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1.
Cell ; 186(7): 1432-1447.e17, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37001503

RESUMO

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.


Assuntos
Melanoma , Linfócitos T , Camundongos , Animais , Linfócitos T/patologia , Neutrófilos/patologia , Deriva e Deslocamento Antigênicos , Imunoterapia , Antígeno CTLA-4
2.
Cell ; 170(5): 875-888.e20, 2017 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-28757253

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Epigenômica , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Organoides/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
3.
Immunity ; 53(2): 238-240, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32814021

RESUMO

Stress is linked to negative outcomes in cardiovascular diseases but exactly why is unclear. In this issue of Immunity, Xu et al. report that stress elicits glucocorticoid-induced gut permeability, in turn triggering the expansion of a population of neutrophils that can stimulate vaso-occlusive episodes.


Assuntos
Microbioma Gastrointestinal , Microbiota , Doenças Vasculares , Emoções , Humanos , Inflamação
4.
Nature ; 618(7964): 374-382, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37225988

RESUMO

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.


Assuntos
Vesículas Extracelulares , Ácidos Graxos , Fígado Gorduroso , Fígado , Neoplasias Pancreáticas , Animais , Camundongos , Sistema Enzimático do Citocromo P-450/genética , Vesículas Extracelulares/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias Hepáticas/secundário , Humanos , Inflamação/metabolismo , Ácido Palmítico/metabolismo , Células de Kupffer , Fosforilação Oxidativa , Proteínas rab27 de Ligação ao GTP/deficiência
5.
Nature ; 607(7917): 169-175, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35576971

RESUMO

Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1. Recent studies have also revealed tuft-cell-like human tumours2,3, particularly as a variant of small-cell lung cancer. Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F3 (refs. 2,4), although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1/POU2AF2 and OCA-T2/POU2AF3, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogues of the B-cell-specific coactivator OCA-B; all three proteins are encoded in a gene cluster and contain a conserved peptide that binds to class II POU transcription factors and a DNA octamer motif in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft-cell-like small-cell lung cancer. Moreover, we generated OCA-T1-deficient mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal that the POU2F3-OCA-T complex is the master regulator of tuft cell identity and a molecular vulnerability of tuft-cell-like small-cell lung cancer.


Assuntos
Linhagem da Célula , Neoplasias Pulmonares , Proteínas de Neoplasias , Fatores de Transcrição de Octâmero , Carcinoma de Pequenas Células do Pulmão , Animais , Humanos , Camundongos , Neoplasias Pulmonares/patologia , Mucosa/patologia , Família Multigênica/genética , Proteínas de Neoplasias/metabolismo , Motivos de Nucleotídeos , Fatores de Transcrição de Octâmero/metabolismo , Fatores do Domínio POU/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Transativadores
6.
Genes Dev ; 32(13-14): 915-928, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29945888

RESUMO

Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Fatores de Transcrição de Octâmero/genética , Fatores de Transcrição de Octâmero/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Humanos , Pulmão/patologia , Camundongos , Receptor IGF Tipo 1/metabolismo
7.
Cell ; 139(5): 891-906, 2009 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-19931152

RESUMO

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.


Assuntos
Neoplasias da Mama/patologia , Matriz Extracelular/metabolismo , Integrinas/metabolismo , Envelhecimento , Animais , Colágeno/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Feminino , Fibrose/patologia , Genes ras , Humanos , Glândulas Mamárias Humanas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína-Lisina 6-Oxidase/metabolismo , Transdução de Sinais
8.
Genes Dev ; 30(1): 34-51, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26701265

RESUMO

Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.


Assuntos
Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/fisiopatologia , Regulação Neoplásica da Expressão Gênica/genética , RNA Longo não Codificante/genética , Animais , Adesão Celular/genética , Movimento Celular/genética , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Morfogênese/genética , Metástase Neoplásica/genética , Processamento de Proteína/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética
9.
Blood ; 136(10): 1169-1179, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32597954

RESUMO

COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.


Assuntos
Infecções por Coronavirus/complicações , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Pneumonia Viral/complicações , Trombose/complicações , Adulto , Idoso , Betacoronavirus/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Proteínas Sanguíneas/imunologia , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos , Neutrófilos/patologia , Pandemias , Peroxidase/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Estudos Prospectivos , SARS-CoV-2 , Trombose/imunologia , Trombose/patologia
10.
Angew Chem Int Ed Engl ; 61(5): e202113020, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34762762

RESUMO

The detection and quantification of apoptotic cells is a key process in cancer research, particularly during the screening of anticancer therapeutics and in mechanistic studies using preclinical models. Intravital optical imaging enables high-resolution visualisation of cellular events in live organisms; however, there are few fluorescent probes that can reliably provide functional readouts in situ without interference from tissue autofluorescence. We report the design and optimisation of the fluorogenic probe Apotracker Red for real-time detection of cancer cell death. The strong fluorogenic behaviour, high selectivity, and excellent stability of Apotracker Red make it a reliable optical reporter for the characterisation of the effects of anticancer drugs in cells in vitro and for direct imaging of chemotherapy-induced apoptosis in vivo in mouse models of breast cancer.


Assuntos
Corantes Fluorescentes
11.
Nat Mater ; 19(5): 566-575, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31932672

RESUMO

The concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment. Here we show that these inter-endothelial gaps are not responsible for the transport of nanoparticles into solid tumours. Instead, we found that up to 97% of nanoparticles enter tumours using an active process through endothelial cells. This result is derived from analysis of four different mouse models, three different types of human tumours, mathematical simulation and modelling, and two different types of imaging techniques. These results challenge our current rationale for developing cancer nanomedicine and suggest that understanding these active pathways will unlock strategies to enhance tumour accumulation.


Assuntos
Ouro , Nanopartículas Metálicas , Modelos Biológicos , Neoplasias Experimentais , Microambiente Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Ouro/química , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Mol Med ; 26(1): 91, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993479

RESUMO

BACKGROUND: Mechanically ventilated patients with COVID-19 have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. METHODS: Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19-including three requiring veno-venous extracorporeal membrane oxygenation-treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. RESULTS: The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. CONCLUSIONS: Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.


Assuntos
Albuterol/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Desoxirribonuclease I/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Respiração Artificial , Adulto , Idoso , Albuterol/uso terapêutico , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , COVID-19 , Infecções por Coronavirus/terapia , Desoxirribonuclease I/uso terapêutico , Feminino , Humanos , Intubação Intratraqueal , Masculino , Nebulizadores e Vaporizadores , Pandemias , Pneumonia Viral/terapia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
14.
Cancer Cell ; 13(2): 141-52, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18242514

RESUMO

How breast cancers are able to disseminate and metastasize is poorly understood. Using a hyperplasia transplant system, we show that tumor dissemination and metastasis occur in discrete steps during tumor progression. Bioinformatic analysis revealed that loss of the transcription factor GATA-3 marked progression from adenoma to early carcinoma and onset of tumor dissemination. Restoration of GATA-3 in late carcinomas induced tumor differentiation and suppressed tumor dissemination. Targeted deletion of GATA-3 in early tumors led to apoptosis of differentiated cells, indicating that its loss is not sufficient for malignant conversion. Rather, malignant progression occurred with an expanding GATA-3-negative tumor cell population. These data indicate that GATA-3 regulates tumor differentiation and suppresses tumor dissemination in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Diferenciação Celular , Fator de Transcrição GATA3/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Células Epiteliais/patologia , Feminino , Fator de Transcrição GATA3/deficiência , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hiperplasia , Imuno-Histoquímica , Glândulas Mamárias Animais , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia
15.
PLoS Genet ; 9(9): e1003789, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24068959

RESUMO

Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted.


Assuntos
Neoplasias da Mama/genética , Carcinogênese , Proliferação de Células , Fibroblastos/metabolismo , Microambiente Tumoral/genética , Anfirregulina , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Quimiocina CCL2 , Quimiocina CCL7/genética , Quimiocina CCL7/metabolismo , Técnicas de Cocultura , Família de Proteínas EGF , Feminino , Fibroblastos/patologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
17.
Cancer Cell ; 42(3): 474-486.e12, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38402610

RESUMO

Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress significantly alters the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis. Chronic stress shifts normal circadian rhythm of neutrophils and causes increased neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Furthermore, digesting NETs with DNase I prevents chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease.


Assuntos
Armadilhas Extracelulares , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Neutrófilos/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologia , Microambiente Tumoral
18.
Nat Commun ; 15(1): 3282, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627380

RESUMO

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.


Assuntos
Glândulas Mamárias Animais , Infecções Urinárias , Animais , Feminino , Camundongos , Colágeno , Matriz Extracelular/fisiologia , Homeostase
19.
Nat Genet ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886586

RESUMO

The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

20.
Cancer Discov ; 14(4): 669-673, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38571430

RESUMO

SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.


Assuntos
Neoplasias , Neurociências , Humanos , Sistema Nervoso Central , Previsões , Proteômica
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