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1.
Cell ; 185(1): 184-203.e19, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34963056

RESUMEN

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.


Asunto(s)
Censos , Neoplasias/genética , Neoplasias/inmunología , Transcriptoma/genética , Microambiente Tumoral/inmunología , Biomarcadores de Tumor , Análisis por Conglomerados , Estudios de Cohortes , Biología Computacional/métodos , Citometría de Flujo/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/clasificación , Neoplasias/patología , RNA-Seq/métodos , San Francisco , Universidades
2.
Cell ; 168(5): 817-829.e15, 2017 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-28215705

RESUMEN

Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.


Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasias Colorrectales/genética , Difenilamina/análogos & derivados , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Antineoplásicos/farmacología , Benzamidas/farmacología , Línea Celular Tumoral , Evolución Clonal , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Difenilamina/farmacología , Difenilamina/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Mutación , Retroviridae
3.
Blood ; 130(1): 48-58, 2017 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-28490572

RESUMEN

Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor therapy have not fully reflected this heterogeneity because resistance in individual patients has been ascribed to largely mutually exclusive on-target or off-target mechanisms in which tumors either retain dependency on the target oncogene or subvert it through a parallel pathway. Using targeted sequencing from single cells and colonies from patient samples, we demonstrate tremendous clonal diversity in the majority of acute myeloid leukemia (AML) patients with activating FLT3 internal tandem duplication mutations at the time of acquired resistance to the FLT3 inhibitor quizartinib. These findings establish that clinical resistance to quizartinib is highly complex and reflects the underlying clonal heterogeneity of AML.


Asunto(s)
Benzotiazoles/administración & dosificación , Resistencia a Antineoplásicos , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación INDEL , Leucemia Mieloide Aguda , Compuestos de Fenilurea/administración & dosificación , Tirosina Quinasa 3 Similar a fms/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino
4.
Proc Natl Acad Sci U S A ; 113(32): 9015-20, 2016 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-27450084

RESUMEN

Cytosolic and organelle-based heat-shock protein (HSP) chaperones ensure proper folding and function of nascent and injured polypeptides to support cell growth. Under conditions of cellular stress, including oncogenic transformation, proteostasis components maintain homeostasis and prevent apoptosis. Although this cancer-relevant function has provided a rationale for therapeutically targeting proteostasis regulators (e.g., HSP90), cancer-subtype dependencies upon particular proteostasis components are relatively undefined. Here, we show that human rhabdomyosarcoma (RMS) cells, but not several other cancer cell types, depend upon heat-shock protein 70 kDA (HSP70) for survival. HSP70-targeted therapy (but not chemotherapeutic agents) promoted apoptosis in RMS cells by triggering an unfolded protein response (UPR) that induced PRKR-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor α (eIF2α)-CEBP homologous protein (CHOP) signaling and CHOP-mediated cell death. Intriguingly, inhibition of only cytosolic HSP70 induced the UPR, suggesting that the essential activity of HSP70 in RMS cells lies at the endoplasmic reticulum-cytosol interface. We also found that increased CHOP mRNA in clinical specimens was a biomarker for poor outcomes in chemotherapy-treated RMS patients. The data suggest that, like human epidermal growth factor receptor 2 (HER2) amplification in breast cancer, increased CHOP in RMS is a biomarker of decreased response to chemotherapy but enhanced response to targeted therapy. Our findings identify the cytosolic HSP70-UPR axis as an unexpected regulator of RMS pathogenesis, revealing HSP70-targeted therapy as a promising strategy to engage CHOP-mediated apoptosis and improve RMS treatment. Our study highlights the utility of dissecting cancer subtype-specific dependencies on proteostasis networks to uncover unanticipated cancer vulnerabilities.


Asunto(s)
Proteínas HSP70 de Choque Térmico/fisiología , Rabdomiosarcoma/etiología , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Humanos , Factor de Transcripción PAX3/fisiología , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Factor de Transcripción CHOP/fisiología , Respuesta de Proteína Desplegada
5.
Proc Natl Acad Sci U S A ; 111(7): E748-57, 2014 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-24550319

RESUMEN

Oncogenic mutations in the BRAF kinase occur in 6-8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF(V600E), but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF(V600E) NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF(V600E) coupled with expression of an aberrant form of BRAF(V600E) that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun-mediated EGFR ligand expression. BRAF(V600E) cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF-EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.


Asunto(s)
Comunicación Autocrina/fisiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Comunicación Autocrina/genética , Secuencia de Bases , Humanos , Inmunohistoquímica , Datos de Secuencia Molecular , Mutación Missense/genética , Proteína Oncogénica v-akt/metabolismo , Fosforilación , Análisis de Secuencia de ARN
6.
J Natl Compr Canc Netw ; 13(7): 835-45, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26150578

RESUMEN

Cancer is currently classified and treated using an approach based on tissue of origin. Ambiguous or incorrect diagnoses, however, are common and often go unnoticed. Clinical cancer sequencing can provide diagnostic precision, therapeutic direction, and hereditary cancer risk assessment. This report presents a patient with an initial diagnosis of metastatic pancreatic adenocarcinoma (PDA), a disease with a dismal prognosis. Tumor sequencing revealed genomic abnormalities inconsistent with PDA, instead suggesting serous ovarian cancer. This molecular rediagnosis was further refined by the identification of a BRCA2 truncating mutation in the tumor, subsequently confirmed to be a germline event. These findings prompted the initiation of platinum-based chemotherapy, which produced a life-altering response, and referral to genetic counseling for her offspring. These results suggest that clinical tumor sequencing can simultaneously clarify diagnoses, guide therapy, and inform familial risk, even in patients with end-stage metastatic disease, making the case for the development of specific strategies to deploy sequencing coupled with big data in oncology to improve clinical cancer management.


Asunto(s)
Adenocarcinoma/diagnóstico , Cistadenocarcinoma Seroso/genética , Errores Diagnósticos , Genes BRCA2 , Neoplasias Ováricas/genética , Neoplasias Pancreáticas/diagnóstico , Biomarcadores de Tumor/análisis , Cistadenocarcinoma Seroso/diagnóstico , Femenino , Mutación del Sistema de Lectura , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Tomografía Computarizada por Rayos X
7.
Nature ; 447(7146): 799-816, 2007 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-17571346

RESUMEN

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.


Asunto(s)
Genoma Humano/genética , Genómica , Secuencias Reguladoras de Ácidos Nucleicos/genética , Transcripción Genética/genética , Cromatina/genética , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Secuencia Conservada/genética , Replicación del ADN , Evolución Molecular , Exones/genética , Variación Genética/genética , Heterocigoto , Histonas/metabolismo , Humanos , Proyectos Piloto , Unión Proteica , ARN Mensajero/genética , ARN no Traducido/genética , Factores de Transcripción/metabolismo , Sitio de Iniciación de la Transcripción
8.
Commun Biol ; 3(1): 388, 2020 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-32681145

RESUMEN

Autophagy promotes protein degradation, and therefore has been proposed to maintain amino acid pools to sustain protein synthesis during metabolic stress. To date, how autophagy influences the protein synthesis landscape in mammalian cells remains unclear. Here, we utilize ribosome profiling to delineate the effects of genetic ablation of the autophagy regulator, ATG12, on translational control. In mammalian cells, genetic loss of autophagy does not impact global rates of cap dependent translation, even under starvation conditions. Instead, autophagy supports the translation of a subset of mRNAs enriched for cell cycle control and DNA damage repair. In particular, we demonstrate that autophagy enables the translation of the DNA damage repair protein BRCA2, which is functionally required to attenuate DNA damage and promote cell survival in response to PARP inhibition. Overall, our findings illuminate that autophagy impacts protein translation and shapes the protein landscape.


Asunto(s)
Autofagia , Regulación de la Expresión Génica , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , Ribosomas/metabolismo , Animales , Autofagia/fisiología , Proteína 12 Relacionada con la Autofagia/metabolismo , Proteína BRCA2/metabolismo , Daño del ADN , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , ARN Mensajero/fisiología , Ribosomas/fisiología
9.
Oncogenesis ; 9(11): 102, 2020 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-33214553

RESUMEN

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.

10.
Nat Med ; 25(2): 301-311, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30643286

RESUMEN

Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.


Asunto(s)
Inmunoterapia , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Biosíntesis de Proteínas , Regiones no Traducidas 5'/genética , Animales , Antígeno B7-H1/metabolismo , Secuencia de Bases , Progresión de la Enfermedad , Regulación hacia Abajo , Factor 4E Eucariótico de Iniciación/metabolismo , Regulación Neoplásica de la Expresión Génica , Evasión Inmune , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Sistemas de Lectura Abierta/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , Transcripción Genética , Microambiente Tumoral , Regulación hacia Arriba/genética
11.
Cancer Discov ; 9(8): 1050-1063, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31088841

RESUMEN

Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983.


Asunto(s)
Evolución Clonal/genética , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Proteínas ras/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Resistencia a Antineoplásicos/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Análisis de la Célula Individual , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo
12.
Cell Rep ; 28(9): 2317-2330.e8, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31461649

RESUMEN

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.


Asunto(s)
Neoplasias/metabolismo , Fosfohidrolasa PTEN/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Animales , Línea Celular Tumoral , Femenino , Glucólisis , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , FN-kappa B/metabolismo , Neoplasias/genética , Neoplasias/patología , Fosfohidrolasa PTEN/economía , Fosfohidrolasa PTEN/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Proteínas Represoras/metabolismo
13.
Trends Genet ; 21(1): 30-2, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15680511

RESUMEN

Balancing selection has been shown to act on several genes in short-term evolutionary contexts, but it is not known whether this force is responsible for maintaining a significant number of long-term polymorphisms. We aligned 7628 chimpanzee virtual transcripts and 5524 chimp ESTs to the 4x chimp draft genome assembly and identified polymorphisms in chimpanzee that also occurred in the human single nucleotide polymorphism database (dbSNP). Our analysis suggests that the incidence of ancestral polymorphism is low or absent and that balancing selection on the time-scale of chimpanzee-human divergence has not been a significant force in human evolution.


Asunto(s)
Selección Genética , Animales , Humanos , Polimorfismo Genético
14.
PLoS Comput Biol ; 3(12): e254, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18166073

RESUMEN

One of the major goals of comparative genomics is to understand the evolutionary history of each nucleotide in the human genome sequence, and the degree to which it is under selective pressure. Ascertainment of selective constraint at nucleotide resolution is particularly important for predicting the functional significance of human genetic variation and for analyzing the sequence substructure of cis-regulatory sequences and other functional elements. Current methods for analysis of sequence conservation are focused on delineation of conserved regions comprising tens or even hundreds of consecutive nucleotides. We therefore developed a novel computational approach designed specifically for scoring evolutionary conservation at individual base-pair resolution. Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score. We computed SCONE scores in a continuous fashion across 1% of the human genome for which high-quality sequence information from up to 23 genomes are available. We show that SCONE scores are clearly correlated with the allele frequency of human polymorphisms in both coding and noncoding regions. We find that the majority of noncoding conserved nucleotides lie outside of longer conserved elements predicted by other conservation analyses, and are experiencing ongoing selection in modern humans as evident from the allele frequency spectrum of human polymorphism. We also applied SCONE to analyze the distribution of conserved nucleotides within functional regions. These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved "chunks." Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences. A small subset of these fragmented positions may be identified with high confidence.


Asunto(s)
Disparidad de Par Base/genética , Mapeo Cromosómico/métodos , Secuencia Conservada/genética , Evolución Molecular , Genoma Humano/genética , Análisis de Secuencia de ADN/métodos , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de Ácido Nucleico
15.
Nat Med ; 24(8): 1178-1191, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29942093

RESUMEN

Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.


Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia , Células Asesinas Naturales/inmunología , Microambiente Tumoral/inmunología , Antígenos de Superficie/metabolismo , Comunicación Celular , Supervivencia Celular , Humanos , Linfocitos/metabolismo , Melanoma/inmunología , Melanoma/patología , Proteínas de la Membrana/metabolismo , Análisis de Supervivencia , Trombomodulina
16.
PLoS One ; 12(2): e0172620, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28207875

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0170348.].

17.
PLoS One ; 12(1): e0170348, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28099461

RESUMEN

The growth behaviors of cutaneous neurofibromas in patients with Neurofibromatosis type 1 are highly variable. The role of the germline NF1 mutation, somatic NF1 mutation and mutations at modifying loci, are poorly understood. We performed whole exome sequencing of three growing and three non-growing neurofibromas from a single individual to assess the role of acquired somatic mutations in neurofibroma growth behavior. 1-11 mutations were identified in each sample, including two deleterious NF1 mutations. No trends were present between the types of somatic mutations identified and growth behavior. Mutations in the HIPPO signaling pathway appeared to be overrepresented.


Asunto(s)
Exoma/genética , Genes de Neurofibromatosis 1 , Neurofibroma/genética , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Adulto , Secuencia de Bases , Vía de Señalización Hippo , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Análisis de Secuencia de ADN
18.
Oral Oncol ; 69: 1-10, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28559012

RESUMEN

OBJECTIVE: The rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker. MATERIALS AND METHODS: Fresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109. RESULTS: UCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC-specific microscopic appearance. Sphere-forming assays supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non-synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed >3- to 4-fold amplification and could be potential oncogenic drivers. CONCLUSION: We have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never-smokers.


Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias de la Lengua/patología , Adulto , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Medio de Cultivo Libre de Suero , Femenino , Humanos , Mutación , Fumar , Cariotipificación Espectral , Neoplasias de la Lengua/genética
19.
Sci Rep ; 7: 44206, 2017 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-28287179

RESUMEN

The success of targeted cancer therapy is limited by drug resistance that can result from tumor genetic heterogeneity. The current approach to address resistance typically involves initiating a new treatment after clinical/radiographic disease progression, ultimately resulting in futility in most patients. Towards a potential alternative solution, we developed a novel computational framework that uses human cancer profiling data to systematically identify dynamic, pre-emptive, and sometimes non-intuitive treatment strategies that can better control tumors in real-time. By studying lung adenocarcinoma clinical specimens and preclinical models, our computational analyses revealed that the best anti-cancer strategies addressed existing resistant subpopulations as they emerged dynamically during treatment. In some cases, the best computed treatment strategy used unconventional therapy switching while the bulk tumor was responding, a prediction we confirmed in vitro. The new framework presented here could guide the principled implementation of dynamic molecular monitoring and treatment strategies to improve cancer control.


Asunto(s)
Adenocarcinoma/terapia , Simulación por Computador , Neoplasias Pulmonares/terapia , Modelos Biológicos , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Línea Celular Tumoral , Terapia Combinada , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología
20.
Nat Genet ; 49(1): 87-96, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27869830

RESUMEN

Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.


Asunto(s)
Proteínas E1A de Adenovirus/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/patología , Metaloproteinasas de la Matriz Asociadas a la Membrana/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Proteínas E1A de Adenovirus/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metaloproteinasas de la Matriz Asociadas a la Membrana/genética , Ratones , Ratones SCID , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Células Tumorales Cultivadas
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