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1.
J Biol Chem ; 300(7): 107462, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38876303

RESUMO

Intracellular signaling by the pleiotropic cytokine transforming growth factor-ß (TGF-ß) is inhibited by Smad7 in a feedback control mechanism. The activity of Smad7 is tightly regulated by multiple post-translational modifications. Using resin-assisted capture and metabolic labeling methods, we show here that Smad7 is S-palmitoylated in mammary epithelial cell models that are widely studied because of their strong responses to TGF-ß and their biological relevance to mammary development and tumor progression. S-palmitoylation of Smad7 is mediated by zDHHC17, a member of a family of 23 S-acyltransferase enzymes. Moreover, we identified four cysteine residues (Cys202, Cys225, Cys415, and Cys417) in Smad7 as palmitoylation acceptor sites. S-palmitoylation of Smad7 on Cys415 and Cys417 promoted the translocation of Smad7 from the nucleus to the cytoplasm, enhanced the stability of the Smad7 protein, and enforced its inhibitory effect on TGF-ß-induced Smad transcriptional response. Thus, our findings reveal a new post-translational modification of Smad7, and highlight an important role of S-palmitoylation to enhance inhibition of TGF-ß/Smad signaling by Smad7.


Assuntos
Aciltransferases , Lipoilação , Transdução de Sinais , Proteína Smad7 , Fator de Crescimento Transformador beta , Proteína Smad7/metabolismo , Proteína Smad7/genética , Humanos , Aciltransferases/metabolismo , Aciltransferases/genética , Fator de Crescimento Transformador beta/metabolismo , Células HEK293 , Processamento de Proteína Pós-Traducional , Animais , Núcleo Celular/metabolismo , Cisteína/metabolismo
3.
Lab Chip ; 24(3): 422-433, 2024 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-38087979

RESUMO

Within the tumor microenvironment (TME), cancer cells use mechanotransduction pathways to convert biophysical forces to biochemical signals. However, the underlying mechanisms and functional significance of these pathways remain largely unclear. The upregulation of mechanosensitive pathways from biophysical forces such as interstitial flow (IF), leads to the activation of various cytokines, including transforming growth factor-ß (TGF-ß). TGF-ß promotes in part via a Smad-dependent signaling pathway the epithelial-mesenchymal transition (EMT) in cancer cells. The latter process is linked to increased cancer cell motility and invasion. Current research models have limited ability to investigate the combined effects of biophysical forces (such as IF) and cytokines (TGF-ß) in a 3D microenvironment. We used a 3D-matrix based microfluidic platform to demonstrate the potentiating effect of IF on exogenous TGF-ß induced upregulation of the Smad-signaling activity and the expression of mesenchymal marker vimentin in A549 lung cancer spheroids. To monitor this, we used stably integrated fluorescent based reporters into the A549 cancer cell genome. Our results demonstrate that IF enhances exogenous TGF-ß induced Smad-signaling activity in lung cancer spheroids embedded in a matrix microenvironment. In addition, we observed an increased cell motility for A549 spheroids when exposed to IF and TGF-ß. Our 3D-microfluidic model integrated with real-time imaging provides a powerful tool for investigating cancer cell signaling and motility associated with invasion characteristics in a physiologically relevant TME.


Assuntos
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Fator de Crescimento Transformador beta/genética , Microfluídica , Mecanotransdução Celular , Linhagem Celular Tumoral , Transdução de Sinais , Citocinas , Transição Epitelial-Mesenquimal , Movimento Celular , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Microambiente Tumoral
4.
J Pathol ; 262(1): 90-104, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37929635

RESUMO

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor ß availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Miofibroblastos , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Diferenciação Celular , Colágeno/metabolismo , Miofibroblastos/metabolismo , Neoplasias Pancreáticas/patologia , Proteômica
5.
Signal Transduct Target Ther ; 8(1): 456, 2023 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-38105247

RESUMO

Metastasis is the leading cause of cancer-related deaths. Transforming growth factor beta (TGF-ß) signaling drives metastasis and is strongly enhanced during cancer progression. Yet, the use of on-target TGF-ß signaling inhibitors in the treatment of cancer patients remains unsuccessful, highlighting a gap in the understanding of TGF-ß biology that limits the establishment of efficient anti-metastatic therapies. Here, we show that TGF-ß signaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle (sEV) secretion. Demonstrating sEV's unique role, TGF-ß signaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-ß. Further, genetic disruption of sEV secretion in highly-metastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-ß signaling to nearly-normal levels. Otherwise, TGF-ß signaling activity in non-invasive breast cancer cells is inherently low, but can be amplified by sEVs, enabling invasion and metastasis of poorly-metastatic breast cancer cells. Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers, treatment with dimethyl amiloride (DMA) decreases sEV secretion, TGF-ß signaling activity, and breast cancer progression in vivo. Targeting both the sEV trafficking and TGF-ß signaling by combining DMA and SB431542 at suboptimal doses potentiated this effect, normalizing the TGF-ß signaling in primary tumors to potently reduce circulating tumor cells, metastasis, and tumor self-seeding. Collectively, this study establishes sEVs as critical elements in TGF-ß biology, demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-ß signaling levels in breast cancer cells.


Assuntos
Neoplasias da Mama , Vesículas Extracelulares , Humanos , Feminino , Linhagem Celular Tumoral , Fator de Crescimento Transformador beta/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/uso terapêutico , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo
6.
MedComm (2020) ; 4(4): e339, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37560754

RESUMO

Immune checkpoint inhibitors (ICIs) have shown remarkable success in cancer treatment. However, in cancer patients without sufficient antitumor immunity, numerous data indicate that blocking the negative signals elicited by immune checkpoints is ineffective. Drugs that stimulate immune activation-related pathways are emerging as another route for improving immunotherapy. In addition, the development of nanotechnology presents a promising platform for tissue and cell type-specific delivery and improved uptake of immunomodulatory agents, ultimately leading to enhanced cancer immunotherapy and reduced side effects. In this review, we summarize and discuss the latest developments in nanoparticles (NPs) for cancer immuno-oncology therapy with a focus on lipid-based NPs (lipid-NPs), including the characteristics and advantages of various types. Using the agonists targeting stimulation of the interferon genes (STING) transmembrane protein as an exemplar, we review the potential of various lipid-NPs to augment STING agonist therapy. Furthermore, we present recent findings and underlying mechanisms on how STING pathway activation fosters antitumor immunity and regulates the tumor microenvironment and provide a summary of the distinct STING agonists in preclinical studies and clinical trials. Ultimately, we conduct a critical assessment of the obstacles and future directions in the utilization of lipid-NPs to enhance cancer immunotherapy.

7.
J Cell Commun Signal ; 17(4): 1517-1526, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37615860

RESUMO

GREMLIN1 (GREM1) is member of a family of structurally and functionally related secreted cysteine knot proteins, which act to sequester and inhibit the action of multifunctional bone morphogenetic proteins (BMPs). GREM1 binds directly to BMP dimers, thereby preventing BMP-mediated activation of BMP type I and type II receptors. Multiple reports identify the overexpression of GREM1 as a contributing factor in a broad range of cancers. Additionally, the GREM1 gene is amplified in a rare autosomal dominant inherited form of colorectal cancer. The inhibitory effects of GREM1 on BMP signaling have been linked to these tumor-promoting effects, including facilitating cancer cell stemness and the activation of cancer-associated fibroblasts. Moreover, GREM1 has been described to bind and signal to vascular endothelial growth factor receptor (VEGFR) and stimulate angiogenesis, as well as epidermal and fibroblast growth factor receptor (EGFR and FGFR) to elicit tumor-promoting effects in breast and prostate cancer, respectively. In contrast, a 2022 report revealed that GREM1 can promote an epithelial state in pancreatic cancers, thereby inhibiting pancreatic tumor growth and metastasis. In this commentary, we will review these disparate findings and attempt to provide clarity around the role of GREM1 signaling in cancer.

8.
Sci Adv ; 9(28): eadf9915, 2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37450593

RESUMO

The genetic circuits that allow cancer cells to evade immune killing via epithelial mesenchymal plasticity remain poorly understood. Here, we showed that mesenchymal-like (Mes) KPC3 pancreatic cancer cells were more resistant to cytotoxic T lymphocyte (CTL)-mediated killing than the parental epithelial-like (Epi) cells and used parallel genome-wide CRISPR screens to assess the molecular underpinnings of this difference. Core CTL-evasion genes (such as IFN-γ pathway components) were clearly evident in both types. Moreover, we identified and validated multiple Mes-specific regulators of cytotoxicity, such as Egfr and Mfge8. Both genes were significantly higher expressed in Mes cancer cells, and their depletion sensitized Mes cancer cells to CTL-mediated killing. Notably, Mes cancer cells secreted more Mfge8 to inhibit proliferation of CD8+ T cells and production of IFN-γ and TNFα. Clinically, increased Egfr and Mfge8 expression was correlated with a worse prognosis. Thus, Mes cancer cells use Egfr-mediated intrinsic and Mfge8-mediated extrinsic mechanisms to facilitate immune escape from CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias Pancreáticas , Humanos , Transição Epitelial-Mesenquimal/genética , Evasão da Resposta Imune/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Receptores ErbB/genética , Linhagem Celular Tumoral , Neoplasias Pancreáticas/genética
9.
Sci Signal ; 16(790): eadf1947, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37339182

RESUMO

Transforming growth factor-ß (TGF-ß) signaling is a critical driver of epithelial-to-mesenchymal transition (EMT) and cancer progression. In SMAD-dependent TGF-ß signaling, activation of the TGF-ß receptor complex stimulates the phosphorylation of the intracellular receptor-associated SMADs (SMAD2 and SMAD3), which translocate to the nucleus to promote target gene expression. SMAD7 inhibits signaling through the pathway by promoting the polyubiquitination of the TGF-ß type I receptor (TßRI). We identified an unannotated nuclear long noncoding RNA (lncRNA) that we designated LETS1 (lncRNA enforcing TGF-ß signaling 1) that was not only increased but also perpetuated by TGF-ß signaling. Loss of LETS1 attenuated TGF-ß-induced EMT and migration in breast and lung cancer cells in vitro and extravasation of the cells in a zebrafish xenograft model. LETS1 potentiated TGF-ß-SMAD signaling by stabilizing cell surface TßRI, thereby forming a positive feedback loop. Specifically, LETS1 inhibited TßRI polyubiquitination by binding to nuclear factor of activated T cells (NFAT5) and inducing the expression of the gene encoding the orphan nuclear receptor 4A1 (NR4A1), a component of a destruction complex for SMAD7. Overall, our findings characterize LETS1 as an EMT-promoting lncRNA that potentiates signaling through TGF-ß receptor complexes.


Assuntos
Neoplasias , RNA Longo não Codificante , Animais , Humanos , Fator de Crescimento Transformador beta/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Movimento Celular/genética
10.
Int J Mol Sci ; 24(10)2023 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-37240029

RESUMO

Despite advances in treatment for metastatic melanoma patients, patients with liver metastasis have an unfavorable prognosis. A better understanding of the development of liver metastasis is needed. The multifunctional cytokine Transforming Growth Factor ß (TGF-ß) plays various roles in melanoma tumors and metastasis, affecting both tumor cells and cells from the surrounding tumor microenvironment. To study the role of TGF-ß in melanoma liver metastasis, we created a model to activate or repress the TGF-ß receptor pathway in vitro and in vivo in an inducible manner. For this, we engineered B16F10 melanoma cells to have inducible ectopic expression of a constitutively active (ca) or kinase-inactive (ki) TGF-ß receptor I, also termed activin receptor-like kinase (ALK5). In vitro, stimulation with TGF-ß signaling and ectopic caALK5 expression reduced B16F10 cell proliferation and migration. Contrasting results were found in vivo; sustained caALK5 expression in B16F10 cells in vivo increased the metastatic outgrowth in liver. Blocking microenvironmental TGF-ß did not affect metastatic liver outgrowth of both control and caALK5 expressing B16F10 cells. Upon characterizing the tumor microenvironment of control and caALk5 expressing B16F10 tumors, we observed reduced (cytotoxic) T cell presence and infiltration, as well as an increase in bone marrow-derived macrophages in caALK5 expressing B16F10 tumors. This suggests that caALK5 expression in B16F10 cells induces changes in the tumor microenvironment. A comparison of newly synthesized secreted proteins upon caALK5 expression by B16F10 cells revealed increased secretion of matrix remodeling proteins. Our results show that TGF-ß receptor activation in B16F10 melanoma cells can increase metastatic outgrowth in liver in vivo, possibly through remodeling of the tumor microenvironment leading to altered infiltration of immune cells. These results provide insights in the role of TGF-ß signaling in B16F10 liver metastasis and could have implications regarding the use of TGF-ß inhibitors for the treatment of melanoma patients with liver metastasis.


Assuntos
Neoplasias Hepáticas , Melanoma , Humanos , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Citocinas , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral
11.
J Control Release ; 357: 531-544, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37030544

RESUMO

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence suggests that chemotherapy-induced DNA damage can directly induce dendritic cell (DC) maturation and recruitment, which synergizes with STING activation to enhance anti-tumor effects. As an immunogenic cell death (ICD) inducer, oxaliplatin generates massive double-stranded DNA (dsDNA) crosslinks, release of tumor-associated antigens and promoting the "eat me" signal. STING activation improves antigen immunogenicity, which can promote T cell activation and infiltration. In this study, we developed liposomes encapsulating oxaliplatin and combine this formulation with a STING agonist (ADU-S100) for treating colorectal cancer. The liposomes efficiently inhibited the proliferation of tumor cells while induced ICD in CT26 colorectal cancer cells, which enhanced dendritic cell maturation and phagocytosis in vitro. The liposome-based immunochemotherapy exhibited the strongest efficacy, resulting in complete remission upon tumor inoculation. Mechanistic studies showed this potent anti-cancer effect was related to the significant recruitment of infiltrating CD8 and CD4 T cells, reduction of suppressive Treg cells, and a shift in the phenotype of tumor-associated suppressive macrophages that promote cancer to immune stimulating macrophages. Thus, our study demonstrated the potential of combining oxaliplatin-loaded liposomes with a STING agonist to reduce tumor growth by regulating the immunosuppressive state in the tumor.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Humanos , Oxaliplatina , Lipossomos , Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Colorretais/tratamento farmacológico
12.
EMBO J ; 42(10): e112806, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36994542

RESUMO

Epithelial cells acquire mesenchymal phenotypes through epithelial-mesenchymal transition (EMT) during cancer progression. However, how epithelial cells retain their epithelial traits and prevent malignant transformation is not well understood. Here, we report that the long noncoding RNA LITATS1 (LINC01137, ZC3H12A-DT) is an epithelial gatekeeper in normal epithelial cells and inhibits EMT in breast and non-small cell lung cancer cells. Transcriptome analysis identified LITATS1 as a TGF-ß target gene. LITATS1 expression is reduced in lung adenocarcinoma tissues compared with adjacent normal tissues and correlates with a favorable prognosis in breast and non-small cell lung cancer patients. LITATS1 depletion promotes TGF-ß-induced EMT, migration, and extravasation in cancer cells. Unbiased pathway analysis demonstrated that LITATS1 knockdown potently and selectively potentiates TGF-ß/SMAD signaling. Mechanistically, LITATS1 enhances the polyubiquitination and proteasomal degradation of TGF-ß type I receptor (TßRI). LITATS1 interacts with TßRI and the E3 ligase SMURF2, promoting the cytoplasmic retention of SMURF2. Our findings highlight a protective function of LITATS1 in epithelial integrity maintenance through the attenuation of TGF-ß/SMAD signaling and EMT.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Plasticidade Celular , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina-Proteína Ligases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I
13.
EJNMMI Res ; 13(1): 23, 2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36947258

RESUMO

Transforming growth factor ß (TGFß) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFß, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [11C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [11C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [18F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [18F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH.

14.
Cancer Res Commun ; 3(2): 325-337, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36860656

RESUMO

The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8+ T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-ß signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteristics. Here, we investigated the effect of TGF-ß blockade on the antitumor efficacy of Reo&CD3-bsAb therapy in the preclinical pancreatic KPC3 and colon MC38 tumor models, where TGF-ß signaling is active. TGF-ß blockade impaired tumor growth in both KPC3 and MC38 tumors. Furthermore, TGF-ß blockade did not affect reovirus replication in both models and significantly enhanced the Reo-induced T-cell influx in MC38 colon tumors. Reo administration decreased TGF-ß signaling in MC38 tumors but instead increased TGF-ß activity in KPC3 tumors, resulting in the accumulation of α-smooth muscle actin (αSMA+) fibroblasts. In KPC3 tumors, TGF-ß blockade antagonized the antitumor effect of Reo&CD3-bsAb therapy, even though T-cell influx and activity were not impaired. Moreover, genetic loss of TGF-ß signaling in CD8+ T cells had no effect on therapeutic responses. In contrast, TGF-ß blockade significantly improved therapeutic efficacy of Reo&CD3-bsAb in mice bearing MC38 colon tumors, resulting in a 100% complete response. Further understanding of the factors that determine this intertumor dichotomy is required before TGF-ß inhibition can be exploited as part of viroimmunotherapeutic combination strategies to improve their clinical benefit. Significance: Blockade of the pleiotropic molecule TGF-ß can both improve and impair the efficacy of viro-immunotherapy, depending on the tumor model. While TGF-ß blockade antagonized Reo&CD3-bsAb combination therapy in the KPC3 model for pancreatic cancer, it resulted in 100% complete responses in the MC38 colon model. Understanding factors underlying this contrast is required to guide therapeutic application.


Assuntos
Neoplasias do Colo , Neoplasias Pancreáticas , Camundongos , Animais , Linfócitos T CD8-Positivos , Fator de Crescimento Transformador beta , Neoplasias Pancreáticas/tratamento farmacológico , Imunoterapia , Microambiente Tumoral
15.
Cell Mol Immunol ; 20(4): 318-340, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36823234

RESUMO

Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-to-mesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistance in cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsic mechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulate tumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects to enhance the ICB response for therapeutic gain in cancer patients.


Assuntos
Neoplasias , Humanos , Neoplasias/patologia , Imunoterapia , Terapia de Imunossupressão , Microambiente Tumoral
16.
Int J Cancer ; 152(12): 2594-2606, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-36823950

RESUMO

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better understanding of the mechanisms underlying TNBC metastasis may lead to new strategies of early diagnosis and more efficient treatment. In our study, we uncovered that the autophagy receptor optineurin (OPTN) plays an unexpected role in TNBC metastasis. Data mining of publicly available data bases revealed that the mRNA level of OPTN in TNBC patients positively correlates with relapse free and distance metastasis free survival. Importantly, in vitro and in vivo models demonstrated that OPTN suppresses TNBC metastasis. Mechanistically, OPTN inhibited the pro-oncogenic transforming growth factor-ß (TGFß) signaling in TNBC cells by interacting with TGFß type I receptor (TßRI) and promoting its ubiquitination for degradation. Consistent with our experimental findings, the clinical TNBC samples displayed a negative correlation between OPTN mRNA expression and TGFß gene response signature and expression of proto-typic TGFß target genes. Altogether, our study demonstrates that OPTN is a negative regulator for TGFß receptor/SMAD signaling and suppresses metastasis in TNBC.


Assuntos
Proteínas de Ciclo Celular , Proteínas de Membrana Transportadoras , Neoplasias de Mama Triplo Negativas , Humanos , Linhagem Celular Tumoral , Metástase Neoplásica , Recidiva Local de Neoplasia , RNA Mensageiro/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Membrana Transportadoras/metabolismo
18.
Cell Mol Life Sci ; 80(2): 43, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36646950

RESUMO

Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-ß signaling by directly interacting with TGF-ß type I receptor (TßRI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters TßRI in the ER. By decreasing cell surface TßRI levels, USP19-ER inhibits TGF-ß/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-ß-induced epithelial-mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast cancer.


Assuntos
Neoplasias da Mama , Fator de Crescimento Transformador beta , Humanos , Feminino , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias da Mama/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Membrana Celular/metabolismo , Movimento Celular/genética , Linhagem Celular Tumoral , Endopeptidases/metabolismo
19.
EMBO J ; 42(2): e110553, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36504224

RESUMO

Epithelial-mesenchymal transition (EMT) is pivotal in the initiation and development of cancer cell metastasis. We observed that the abundance of glycosphingolipids (GSLs), especially ganglioside subtypes, decreased significantly during TGF-ß-induced EMT in NMuMG mouse mammary epithelial cells and A549 human lung adenocarcinoma cells. Transcriptional profiling showed that TGF-ß/SMAD response genes and EMT signatures were strongly enriched in NMuMG cells, along with depletion of UDP-glucose ceramide glucosyltransferase (UGCG), the enzyme that catalyzes the initial step in GSL biosynthesis. Consistent with this finding, genetic or pharmacological inhibition of UGCG promoted TGF-ß signaling and TGF-ß-induced EMT. UGCG inhibition promoted A549 cell migration, extravasation in the zebrafish xenograft model, and metastasis in mice. Mechanistically, GSLs inhibited TGF-ß signaling by promoting lipid raft localization of the TGF-ß type I receptor (TßRI) and by increasing TßRI ubiquitination and degradation. Importantly, we identified ST3GAL5-synthesized a-series gangliosides as the main GSL subtype involved in inhibition of TGF-ß signaling and TGF-ß-induced EMT in A549 cells. Notably, ST3GAL5 is weakly expressed in lung cancer tissues compared to adjacent nonmalignant tissues, and its expression correlates with good prognosis.


Assuntos
Neoplasias Pulmonares , Fator de Crescimento Transformador beta , Humanos , Animais , Camundongos , Fator de Crescimento Transformador beta/metabolismo , Gangliosídeos , Transição Epitelial-Mesenquimal/genética , Peixe-Zebra/metabolismo , Neoplasias Pulmonares/metabolismo , Glicoesfingolipídeos , Catálise , Movimento Celular , Linhagem Celular Tumoral
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