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Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 308-325页

作者： Adilson Fonseca Teixeira Yanhong Wang Josephine Iaria peter ten dijke Hong-Jian Zhu Department of Surgery(The Royal Melbourne Hospital) The University of MelbourneParkvilleVICAustralia Huagene Institute Kecheng Science and Technology ParkPukou DistrictNanjingJiangsuChina Department of Cell and Chemical Biology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands

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

关键词： metastasis doses invasion

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Targeting TGFβ signal transduction for cancer therapy

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Signal Transduction and Targeted Therapy 2021年第2期6卷 277-296页

作者： Sijia Liu Jiang Ren peter ten dijke Oncode Institute and Department of Cell and Chemical Biology Leiden University Medical CenterEinthovenweg 202300 RC LeidenThe Netherlands

Transforming growth factor-β(TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis.Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases,including cancer,immune dysfunction,and fbrosis.In this review,we focus on TGFβ,a well-characterized family member that has a dichotomous role in cancer progression,acting in early stages as a tumor suppressor and in late stages as a tumor promoter.The functions of TGFβ are not limited to the regulation of proliferation,differentiation,apoptosis,epithelial-mesenchymal transition,and metastasis of cancer cells.Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition,promotion of angiogenesis,and suppression of the ant-tumor immune reaction.The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients.However,the critical function of TGFβin maintaining tissue homeostasis makes targeting TGFβa challenge.Here,we review the pleiotropic functions of TGFβin cancer initiation and progression,summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment,and discuss the remaining challenges and opportunities related to targeting this pathway.We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy,targeted therapy,radiotherapy,or immunotherapy.

关键词： TGFβ homeostasis stimulation

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OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-β type I receptor

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1842-1859页

作者： Chuannan Fan Qian Wang Gerard van der Zon Jiang Ren Cedrick Agaser Roderick C.Slieker Prasanna Vasudevan Iyengar Hailiang Mei peter ten dijke Department of Cell and Chemical Biology Leiden University Medical CenterLeiden 2300 RCThe Netherlands Oncode Institute Leiden University Medical CenterLeiden 2300 RCThe Netherlands Department of Biomedical Data Sciences Sequencing Analysis Support CoreLeiden University Medical CenterLeiden 2300 RCThe Netherlands Department of Epidemiology and Data Science Amsterdam Public Health InstituteAmsterdam Cardiovascular Sciences InstituteAmsterdam UMClocation VUmcAmsterdam 1081 HVThe Netherlands

Ovo-like transcriptional repressor 1(OVOL1)is a key mediator of epithelial lineage determination and mesenchymal–epithelial transition(MET).The cytokines transforming growth factor-β(TGF-β)and bone morphogenetic proteins(BMP)control the epithelial–mesenchymal plasticity(EMP)of cancer cells,but whether this occurs through interplay with OVOL1 is not known.Here,we show that OVOL1 is inversely correlated with the epithelial–mesenchymal transition(EMT)signature,and is an indicator of a favorable prognosis for breast cancer patients.OVOL1 suppresses EMT.

关键词： invasion breast cancer

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Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer

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Protein & Cell 2021年第2期12卷 89-106页

作者： Jing Zhang peter ten dijke Manfred Wuhrer Tao Zhang Oncode Institute and Cell Chemical Biology Leiden University Medical Center2300 RC LeidenThe Netherlands Center for Proteomics and Metabolomics Leiden University Medical CenterLeidenThe Netherlands

Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions.Aberrant glycosylation can lead to uncontrolled cell proliferation,cell-matrix interactions,migration and differentiation,and has been shown to be involved in cancer and other diseases.The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream.This cellular transformation process,which is associated by morphological change,loss of epithelial traits and gain of mesenchymal markers,is triggered by the secreted cytokine transforming growth factor-β(TGF-β).TGF-βbioactivity is carefully regulated,and its effects on cells are mediated by its receptors on the cell surface.In this review,we first provide a brief overview of major types of glycans,namely,N-glycans,O-glycans,glycosphingolipids and glycosaminoglycans that are involved in cancer progression.Thereafter,we summarize studies on how the glycosylation of TGF-βsignaling components regulates TGF-βsecretion,bioavailability and TGF-βreceptor function.Then,we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer.Identifying and understanding the mechanisms by which glycosylation affects TGF-βsignaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.

关键词： cancer epithelial-to-mesenchymal transition glycosphingolipids N-glycosylation Oglycosylation transforming growth factor-β

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Combination of photodynamic therapy and stimulator of interferon genes(STING)agonist inhibits colorectal tumor growth and recurrence

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Cancer Communications 2023年第4期43卷 513-518页

作者： Yang Hao Sen Ma Zili Gu Alireza Haghparast Timo Schomann Zhenfeng Yu Yuanyuan He Xiaoxv Dong Luis J Cruz peter ten dijke Translational Nanobiomaterials and Imaging(TNI)Group Department of RadiologyLeiden University Medical CenterZA Leidenthe Netherlands Department of Laboratory Animals College of Animal SciencesJilin UniversityChangchunChina Department of Ophthalmology Leiden University Medical Center(LUMC)ZA Leidenthe Netherlands Percuros B.V. CL Leidenthe Netherlands Immunology Section Department of PathobiologyFaculty of Veterinary MedicineFerdowsi University of Mashhad.MashhadIran School of Chinese Material Medica Beijing University of Chinese MedicineBeijingP.R.China Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical CenterRC Leidenthe Netherlands

Dear Editor,Great progress has been made in the clinical use of photodynamic therapy(PDT)for the treatment of patients with superficial tumors[1].However,cancer recurrence and metastasis have limited the application of PDT in the treatment of solid tumors and advanced cancers.In this context,combining PDT with other complementary immunotherapy regimens may overcome these limitations of PDT[2].

关键词： stimulator superficial clinical

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VprBP mitigates TGF-β and Activin signaling by promoting Smurf1-mediated type Ⅰ receptor degradation

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Journal of Molecular Cell Biology 2020年第2期12卷 138-151页

作者： Yihao Li Chao Cui Feng Xie Szymon Kietbasa Hailiang Mei Maarten van Dinther Hans van Dam Andreas Bauer Long Zhang peterten dijke Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center2300RC LeidenThe Netherlands MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network Life Sciences InstituteZhejiang UniversityHangzhou 310058China Department of Human Genetics Leiden Genome Technology CentreLeiden University Medical Center2300RC LeidenThe Netherlands Sequence Analysis Support Core Leiden University Medical Center2300RC LeidenThe Netherlands Novartis Institutes for BioMedical Research Inc.Novartis CampusForum 2.5.01.30CH-4056BaselSwitzerland

The transforming growth factor-β(TGF-β)family controls embryogenesis,stem cell differentiation,and tissue homeostasis.However,how post-translation modifications contribute to fine-tuning of TGF-βfamily signaling responses is not well understood.Inhibitory(I)-Smads can antagonize TGF-β/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-βreceptor for proteasomal degradation.A proteomic interaction screen identified Vpr binding protein(VprBP)as novel binding partner of Smad7.Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation,Smad2–Smad4 interaction,as well as TGF-βtarget gene expression.VprBP was found to promote Smad7–Smurf1–TβRI complex formation and induce proteasomal degradation of TGF-βtype I receptor(TβRI).Moreover,VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination.In multiple adult and mouse embryonic stem cells,depletion of VprBP promotes TGF-βor Activin-induced responses.In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression,and VprBP attenuated mesoderm induction during zebrafish embryogenesis.Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-βand Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction.

关键词： Smurfl TGF-βtype I receptor ubiquitination Activin mesoderm induction

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Smad7过度表达干扰了毛囊的发育和分化

Smad7过度表达干扰了毛囊的发育和分化

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2003中国中西医结合皮肤性病学术会议

作者：何威 Li.Allen G. Wang.Dongyan Goumans.Harie-José ten dijke.peter Wang.Xiao-Jing 第三军医大学新桥医院皮肤科 Department of Detmatology Baylor College of Medicine Houston. TX 77030 USA Division of Cellular Biochemistry The Netherlands Cancer Institute Amsterdam The Netherlands Department of Detmatology Baylor College of Medicine Houston TX 77030 USA Department of Nolecular and Cellular Biology Baylor College of Nedicine Houston TX 77030 USA

生化研究已显示Smad7能阻断转化生长因子β(transforming growth factor β,TGF β)超家族的信号传导。为了确定Smad7在皮肤中的功能,我们利用K5启动子,发展了Smad7转基因小鼠(K5.Smad7)。K5.Smad7小鼠出生时有稀疏而卷曲的胡须,通常在...

生化研究已显示Smad7能阻断转化生长因子β(transforming growth factor β,TGF β)超家族的信号传导。为了确定Smad7在皮肤中的功能,我们利用K5启动子,发展了Smad7转基因小鼠(K5.Smad7)。K5.Smad7小鼠出生时有稀疏而卷曲的胡须,通常在出生后10天内死亡。新生K5.Smad7小鼠的毛囊仍处于发育阶段,仅相当于正常小鼠胚胎16至17天时的毛囊。出生第10天的K5.Smad7小鼠的毛囊并未显示有显显的毛干结构,这也被毛囊分化表记物AE13和AE15的缺失而证实。此外,K5.Smad7小鼠的毛囊排列紊乱。只有少数K5.Smad7小鼠存活至成年期,并在第一个休止期时发生脱发,经过若干个毛囊周期后最终形成永久性秃发,晚期的毛囊可退化形成毛发囊肿。K5.Smad7小鼠的毛囊还显示进入退行期的延迟,伴有凋亡减少,提示TGF β诱导的凋亡被阻断。Smad7转基因小鼠显示了表皮增生、严重的毛囊发育延迟、异常的毛囊分化和周期性脱发。令人感兴趣的是,除了Smad磷酸化减少外,K5.Smad7小鼠皮肤中TGF β、activin和骨形态发生蛋白(bone morphogeneticprotein)之受体的蛋白质水平也显著降低。我们的研究提供了进一步的证据,Smad7是活体中对毛囊发育、分化和周期所必需的TGF β超家族信号传导的一种强有力的抑制剂。

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