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1.
Immunity ; 54(4): 797-814.e6, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33765436

RESUMO

Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.


Assuntos
COVID-19/imunologia , Pulmão/imunologia , Células Mieloides/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , COVID-19/mortalidade , COVID-19/patologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação , Estudos Longitudinais , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Células Mieloides/patologia , SARS-CoV-2 , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Adulto Jovem
3.
Stem Cells ; 36(10): 1603-1616, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29938858

RESUMO

The role of lipid metabolism in epithelial stem cell (SC) function and carcinogenesis is poorly understood. The transcription factor Runx1 is known to regulate proliferation in mouse epithelial hair follicle (HF) SCs in vivo and in several mouse and human epithelial cancers. We found a novel subset of in vivo Runx1 HFSC target genes related to lipid metabolism and demonstrated changes in distinct classes of lipids driven by Runx1. Inhibition of lipid-enzymes Scd1 and Soat1 activity synergistically reduces proliferation of mouse skin epithelial cells and of human skin and oral squamous cell carcinoma cultured lines. Varying Runx1 levels induces changes in skin monounsaturated fatty acids (e.g., oleate, a product of Scd1) as shown by our lipidome analysis. Furthermore, varying Runx1 levels, the inhibition of Scd1, or the addition of Scd1-product oleate, individually affects the plasma membrane organization (or fluidity) in mouse keratinocytes. These factors also affect the strength of signal transduction through the membranes for Wnt, a pathway that promotes epithelial (cancer) cell proliferation and HFSC activation. Our working model is that HFSC factor Runx1 modulates the fatty acid production, which affects membrane organization, facilitating signal transduction for rapid proliferation of normal and cancer epithelial cells. Stem Cells 2018;36:1603-1616.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células Epiteliais/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Esterol O-Aciltransferase/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células Epiteliais/citologia , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Knockout , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estearoil-CoA Dessaturase/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Esterol O-Aciltransferase/genética , Transfecção
4.
Development ; 140(18): 3809-18, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23946441

RESUMO

Hair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain- and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.


Assuntos
Ciclo Celular , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Folículo Piloso/citologia , Proteínas Repressoras/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Contagem de Células , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Embrião de Mamíferos/citologia , Fatores de Crescimento de Fibroblastos/genética , Células HEK293 , Humanos , Camundongos
5.
Front Immunol ; 15: 1258369, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38933266

RESUMO

Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA used (hydrolysable (hSAgA) and non-hydrolysable 'click' SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Over time, the peptides induced an IgE-independent anaphylactic reaction, the incidence of which was significantly delayed when peptides were in SAgA form rather than in free form. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Immunologic anaphylaxis occurred in NOD mice in a dose-dependent manner but not in C57BL/6 or BALB/c mice; however, its incidence did not correlate with the level of anti-peptide antibodies. We provide evidence that SAgAs significantly improve the efficacy of peptides to induce tolerance and prevent autoimmune diabetes while at the same time reducing their anaphylactogenic potential.


Assuntos
Diabetes Mellitus Tipo 1 , Tolerância Imunológica , Camundongos Endogâmicos NOD , Peptídeos , Animais , Camundongos , Diabetes Mellitus Tipo 1/imunologia , Peptídeos/imunologia , Peptídeos/administração & dosagem , Feminino , Autoantígenos/imunologia , Linfócitos T Reguladores/imunologia , Imunoterapia/métodos , Anafilaxia/prevenção & controle , Anafilaxia/imunologia , Dessensibilização Imunológica/métodos , Dessensibilização Imunológica/efeitos adversos
6.
bioRxiv ; 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38260423

RESUMO

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the most negatively correlated protein with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data highlight ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptor, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.

7.
Int J Hyperthermia ; 29(5): 464-73, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23862980

RESUMO

Cancer immunotherapy aims to generate long-lived, tumour-specific adaptive immunity to limit dysregulated tumour progression and metastasis. Tumour vasculature has emerged as a critical checkpoint controlling the efficacy of immunotherapy since it is the main access point for cytotoxic T cells to reach tumour cell targets. Therapeutic success has been particularly challenging to achieve because of the local, cytokine-rich inflammatory milieu that drives a pro-tumourigenic programme supporting the growth and survival of malignant cells. Here, we focus on recent evidence that systemic thermal therapy can switch the activities of the inflammatory cytokine, interleukin-6 (IL-6), to a predominantly anti-tumourigenic function that promotes anti-tumour immunity by mobilising T cell trafficking in the recalcitrant tumour microenvironment.


Assuntos
Hipertermia Induzida , Interleucina-6/imunologia , Neoplasias/terapia , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias/imunologia , Microambiente Tumoral/imunologia
8.
Cancer Prev Res (Phila) ; 16(2): 65-73, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36343340

RESUMO

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer. PREVENTION RELEVANCE: PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.


Assuntos
Lesões Pré-Cancerosas , Tiazóis , Animais , Camundongos , Feminino , Hiperplasia/tratamento farmacológico , Tiazóis/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase , Lesões Pré-Cancerosas/tratamento farmacológico , Moduladores de Receptor Estrogênico , Classe I de Fosfatidilinositol 3-Quinases
9.
Sci Adv ; 9(19): eade0059, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37172086

RESUMO

CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either Kras or Pik3ca in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less intertumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing.


Assuntos
Edição de Genes , Neoplasias , Animais , Camundongos , Humanos , Edição de Genes/métodos , Sistemas CRISPR-Cas/genética , Neoplasias/genética , Neoplasias/terapia , Reparo de DNA por Recombinação , Modelos Animais de Doenças
10.
Cancer Cell ; 41(9): 1586-1605.e15, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37567170

RESUMO

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of ß-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.


Assuntos
Neoplasias do Endométrio , Metformina , Proteogenômica , Feminino , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Estudos Prospectivos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Metformina/farmacologia
11.
Cancer Prev Res (Phila) ; 15(1): 3-10, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34667127

RESUMO

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. PREVENTION RELEVANCE: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.


Assuntos
Neoplasias da Mama , Animais , Apoptose , Proteínas Reguladoras de Apoptose , Neoplasias da Mama/patologia , Feminino , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2 , Receptores de Estrogênio
12.
Oncogene ; 41(48): 5214-5222, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36261627

RESUMO

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in vitro. Furthermore, we demonstrated that STAT5aca overexpression in human breast cancer cells lowered their metastatic burden in xenografted mice. Moreover, RPPA, Western blotting, and studies of ChIPseq data identified several EMT drivers regulated by STAT5. In addition, bioinformatic studies detected a correlation between STAT5 activity and better prognosis of breast cancer patients. Together, we conclude that STAT5 activation during mammary tumorigenesis specifies a tumor phenotype of lactogenic differentiation, suppresses EMT, and diminishes potential for subsequent metastasis.


Assuntos
Neoplasias da Mama , Fator de Transcrição STAT5 , Animais , Feminino , Humanos , Camundongos , Mama/patologia , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/metabolismo , Glândulas Mamárias Animais/patologia , Fator de Transcrição STAT5/metabolismo
13.
JCI Insight ; 7(11)2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35446789

RESUMO

Respiratory failure in COVID-19 is characterized by widespread disruption of the lung's alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased perialveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there was also progressive loss of T2AE cells with increasing age, which may increase susceptibility to COVID-19-mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that expressed distinctly high levels of T cell activation and costimulation genes and strongly correlated with increased extent of alveolar epithelial cell depletion and CD8+ T cell cytotoxicity. Together, our results show that T2AE cell deficiency may underlie age-related COVID-19 risk and initiate alveolar dysfunction shortly after infection, and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of fatal COVID-19.


Assuntos
Lesão Pulmonar Aguda , COVID-19 , Lesão Pulmonar Aguda/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Epiteliais Alveolares/patologia , Autopsia , Humanos , Pulmão/patologia , Pessoa de Meia-Idade , Adulto Jovem
14.
J Virol ; 84(14): 6923-34, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20484510

RESUMO

Redirecting the tropism of viral vectors enables specific transduction of selected cells by direct administration of vectors. We previously developed targeting lentiviral vectors by pseudotyping with modified Sindbis virus envelope proteins. These modified Sindbis virus envelope proteins have mutations in their original receptor-binding regions to eliminate their natural tropisms, and they are conjugated with targeting proteins, including antibodies and peptides, to confer their tropisms on target cells. We investigated whether our targeting vectors interact with DC-SIGN, which traps many types of viruses and gene therapy vectors by binding to the N-glycans of their envelope proteins. We found that these vectors do not interact with DC-SIGN. When these vectors were produced in the presence of deoxymannojirimycin, which alters the structures of N-glycans from complex to high mannose, these vectors used DC-SIGN as their receptor. Genetic analysis demonstrated that the N-glycans at E2 amino acid (aa) 196 and E1 aa 139 mediate binding to DC-SIGN, which supports the results of a previous report of cryoelectron microscopy analysis. In addition, we investigated whether modification of the N-glycan structures could activate serum complement activity, possibly by the lectin pathway of complement activation. DC-SIGN-targeted transduction occurs in the presence of human serum complement, demonstrating that high-mannose structure N-glycans of the envelope proteins do not activate human serum complement. These results indicate that the strategy of redirecting viral vectors according to alterations of their N-glycan structures would enable the vectors to target specific cells types expressing particular types of lectins.


Assuntos
Moléculas de Adesão Celular/metabolismo , Vetores Genéticos , Lectinas Tipo C/metabolismo , Lentivirus , Polissacarídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Sindbis virus/metabolismo , Proteínas do Envelope Viral , Animais , Configuração de Carboidratos , Sequência de Carboidratos , Moléculas de Adesão Celular/genética , Linhagem Celular , Proteínas do Sistema Complemento/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Humanos , Lectinas Tipo C/genética , Lentivirus/genética , Lentivirus/metabolismo , Dados de Sequência Molecular , Polissacarídeos/química , Polissacarídeos/genética , Receptores de Superfície Celular/genética , Sindbis virus/genética , Transdução Genética , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
15.
Cancer Res ; 81(17): 4441-4454, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34099494

RESUMO

Leucine-rich repeat-containing G protein-coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Multiomic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4-EGFR signaling axis with broad implications for cancer progression and targeted therapy. SIGNIFICANCE: This work demonstrates a Wnt-independent mechanism by which LGR4 promotes cancer metastasis.See related commentary by Stevens and Williams, p. 4397.


Assuntos
Receptores ErbB/metabolismo , Metástase Neoplásica , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Feminino , Células HEK293 , Humanos , Técnicas In Vitro , Estimativa de Kaplan-Meier , Camundongos , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Proteoma/metabolismo , Análise Serial de Tecidos , Ubiquitina/metabolismo , Via de Sinalização Wnt
16.
Mini Rev Med Chem ; 20(9): 779-787, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902358

RESUMO

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.


Assuntos
Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Antineoplásicos/uso terapêutico , Biomarcadores/metabolismo , Reparo do DNA/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
17.
medRxiv ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33106817

RESUMO

Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4 + T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163 + and immature phenotypes. Extensive accumulation of CD163 + monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.

18.
Nat Commun ; 10(1): 4042, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492871

RESUMO

Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure. Here, we show that upon damage in a mouse model, epidermal cells at the wound edge convert to an embryonic-like state, altering particularly the cytoskeletal/extracellular matrix (ECM) components and differentiation program. We show that SOX11 and its closest relative SOX4 dictate embryonic epidermal state, regulating genes involved in epidermal development as well as cytoskeletal/ECM organization. Correspondingly, postnatal induction of SOX11 represses epidermal terminal differentiation while deficiency of Sox11 and Sox4 accelerates differentiation and dramatically impairs cell motility and re-epithelialization. Amongst the embryonic genes reactivated at the wound edge, we identify fascin actin-bundling protein 1 (FSCN1) as a critical direct target of SOX11 and SOX4 regulating cell migration. Our study identifies the reactivated embryonic gene program during wound repair and demonstrates that SOX11 and SOX4 play a central role in this process.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição SOXC/genética , Cicatrização/genética , Ferimentos e Lesões/genética , Animais , Diferenciação Celular/genética , Movimento Celular/genética , Citoesqueleto/metabolismo , Células Epidérmicas/citologia , Células Epidérmicas/metabolismo , Epiderme/embriologia , Epiderme/metabolismo , Matriz Extracelular , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Fatores de Transcrição SOXC/metabolismo , Ferimentos e Lesões/embriologia
19.
Ann Bot ; 102(1): 57-67, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18463111

RESUMO

BACKGROUND AND AIMS: The tuberization mechanism of sweet potato (Ipomoea batatas) has long been studied using various approaches. Morphological data have revealed that the tuberizing events result from the activation of the cambium, followed by cell proliferation. However, uncertainties still remain regarding the regulators participating in this signal-transduction pathway. An attempt was made to characterize the role of one MADS-box transcription factor, which was preferentially expressed in sweet potato roots at the early tuberization stage. METHODS: A differential expression level of IbMADS1 (Ipomoea batatas MADS-box 1) was detected temporally and spatially in sweet potato tissues. IbMADS1 responses to tuberization-related hormones were assessed. In order to identify the evolutionary significance, the expression pattern of IbMADS1 was surveyed in two tuber-deficient Ipomoea relatives, I. leucantha and I. trifida, and compared with sweet potato. In functional analyses, potato (Solanum tuberosum) was employed as a heterologous model. The resulting tuber morphogenesis was examined anatomically in order to address the physiological function of IbMADS1, which should act similarly in sweet potato. KEY RESULTS: IbMADS1 was preferentially expressed as tuberous root development proceeded. Its expression was inducible by tuberization-related hormones, such as jasmonic acid and cytokinins. In situ hybridization data showed that IbMADS1 transcripts were specifically distributed around immature meristematic cells within the stele and lateral root primordia. Inter-species examination indicated that IbMADS1 expression was relatively active in sweet potato roots, but undetectable in tuber-deficient Ipomoea species. IbMADS1-transformed potatoes exhibited tuber morphogenesis in the fibrous roots. The partial swellings along fibrous roots were mainly due to anomalous proliferation and differentiation in the xylem. CONCLUSIONS: Based on this study, it is proposed that IbMADS1 is an important integrator at the initiation of tuberization. As a result, the initiation and development of tuberous roots seems to be well regulated by a network involving a MADS-box gene in which such hormones as jasmonic acid and cytokinins may act as trigger factors.


Assuntos
Ipomoea batatas/genética , Proteínas de Domínio MADS/genética , Proteínas de Plantas/genética , Raízes de Plantas/genética , Ácido Abscísico/farmacologia , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Ciclopentanos/farmacologia , Citocininas/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Hibridização In Situ , Ipomoea batatas/crescimento & desenvolvimento , Proteínas de Domínio MADS/isolamento & purificação , Oxilipinas/farmacologia , Proteínas de Plantas/isolamento & purificação , Raízes de Plantas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Elife ; 62017 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-28467300

RESUMO

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with ß-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.


Assuntos
Carcinogênese , Carcinoma de Células Escamosas/fisiopatologia , Lipocalina-2/metabolismo , Neoplasias Cutâneas/fisiopatologia , Proteína 1 Semelhante ao Fator 7 de Transcrição/metabolismo , beta Catenina/metabolismo , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Camundongos
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