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1.
Nat Immunol ; 25(2): 268-281, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38195702

RESUMO

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.


Assuntos
Melanoma , Receptor de Fator de Crescimento Neural , Humanos , Receptor de Fator de Crescimento Neural/genética , Receptor de Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Tropomiosina , Melanoma/terapia , Receptor trkA/genética , Receptor trkA/metabolismo , Citoproteção , Inibidores de Checkpoint Imunológico , Células T de Memória , Terapia de Imunossupressão , Imunoterapia , Receptores de Antígenos de Linfócitos T
2.
Cell Res ; 33(7): 516-532, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37169907

RESUMO

Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.


Assuntos
Células Endoteliais , Trombomodulina , Animais , Senescência Celular , Cirrose Hepática/tratamento farmacológico , Transdução de Sinais , Apoptose , Mamíferos
3.
EMBO Rep ; 19(6)2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29777051

RESUMO

Cellular senescence is a unique cell fate characterized by stable proliferative arrest and the extensive production and secretion of various inflammatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). The molecular mechanisms responsible for generating a SASP in response to senescent stimuli remain largely obscure. Here, using unbiased gene expression profiling, we discover that the scavenger receptor CD36 is rapidly upregulated in multiple cell types in response to replicative, oncogenic, and chemical senescent stimuli. Moreover, ectopic CD36 expression in dividing mammalian cells is sufficient to initiate the production of a large subset of the known SASP components via activation of canonical Src-p38-NF-κB signaling, resulting in the onset of a full senescent state. The secretome is further shown to be ligand-dependent, as amyloid-beta (Aß) is sufficient to drive CD36-dependent NF-κB and SASP activation. Finally, loss-of-function experiments revealed a strict requirement for CD36 in secretory molecule production during conventional senescence reprogramming. Taken together, these results uncover the Aß-CD36-NF-κB signaling axis as an important regulator of the senescent cell fate via induction of the SASP.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Antígenos CD36/fisiologia , Senescência Celular/fisiologia , NF-kappa B/metabolismo , Antígenos CD36/genética , Células Cultivadas , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , Mutação com Perda de Função , Transdução de Sinais
4.
Cell Discov ; 3: 17019, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28626588

RESUMO

Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration.

5.
Nat Cell Biol ; 15(3): 284-94, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23396050

RESUMO

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126(*), a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126(*) directly inhibit stromal cell-derived factor-1 alpha (SDF-1α) expression, and indirectly suppress the expression of chemokine (C-C motif) ligand 2 (Ccl2) by cancer cells in an SDF-1α-dependent manner. miR-126/miR-126(*) expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126(*) downregulation and poor metastasis-free survival of breast cancer patients.


Assuntos
Neoplasias da Mama/prevenção & controle , Inflamação/patologia , Neoplasias Pulmonares/prevenção & controle , Células-Tronco Mesenquimais/patologia , MicroRNAs/genética , Monócitos/patologia , Células Estromais/patologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio , Adesão Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Metilação de DNA , Família de Proteínas EGF , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Inflamação/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/metabolismo , Microambiente Tumoral
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