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1.
Cell ; 157(2): 382-394, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24725405

RESUMO

Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Metástase Neoplásica , Neoplasias Pancreáticas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteína Supressora de Tumor p53/genética
2.
Br J Cancer ; 119(7): 855-863, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30287917

RESUMO

BACKGROUND: Human cancers can be classified based on gene signatures quantifying the degree of cell proliferation and tissue remodelling (PR). However, the specific factors that drive the increased tissue remodelling in tumours are not fully understood. Here we address this question using colorectal cancer as a case study. METHODS: We reanalysed a reported cohort of colorectal cancer patients. The patients were stratified based on gene signatures of cell proliferation and tissue remodelling. Putative transcription factors activity was inferred using gene expression profiles and annotations of transcription factor targets as input. RESULTS: We demonstrate that the PR classification performs better than the currently adopted consensus molecular subtyping (CMS). Although CMS classification differentiates patients with a mesenchymal signature, it cannot distinguish the remaining patients based on survival. We demonstrate that the missing factor is cell proliferation, which is indicative of good prognosis. We also uncover a KLF4 transcription factor activity score associated with the tissue remodelling gene signature. We further show that the KLF4 activity score is significantly higher in colorectal tumours with predicted infiltration of cells from the myeloid lineage. CONCLUSION: The KLF4 activity score is associated with tissue remodelling, myeloid cell infiltration and poor prognosis in colorectal cancer.


Assuntos
Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica/métodos , Fatores de Transcrição Kruppel-Like/genética , Células Mieloides/química , Regulação para Cima , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 4 Semelhante a Kruppel , Masculino , Prognóstico , Análise de Sobrevida
3.
J Cell Sci ; 129(18): 3367-73, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27635066

RESUMO

A defining hallmark of cancer is uncontrolled cell proliferation. This is initiated once cells have accumulated alterations in signaling pathways that control metabolism and proliferation, wherein the metabolic alterations provide the energetic and anabolic demands of enhanced cell proliferation. How these metabolic requirements are satisfied depends, in part, on the tumor microenvironment, which determines the availability of nutrients and oxygen. In this Cell Science at a Glance paper and the accompanying poster, we summarize our current understanding of cancer metabolism, emphasizing pathways of nutrient utilization and metabolism that either appear or have been proven essential for cancer cells. We also review how this knowledge has contributed to the development of anticancer therapies that target cancer metabolism.


Assuntos
Neoplasias/metabolismo , Animais , Ácidos Graxos/biossíntese , Humanos , Redes e Vias Metabólicas , Metaboloma , Metilação , Espécies Reativas de Oxigênio/metabolismo
4.
Proc Natl Acad Sci U S A ; 112(1): 226-31, 2015 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-25535359

RESUMO

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteólise , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Linhagem Celular Tumoral , Progressão da Doença , Deleção de Genes , Humanos , Técnicas In Vitro , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Neovascularização Patológica , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Análise de Sobrevida , Proteína Tumoral p73 , Ubiquitina/metabolismo , Ubiquitinação , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Proc Natl Acad Sci U S A ; 109(38): 15312-7, 2012 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-22949650

RESUMO

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, ΔNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Fosfoproteínas/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Metástase Neoplásica , Transplante de Neoplasias , Isoformas de Proteínas
6.
Proc Natl Acad Sci U S A ; 108(52): 21276-81, 2011 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-22123976

RESUMO

High Gleason score is currently the best prognostic indicator for poor prognosis in prostate cancer. However, a significant number of patients with low Gleason scores develop aggressive disease as well. In an effort to understand molecular signatures associated with poor outcome in prostate cancer, we analyzed a microarray dataset characterizing 281 prostate cancers from a Swedish watchful-waiting cohort. Patients were classified on the basis of their mRNA microarray signature profiles indicating embryonic stem cell expression patterns (stemness), inactivation of the tumor suppressors p53 and PTEN, activation of several oncogenic pathways, and the TMPRSS2-ERG fusion. Unsupervised clustering identified a subset of tumors manifesting stem-like signatures together with p53 and PTEN inactivation, which had very poor survival outcome, a second group with intermediate survival outcome, characterized by the TMPRSS2-ERG fusion, and three groups with benign outcome. The stratification was validated on a second independent dataset of 150 tumor and metastatic samples from a clinical cohort at Memorial Sloan-Kettering Cancer Center. This classification is independent of Gleason score and therefore provides useful unique molecular profiles for prostate cancer prognosis, helping to predict poor outcome in patients with low or average Gleason scores.


Assuntos
Gradação de Tumores/métodos , Neoplasias da Próstata/classificação , Neoplasias da Próstata/genética , RNA Mensageiro , Teorema de Bayes , Células-Tronco Embrionárias/metabolismo , Perfilação da Expressão Gênica , Humanos , Masculino , Análise em Microsséries , Proteínas de Fusão Oncogênica/metabolismo , PTEN Fosfo-Hidrolase/genética , Prognóstico , Suécia , Proteína Supressora de Tumor p53/genética , Conduta Expectante
7.
Front Cell Dev Biol ; 10: 910040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092714

RESUMO

The therapeutic potential of pluripotent stem cells is great as they promise to usher in a new era of medicine where cells or organs may be prescribed to replace dysfunctional tissue. At the forefront are efforts in the eye to develop this technology as it lends itself to in vivo monitoring and sophisticated non-invasive imaging modalities. In the retina, retinal pigment epithelium (RPE) is the most promising replacement cell as it has a single layer, is relatively simple to transplant, and is associated with several eye diseases. However, after transplantation, the cells may transform and cause complications. This transformation may be partially due to incomplete maturation. With the goal of learning how to mature RPE, we compared induced pluripotent stem cell-derived RPE (iPSC-RPE) cells with adult human primary RPE (ahRPE) cells and the immortalized human ARPE-19 line. We cultured ARPE-19, iPSC-RPE, and ahRPE cells for one month, and evaluated morphology, RPE marker staining, and transepithelial electrical resistance (TEER) as quality control indicators. We then isolated RNA for bulk RNA-sequencing and DNA for genotyping. We genotyped ahRPE lines for the top age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR) risk allele polymorphisms. Transcriptome data verified that both adult and iPSC-RPE exhibit similar RPE gene expression signatures, significantly higher than ARPE-19. In addition, in iPSC-RPE, genes relating to stem cell maintenance, retina development, and muscle contraction were significantly upregulated compared to ahRPE. We compared ahRPE to iPSC-RPE in a model of epithelial-mesenchymal transition (EMT) and observed an increased sensitivity of iPSC-RPE to producing contractile aggregates in vitro which resembles incident reports upon transplantation. P38 inhibition was capable of inhibiting iPSC-RPE-derived aggregates. In summary, we find that the transcriptomic signature of iPSC-RPE conveys an immature RPE state which may be ameliorated by targeting "immature" gene regulatory networks.

8.
Nat Commun ; 13(1): 7551, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36477656

RESUMO

The pro-tumourigenic role of epithelial TGFß signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFß signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFß signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFß signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFß signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits.


Assuntos
Apoptose , Fator de Crescimento Transformador beta , Humanos , Apoptose/genética
9.
J Theor Biol ; 264(3): 945-51, 2010 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-20303985

RESUMO

The regulation of the cell state is a complex process involving several components. These complex dynamics can be modeled using Boolean networks, allowing us to explain the existence of different cell states and the transition between them. Boolean models have been introduced both as specific examples and as ensemble or distribution network models. However, current ensemble Boolean network models do not make a systematic distinction between different cell components such as epigenetic factors, gene and transcription factors. Consequently, we still do not understand their relative contributions in controlling the cell fate. In this work we introduce and study higher order Boolean networks, which feature an explicit distinction between the different cell components and the types of interactions between them. We show that the stability of the cell state dynamics can be determined solving the eigenvalue problem of a matrix representing the regulatory interactions and their strengths. The qualitative analysis of this problem indicates that, in addition to the classification into stable and chaotic regimes, the cell state can be simple or complex depending on whether it can be deduced from the independent study of its components or not. Finally, we illustrate how the model can be expanded considering higher levels and higher order dynamics.


Assuntos
Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes , Modelos Genéticos , Fatores de Transcrição/genética , Algoritmos , Animais , Humanos , Cinética , Transdução de Sinais/genética
10.
Nat Cancer ; 1(10): 998-1009, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33479702

RESUMO

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player. In vivo SCD1 overexpression increases CNS disease, whilst genetic or pharmacological inhibition of SCD1 decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Estearoil-CoA Dessaturase , Sistema Nervoso Central/metabolismo , Humanos , Lipogênese , Estearoil-CoA Dessaturase/genética , Microambiente Tumoral
11.
Sci Signal ; 12(567)2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723174

RESUMO

Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry-based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors. Hypoxia induced pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Among those, the uncharacterized protein NCBP2-AS2 that we renamed HIAR (hypoxia-induced angiogenesis regulator) was the protein most increased in abundance in hypoxic CAFs. Silencing of HIAR abrogated the pro-angiogenic and pro-migratory function of hypoxic CAFs by decreasing secretion of the pro-angiogenic factor VEGFA and consequently reducing VEGF/VEGFR downstream signaling in the endothelial cells. Our study has identified a regulator of angiogenesis and provides a map of hypoxia-induced molecular alterations in mammary CAFs.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Hipóxia , Neovascularização Patológica/genética , Proteoma/metabolismo , Proteômica/métodos , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/genética
12.
Cell Death Dis ; 9(11): 1069, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341281

RESUMO

Based on a molecular classification of prostate cancer using gene expression pathway signatures, we derived a set of 48 genes in critical pathways that significantly predicts clinical outcome in all tested patient cohorts. We tested these genes in a functional genomics screen in a panel of three prostate cancer cell lines (LNCaP, PC3, DU145), using RNA interference. The screen revealed several genes whose knockdown caused strong growth inhibition in all cell lines. Additionally, we tested the gene set in the presence of docetaxel to see whether any gene exhibited additive or synergistic effects with the drug. We observed a strong synergistic effect between DLGAP5 knockdown and docetaxel in the androgen-sensitive line LNCaP, but not in the two other androgen-independent lines. We then tested whether this effect was connected to androgen pathways and found that knockdown of the androgen receptor by si-RNA attenuated the synergy significantly. Similarly, androgen desensitized LNCaP-AI cells had a higher IC50 to docetaxel and did not exhibit the synergistic interaction. Short-term exposure to enzalutamide did not significantly alter the behaviour of parental LNCaP cells. An immunofluorescence analysis in LNCaP cells suggests that under the double insult of DLGAP5 knockdown and docetaxel, cells predominantly arrest in metaphase. In contrast, the knockdown of the androgen receptor by siRNA appears to assist cells to progress through metaphase in to anaphase, even in the presence of docetaxel. Our data suggest that DLGAP5 has a unique function in stabilizing spindle formation and surviving microtubule assault from docetaxel, in an androgen-regulated cell cycle system.


Assuntos
Docetaxel/farmacologia , Genômica/métodos , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Benzamidas , Proteínas Cdc20/genética , Proteínas de Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Masculino , Metáfase , Proteínas Associadas aos Microtúbulos/genética , Nitrilas , Células PC-3 , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Receptores Androgênicos/genética , Transfecção
14.
ISRN Oncol ; 2012: 450267, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23227362

RESUMO

Gene expression studies on breast cancer have generally been performed on tissue obtained at the time of surgery. In this study, we have compared the gene expression profiles in preoperative tissue (core needle biopsies) while tumor is still in its normal milieu to postoperative tissue from the same tumor obtained during surgery. Thirteen patients were included of which eleven had undergone sentinel node diagnosis procedure before operation. Microarray gene expression analysis was performed using total RNA from all the samples. Paired significance analysis of microarrays revealed 228 differently expressed genes, including several early response stress-related genes such as members of the fos and jun families as well as genes of which the expression has previously been associated with cancer. The expression profiles found in the analyses of breast cancer tissue must be evaluated with caution. Different profiles may simply be the result of differences in the surgical trauma and timing of when samples are taken and not necessarily associated with tumor biology.

15.
PLoS One ; 6(11): e25881, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22073143

RESUMO

Previous experimental evidence indicates that some cancer cells have an alternative glycolysis pathway with net zero ATP production, implying that upregulation of glycolysis in these cells may not be related to the generation of ATP. Here we use a genome-scale model of human cell metabolism to investigate the potential metabolic alterations in cells using net zero ATP glycolysis. We uncover a novel pathway for ATP generation that involves reactions from serine biosynthesis, one-carbon metabolism and the glycine cleavage system, and show that the pathway is transcriptionally upregulated in an inducible murine model of Myc-driven liver tumorigenesis. This pathway has a predicted two-fold higher flux rate in cells using net zero ATP glycolysis than those using standard glycolysis and generates twice as much ATP with significantly lower rate of lactate - but higher rate of alanine secretion. Thus, in cells using the standard - or the net zero ATP glycolysis pathways a significant portion of the glycolysis flux is always associated with ATP generation, and the ratio between the flux rates of the two pathways determines the rate of ATP generation and lactate and alanine secretion during glycolysis.


Assuntos
Trifosfato de Adenosina/biossíntese , Carbono/metabolismo , Glicina/metabolismo , Serina/biossíntese , Animais , Proliferação de Células , Glicólise , Cinética , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Transcrição Gênica , Regulação para Cima
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