Here, we use genetic engineering approaches to modulate CHD4 expression levels and functionally evaluate hot spot mutations R975H and R1162W. We find that CHD4 depletion induces up-regulation of the cancer stem cell (CSC) marker CD133. This CSC phenotype was verified functionally by invasion ability, spheroid formation, and tumorigenicity in vivo. While cells expressing mutated CHD4 did not display impaired CHD4 DNA recruitment or NuRD complex formation, the mutations did reduce the stability of CHD4 protein to phenocopy CHD4 depletion. Consistently, patients with mutant CHD4 showed overexpression of CD133. Network analysis indicated activation of the TGFß signaling pathway may drive this CSC phenotype, and chemical blockade of TGFß abrogated the ability CHD4 knockdown cells to form spheroids. Taken together, these results indicate that mutations in CHD4 can promote endometrial tumorigenesis by increasing CSC character through TGFß signaling pathway.

17.
Cell Rep ; 23(7): 2095-2106, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768207

RESUMO

Extensive spontaneous DNA damage from oncogene-induced replication stress is ubiquitous in precancerous lesions. While this damage induces differentiation, senescence, or apoptosis in normal cells, defects in DNA replication stress response (RSR) allow cells to continue proliferating, ultimately leading to early tumorigenesis. Using systems-level approaches, we developed a replication stress response defect gene signature that predicted risk of cancer development from hyperplastic lesions. Intriguingly, we found that replication stress response defects rewire non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. High-throughput drug screening to elucidate molecules required for survival of replication stress response defective cells identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. Moreover, MEK/ERK inhibition also depleted CSC populations. Together, these findings provide insights into the role of replication stress response defects in CSCs and an actionable pathway for therapeutic targeting.


Assuntos
Replicação do DNA , Células-Tronco Neoplásicas/patologia , Estresse Fisiológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Senescência Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Células MCF-7 , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Oncogenes , Fenótipo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais
18.
Nat Commun ; 9(1): 1317, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615613

RESUMO

To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration. This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. These findings demonstrate diverse drivers of immune cell infiltration across cancer lineages and may facilitate the clinical adaption of immunotherapies across diverse malignancies.


Assuntos
Antígenos/química , Dosagem de Genes , Genômica , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/genética , Neoplasias/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Movimento Celular , Citocinas/metabolismo , Dano ao DNA , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Leucócitos Mononucleares/metabolismo , Camundongos , Microscopia de Fluorescência , Mutação , Neoplasias/imunologia , Fosforilação , Proteômica , Linfócitos T Citotóxicos/citologia
19.
Cell Rep ; 21(3): 798-812, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29045845

RESUMO

It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.


Assuntos
Processamento Alternativo/genética , Neoplasias/genética , Redes Reguladoras de Genes , Heterogeneidade Genética , Humanos , Internet , Mutação/genética , Neoplasias/imunologia , Fenótipo
20.
NPJ Syst Biol Appl ; 3: 8, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28649435

RESUMO

Despite rapid advancement in generation of large-scale microarray gene expression datasets, robust multigene expression signatures that are capable of guiding the use of specific therapies have not been routinely implemented into clinical care. We have developed an iterative resampling analysis to predict sensitivity algorithm to generate gene expression sensitivity profiles that predict patient responses to specific therapies. The resultant signatures have a robust capacity to accurately predict drug sensitivity as well as the identification of synergistic combinations. Here, we apply this approach to predict response to PARP inhibitors, and show it can greatly outperforms current clinical biomarkers, including BRCA1/2 mutation status, accurately identifying PARP inhibitor-sensitive cancer cell lines, primary patient-derived tumor cells, and patient-derived xenografts. These signatures were also capable of predicting patient response, as shown by applying a cisplatin sensitivity signature to ovarian cancer patients. We additionally demonstrate how these drug-sensitivity signatures can be applied to identify novel synergizing agents to improve drug efficacy. Tailoring therapeutic interventions to improve patient prognosis is of utmost importance, and our drug sensitivity prediction signatures may prove highly beneficial for patient management.

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