Liver cancer represents a major global health concern,with projections indicating that the number of new cases could surpass 1 million annually by 2025.Hepatocellular carcinoma(HCC)constitutes around 90%of liver cance...Liver cancer represents a major global health concern,with projections indicating that the number of new cases could surpass 1 million annually by 2025.Hepatocellular carcinoma(HCC)constitutes around 90%of liver cancer cases and is primarily linked to factors incluidng aflatoxin,hepatitis B(HBV)and C(HCV),and metabolic disorders.There are no obvious symptoms in the early stage of HCC,which often leads to delays in diagnosis.Therefore,HCC patients usually present with tumors in advanced and incurable stages.Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation,metastasis,and recurrence of HCC.Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase(RTK)pathways in HCC,pathways involved in cell differentiation,telomere regulation,epigenetic modification and stress response also provide therapeutic potential.Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC.At present,the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors(TKI),immune checkpoint inhibitors(ICI),and combination regimens.New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF(endothelial growth factor)therapies,as well as combinations of two immunotherapy regimens.The outcomes of these trials are expected to revolutionize HCC management across all stages.Here,we provide here a comprehensive review of cellular signaling pathways,their therapeutic potential,evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials,biomarker identification,and the development of more effective therapeutics for HCC.展开更多
Lenvatinib,a multi-kinase inhibitor,has been approved asfirst-line treatment for advanced hepatocellular carcinoma(HCC),but its efficacy is limited.We have shown previously that lenvatinib and epidermal growth factor ...Lenvatinib,a multi-kinase inhibitor,has been approved asfirst-line treatment for advanced hepatocellular carcinoma(HCC),but its efficacy is limited.We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor(EGFRTKI)combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression(EGFR^(high)).We present here the results of a single-arm,open-label,exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib(NCT04642547;n=30).Only patients with EGFR^(high) HCC and progressive disease after lenvatinib treatment were recruited in the study.The most frequent adverse events of all grades were fatigue(27 patients;90%),followed by rash(25 patients;83.3%),diarrhea(24 patients;80%),and anorexia(12 patients;40%).Among 30 patients,9(30%)achieved a confirmed partial response and 14(46.7%)had stable disease according to mRECIST criteria.Based on RECIST1.1,5(16.7%)achieved a confirmed partial response and 18(60%)had stable disease.The estimated median progression free survival(PFS)and overall survival(OS)time were 4.4 months(95%CI:2.5 to 5.9)and13.7 months(95%CI:9.0 to NA),respectively.The objective response rate(ORR)of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC(cabozantinib ORR of 4%;regorafenib ORR of 11%).Given that this combination was well-tolerated,a further clinical study of this combination is warranted.展开更多
CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s...CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.展开更多
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 i...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.展开更多
The gastrointestinal(GI)tract's primary role is food digestion,relying on coordinated fluid secretion and bowel movements triggered by mechanosensation.Enteroendocrine cells(EECs)are specialized mechanosensitive c...The gastrointestinal(GI)tract's primary role is food digestion,relying on coordinated fluid secretion and bowel movements triggered by mechanosensation.Enteroendocrine cells(EECs)are specialized mechanosensitive cells that convert mechanical forces into electrochemical signals,culminating in serotonin release to regulate GI motility.Despite their pivotal role,knowledge of EEC mechanical properties has been lacking due to their rarity and limited accessibility.In this brief report,we present the first single-cell mechanical characterization of human ECCs isolated from healthy intestinal organoids.Using single-cell optical tweezers,we measured EEC stiffness profiles at the physiological temperature and investigated changes following tryptophan metabolism inhibition.Our findings not only shed light on EEC mechanics but also highlight the potential of adult stem cell-derived organoids for studying these elusive cells.展开更多
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 a...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.展开更多
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 pr...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.展开更多
Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectivenes...Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.展开更多
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 re...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.展开更多
Adult tissue-derived organoids allow for the expansion and maintenance of primary epithelial cells in a near-native state.These 3D and self-organizing organotypic cultures derived from adult tissues have been increasi...Adult tissue-derived organoids allow for the expansion and maintenance of primary epithelial cells in a near-native state.These 3D and self-organizing organotypic cultures derived from adult tissues have been increasingly used in fundamental and translational research.A key feature of this organoid system is that it recapitulates the stem cell lineage and thus,the differentiated cell-type heterogeneity of the in vivo tissue of origin.展开更多
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 pr...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.展开更多
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 o...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].展开更多
Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. R...Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-tomesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistancein cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsicmechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulatetumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects toenhance the ICB response for therapeutic gain in cancer patients.展开更多
In a recent study published in Science,Tiebang Kang and his colleagues1 identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1.Th...In a recent study published in Science,Tiebang Kang and his colleagues1 identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1.The work uncovers a cell cycle-regulated chromatin-associated ubiquitin ligase circuit that maintains epigenetic homeostasis and reveals a novel vulnerability in cancer that may be exploited therapeutically.展开更多
基金funded by grants from the National Natural Science Foundation of China(82222047,82073039)the Science and Technology Commission of Shanghai Municipality(22XD1423100,22S11900500)Shanghai Municipal Health Commission(2022XD057).
文摘Liver cancer represents a major global health concern,with projections indicating that the number of new cases could surpass 1 million annually by 2025.Hepatocellular carcinoma(HCC)constitutes around 90%of liver cancer cases and is primarily linked to factors incluidng aflatoxin,hepatitis B(HBV)and C(HCV),and metabolic disorders.There are no obvious symptoms in the early stage of HCC,which often leads to delays in diagnosis.Therefore,HCC patients usually present with tumors in advanced and incurable stages.Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation,metastasis,and recurrence of HCC.Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase(RTK)pathways in HCC,pathways involved in cell differentiation,telomere regulation,epigenetic modification and stress response also provide therapeutic potential.Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC.At present,the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors(TKI),immune checkpoint inhibitors(ICI),and combination regimens.New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF(endothelial growth factor)therapies,as well as combinations of two immunotherapy regimens.The outcomes of these trials are expected to revolutionize HCC management across all stages.Here,we provide here a comprehensive review of cellular signaling pathways,their therapeutic potential,evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials,biomarker identification,and the development of more effective therapeutics for HCC.
基金supported by the National Natural Science Foundation(Nos.82222047,82073039,82330095,81502672,and 82070619)the Program of Shanghai Academic/Technology Research Leader(No.22XD1423100)+2 种基金the National Key Research and Development Program of China(2022YFC2804300)Shanghai Municipal Commission of Health and Family Planning(2022XD057)the Shanghai Committee of Science and Technology(23ZR1439000 and 22S11900500).
文摘Lenvatinib,a multi-kinase inhibitor,has been approved asfirst-line treatment for advanced hepatocellular carcinoma(HCC),but its efficacy is limited.We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor(EGFRTKI)combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression(EGFR^(high)).We present here the results of a single-arm,open-label,exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib(NCT04642547;n=30).Only patients with EGFR^(high) HCC and progressive disease after lenvatinib treatment were recruited in the study.The most frequent adverse events of all grades were fatigue(27 patients;90%),followed by rash(25 patients;83.3%),diarrhea(24 patients;80%),and anorexia(12 patients;40%).Among 30 patients,9(30%)achieved a confirmed partial response and 14(46.7%)had stable disease according to mRECIST criteria.Based on RECIST1.1,5(16.7%)achieved a confirmed partial response and 18(60%)had stable disease.The estimated median progression free survival(PFS)and overall survival(OS)time were 4.4 months(95%CI:2.5 to 5.9)and13.7 months(95%CI:9.0 to NA),respectively.The objective response rate(ORR)of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC(cabozantinib ORR of 4%;regorafenib ORR of 11%).Given that this combination was well-tolerated,a further clinical study of this combination is warranted.
文摘CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.
基金Research on TGF-βsignaling was supported by the Australia’s National Health and Medical Research Council(NHMRC)(H-JZ),Friends of the Royal Melbourne Hospital Neurosciences Foundation(H-JZ),and the Cancer Genomics Centre Netherlands(CGC.NL)(PtD)AFT and YW were supported by the Melbourne Research Scholarship。
文摘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.
文摘The gastrointestinal(GI)tract's primary role is food digestion,relying on coordinated fluid secretion and bowel movements triggered by mechanosensation.Enteroendocrine cells(EECs)are specialized mechanosensitive cells that convert mechanical forces into electrochemical signals,culminating in serotonin release to regulate GI motility.Despite their pivotal role,knowledge of EEC mechanical properties has been lacking due to their rarity and limited accessibility.In this brief report,we present the first single-cell mechanical characterization of human ECCs isolated from healthy intestinal organoids.Using single-cell optical tweezers,we measured EEC stiffness profiles at the physiological temperature and investigated changes following tryptophan metabolism inhibition.Our findings not only shed light on EEC mechanics but also highlight the potential of adult stem cell-derived organoids for studying these elusive cells.
基金We apologize to authors whose papers could not be cited due to space limitations.We are grateful to Dieuwke Marvin and Adilson Fonseca Teixeira for a critical reading and comments.We thank Gerard van der Zon for the immunofluorescent staining images of NMuMG cells.Research on targeting TGFβ for cancer therapy in our laboratory is supported by the Cancer Genomics Centre Netherlands。
文摘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.
文摘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.
文摘Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.
基金This research was supported by Cancer Genomics Centre Netherlands and a grant from the National Natural Science Foundation of China(31471315).
文摘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.
基金This work was supported by the European Research Council under ERC Advanced Grant Agreement no.67013(H.C.and K.B.)。
文摘Adult tissue-derived organoids allow for the expansion and maintenance of primary epithelial cells in a near-native state.These 3D and self-organizing organotypic cultures derived from adult tissues have been increasingly used in fundamental and translational research.A key feature of this organoid system is that it recapitulates the stem cell lineage and thus,the differentiated cell-type heterogeneity of the in vivo tissue of origin.
基金We acknowledge the support of the Chinese Scholarship Council(CSC)to Chuannan Fan and Qian Wang,and the Cancer Genomics Centre in the Netherlands(CGC,NL)and the ZonMW grant(09120012010061)to Peter ten Dijke.We thank Maarten van Dinther and Martijn Rabelink for excellent technical assistance and Slobodan Vukicevic(University of Zagreb,Croatia),and Andrew Hinck(University of Pittsburgh,USA)for generously providing human recombinant BMP6 and TGF-β3,respectively.We acknowledge A.G.Jochemsen for providing the FH1tUTG vector.We are grateful to Midory Thorikay for help with testing effect of compounds on OVOL1 expression and checking the expression of OVOL1 in breast cancer cell lines,Jing Zhang for the help with GSEA,Sijia Liu for instructions on how to perform the zebrafish xenograft assay,and all other members in ten Dijke’s laboratory and Yuva Oz for their kind support.
文摘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.
基金Yang Hao received finacial support from the China Scholarship and Jilin Province Chinese Postdoctoral International Exchange Program(YJ20220406)Zili Gu,Zhenfeng Yu and Sen Ma received financial support from the China Scholarship Council,and Peter ten Dijke received funding from Cancer Genomics Centre NetherlandsTimo Schomann and Alireza Haghparast received funding from the European Commission,grants H2020-MSCA-RISE CANCER(777682)and H2020-WIDESPREAD-05-2017-Twinning SIMICA(852985).
文摘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].
基金a ZonMW grant(09120012010061)the Cancer Genomics Center Netherlands(CGC.NL.).
文摘Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-tomesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistancein cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsicmechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulatetumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects toenhance the ICB response for therapeutic gain in cancer patients.
基金supported by the ERC award(Project-ID:ChOReS,#10107875)to N.T.
文摘In a recent study published in Science,Tiebang Kang and his colleagues1 identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1.The work uncovers a cell cycle-regulated chromatin-associated ubiquitin ligase circuit that maintains epigenetic homeostasis and reveals a novel vulnerability in cancer that may be exploited therapeutically.
