Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of adv...Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.展开更多
Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prosta...Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.展开更多
1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional ...1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.展开更多
Glycosylphosphatidylinositol-anchored sperm hyaluronidases have long been believed to assist in sperm penetration through the cumulus-oocyte complex(COC);however,their role in mammalian fertilization remains unclear.P...Glycosylphosphatidylinositol-anchored sperm hyaluronidases have long been believed to assist in sperm penetration through the cumulus-oocyte complex(COC);however,their role in mammalian fertilization remains unclear.Previously,we have shown that hyaluronidase 5(Hyal5)/Hyal7 double-knockout(dKO)mice produce significantly fewer offspring than their wild-type(WT)counterparts because of defective COC dispersal.Male infertility is mainly caused by a low sperm count.It can be further exacerbated by the deficiency of sperm hyaluronidase,which disperses the cumulus cells of the outer layer of the COC.In the current study,we evaluated the effects of a low count of Hyal-deficient sperm and conditions of ovulated oocytes on the fertilization rate using a mouse model.Our results demonstrated that a low sperm count further decreases the in vitro fertilization(IVF)rate of Hyal-deficient dKO spermatozoa.In addition,the dKO spermatozoa resulted in a fertilization rate of 12.5%upon fertilizing COCs with a thick cumulus layer,whereas the IVF rate was comparable to that of WT spermatozoa when oocytes with a thin or no cumulus layer were fertilized.Finally,we proved that the IVF rate of dKO spermatozoa could be recovered by adding rat spermatozoa as a source of sperm hyal.Our results suggest that a deficiency of proteins involved in fertilization,such as sperm hyal,has a vital role in fertilization.展开更多
Bone frequently serves as a metastatic site for breast and prostate cancers. Given the potential of low-intensity vibration(LIV) to increase bone health and reduce cancer risk, this study investigated the impact of LI...Bone frequently serves as a metastatic site for breast and prostate cancers. Given the potential of low-intensity vibration(LIV) to increase bone health and reduce cancer risk, this study investigated the impact of LIV on cancer cells, as well as noncancer cells such as lymphocytes and peripheral blood mononuclear cells(PBMCs). The results revealed that LIV exposure not only suppressed cancer cell migration but also triggered the generation of induced tumor-suppressing(iTS) cells. Conditioned medium(CM) derived from LIV-treated PBMCs shrank freshly isolated breast and prostate cancer tissues, and when CM was combined with a chemotherapeutic agent, additional antitumor effects were observed.Notably, iTS cell-derived CM hindered the maturation of the receptor activator of nuclear factor-kappa B ligand(RANKL)-stimulated bone-resorbing osteoclasts while promoting the differentiation of bone-forming osteoblasts. Intriguingly, the anticancer effects induced by LIV were replicated by simply shaking a cell-containing tube with a regular tube shaker. Using mass spectrometry-based proteomics, this study revealed enrichment of tumor-suppressing proteins, including enolase 1, moesin(MSN), and aldolase A(ALDOA), which are commonly found in oncogene-activated iTS cells, in LIV-induced CM. Sad1 and UNC-84 domain containing 1(SUN1), a core component of the linker of the nucleoskeleton and cytoskeleton(LINC) complex, exhibited heightened expression, notably enhancing the response of lymphocytes to LIV. An ex vivo bone cancer model further demonstrated the potent anticancer effects of lymphocyte-derived CM. In conclusion, this study underscores the pivotal role of LIV in preventing bone loss in the tumor microenvironment.展开更多
The androgen receptor(AR)plays a critical role in the development and progression of prostate cancer by regulating key cellular pro-cesses such as cell proliferation and apoptosis.Although traditional AR-targeted ther...The androgen receptor(AR)plays a critical role in the development and progression of prostate cancer by regulating key cellular pro-cesses such as cell proliferation and apoptosis.Although traditional AR-targeted therapies have shown initial success,acquired resis-tance remains a significant clinical challenge,often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency(HRD).Approximately 20%of advanced prostate cancer cases exhibit HRD,resulting in substantial genomic instability and complicating treatment.Fortunately,Food and Drug Administration–approved poly(ADP-ribose)polymerase inhibitors,in-cluding olaparib and rucaparib,exploit synthetic lethality to target prostate cancer with HRD,and additional drugs targeting DNA dam-age response(DDR)proteins are under development.Emerging evidence suggests that AR activity enhances DDR gene expression,with multiple DDR proteins localized near androgen-regulated regions,highlighting a close interaction between AR and DDR pathways.Consequently,recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage,such as radiation therapy,or inhibit DNA repair mechanisms.This review discusses AR's role in cellular processes,the interplay between AR and DDR,and recent advances in prostate cancer treatment strategies.展开更多
Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resourc...Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.展开更多
Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment.These plastic cells can transdifferentiate into Tregs during inflammation resolution,in allogenic heart tra...Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment.These plastic cells can transdifferentiate into Tregs during inflammation resolution,in allogenic heart transplantation models,or in cancer through mechanisms that remain poorly understood.Here,we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism.In the absence of NLRP3,Th17 cells produce more inflammatory cytokines(IFNγ,Granzyme B,TNFα)and exhibit reduced immunosuppressive activity toward CD8+cells.Moreover,the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost.Mechanistically,NLRP3 in Th17 cells interacts with the TGF-βreceptor,enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions.Consequently,the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8+T-cell effectiveness,ultimately inhibiting tumor growth.展开更多
Background Autophagy is critical for cellular homeostasis.Autophagy related 14(ATG14)is a key regulator of autophagy initiation;however,its role in hepatocyte survival remains poorly understood.This study aimed to inv...Background Autophagy is critical for cellular homeostasis.Autophagy related 14(ATG14)is a key regulator of autophagy initiation;however,its role in hepatocyte survival remains poorly understood.This study aimed to investigate the hepatocyte-specific function of ATG14 in vivo.Methods We generated Atg14 hepatocyte-specific knockout(HepKO)mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into Atg14 floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet.Blood and tissue samples were collected for biochemical and histological analyses.Results Atg14 HepKO mice develop severe hepatomegaly under normal dietary conditions.ATG14 deficiency leads to hepatic injury,inflammation and fibrosis.Multiple forms of cell death,including apoptosis and pyroptosis,increase significantly.When challenged with a Western diet for 4 weeks,Atg14 HepKO mice exhibit exacerbated hepatic injury,inflammation and fibrosis despite no significant lipid droplet accumulation in the liver.Transcriptomic analysis reveals upregulation of several cell death pathways,including pyroptosis,apoptosis and necroptosis.Further biochemical and microscopic analyses validate the induction of multiple cell death pathways.In addition,NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in Atg14 HepKO mouse livers and ATG14-deficient hepatocytes.Conclusion Our data suggest that ATG14 is required for maintaining hepatocyte identity,survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly,tissue injury,inflammation and fibrosis.展开更多
Glioblastoma(GBM)is one of the most immunosuppressive and heterogeneous tumors with limited treatment options.Most studies relied on treatment-experienced patient samples to elucidate the origins of tumor heterogeneit...Glioblastoma(GBM)is one of the most immunosuppressive and heterogeneous tumors with limited treatment options.Most studies relied on treatment-experienced patient samples to elucidate the origins of tumor heterogeneity,introducing bias into the analysis.The analysis of samples from multifocal GBM patients,in which independent lesions arise from the same progenitor and undergo parallel evolution,enables the study of the natural evolution of GBM while removing the effect of therapy on the emergence of heterogeneity.This enables the identification of critical events in the evolution of GBM and the unbiased study of subtype progression,diversity,and invasive potential.The tumor microenvironment of GBM undergoes significant changes throughout tumor progression.Recent studies have highlighted the switch from an abundance of resident microglia-derived macrophages in earlier stages to the prevalence of blood-derived macrophages in later stages of GBM.There is conclusive evidence that these alterations cannot be viewed in isolation and that the tumor microenvironment co-evolves with tumor cells during cancer progression.Together with an increasingly hypoxic environment,this culminates in highly immunosuppressive conditions,resulting in a feedback loop further reinforcing evolutionary changes in the tumor.A new study now provides a unique look at the natural evolution of GBM,identifies critical events in its development,and has the potential to help improve the diagnosis and therapy of this deadly disease.展开更多
Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the i...Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.展开更多
Cancer cells tend to develop resistance to chemotherapy and enhance aggressive-ness.A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents.Based on this strateg...Cancer cells tend to develop resistance to chemotherapy and enhance aggressive-ness.A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents.Based on this strategy,induced tumor-suppressing cells(iTSCs)have been generated from tumor cells and mesenchymal stem cells.Here,we examined the possi-bility of generating iTSCs from lymphocytes by activating PKA signaling for suppressing the pro-gression of osteosarcoma(OS).While lymphocyte-derived CM did not present anti-tumor capabilities,the activation of PKA converted them into iTSCs.Inhibiting PKA conversely gener-ated tumor-promotive secretomes.In a mouse model,PKA-activated CM suppressed tumorinduced bone destruction.Proteomics analysis revealed that moesin(MSN)and calreticulin(Calr),which are highly expressed intracellular proteins in many cancers,were enriched in PKA-activated CM,and they acted as extracellular tumor suppressors through CD44,CD47,and CD91.The study presented a unique option for cancer treatment by generating iTSCs that secret tumor-suppressive proteins such as MSN and Calr.We envision that identifying these tu-mor suppressors and predicting their binding partners such as CD44,which is an FDA-approved oncogenic target to be inhibited,may contribute to developing targeted protein therapy.展开更多
Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensiona...Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.展开更多
基金Supported by IU Simon Comprehensive Cancer Center grant,No.5P30CA082709-24.
文摘Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
基金This work was supported by the National Institutes of Health grant R01CA248033(to Xin L)Department of Defense CDMRP PCRP grants W81XWH2010312(to Xin L)+3 种基金W81XWH2010332(to Xin L)an Investigator-Initiated Research Grant from American Institute for Cancer Research(to Xin L),Indiana CTSI pilot grants(to Xin L)through the NIH NCATS CTSA grant ULITR002529an Exceptional Project Award Grant from Breast Cancer Alliance(to Xin L)CCV and IITP grants from Walther Cancer Foundation(to YZ and LD).
文摘Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.
文摘1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.
基金supported by the KRIBB Research Initiative Program(KGM4252122)the National Research Foundation(2018M2A9Hl078340)the National Research Foundation of Korea Grant funded by the Korean Government(NRF-2020R111A3072358).
文摘Glycosylphosphatidylinositol-anchored sperm hyaluronidases have long been believed to assist in sperm penetration through the cumulus-oocyte complex(COC);however,their role in mammalian fertilization remains unclear.Previously,we have shown that hyaluronidase 5(Hyal5)/Hyal7 double-knockout(dKO)mice produce significantly fewer offspring than their wild-type(WT)counterparts because of defective COC dispersal.Male infertility is mainly caused by a low sperm count.It can be further exacerbated by the deficiency of sperm hyaluronidase,which disperses the cumulus cells of the outer layer of the COC.In the current study,we evaluated the effects of a low count of Hyal-deficient sperm and conditions of ovulated oocytes on the fertilization rate using a mouse model.Our results demonstrated that a low sperm count further decreases the in vitro fertilization(IVF)rate of Hyal-deficient dKO spermatozoa.In addition,the dKO spermatozoa resulted in a fertilization rate of 12.5%upon fertilizing COCs with a thick cumulus layer,whereas the IVF rate was comparable to that of WT spermatozoa when oocytes with a thin or no cumulus layer were fertilized.Finally,we proved that the IVF rate of dKO spermatozoa could be recovered by adding rat spermatozoa as a source of sperm hyal.Our results suggest that a deficiency of proteins involved in fertilization,such as sperm hyal,has a vital role in fertilization.
基金funded by the Indiana Clinical and Translational Science Institute and Showalter Trust (to Uma K. Aryal)the Human Resources Program in Energy Technology of the Korea Institute of Energy Technology Evaluation and Planning (20214000000140 (to HeeChang Lim))+2 种基金the National Institutes of Health R35GM147412 (to Jing Liu) and R01AR074473 (to William R. Thompson)the National Natural Science Foundation of China, 81971326 (to Bai-Yan Li)the 100 Voices of Hope (to Hiroki Yokota)。
文摘Bone frequently serves as a metastatic site for breast and prostate cancers. Given the potential of low-intensity vibration(LIV) to increase bone health and reduce cancer risk, this study investigated the impact of LIV on cancer cells, as well as noncancer cells such as lymphocytes and peripheral blood mononuclear cells(PBMCs). The results revealed that LIV exposure not only suppressed cancer cell migration but also triggered the generation of induced tumor-suppressing(iTS) cells. Conditioned medium(CM) derived from LIV-treated PBMCs shrank freshly isolated breast and prostate cancer tissues, and when CM was combined with a chemotherapeutic agent, additional antitumor effects were observed.Notably, iTS cell-derived CM hindered the maturation of the receptor activator of nuclear factor-kappa B ligand(RANKL)-stimulated bone-resorbing osteoclasts while promoting the differentiation of bone-forming osteoblasts. Intriguingly, the anticancer effects induced by LIV were replicated by simply shaking a cell-containing tube with a regular tube shaker. Using mass spectrometry-based proteomics, this study revealed enrichment of tumor-suppressing proteins, including enolase 1, moesin(MSN), and aldolase A(ALDOA), which are commonly found in oncogene-activated iTS cells, in LIV-induced CM. Sad1 and UNC-84 domain containing 1(SUN1), a core component of the linker of the nucleoskeleton and cytoskeleton(LINC) complex, exhibited heightened expression, notably enhancing the response of lymphocytes to LIV. An ex vivo bone cancer model further demonstrated the potent anticancer effects of lymphocyte-derived CM. In conclusion, this study underscores the pivotal role of LIV in preventing bone loss in the tumor microenvironment.
基金supported by the Indiana CTSI Core Pilot Funding(FY24CTSIE)the Startup Funding of JL from the University of Notre Dame(START097S).
文摘The androgen receptor(AR)plays a critical role in the development and progression of prostate cancer by regulating key cellular pro-cesses such as cell proliferation and apoptosis.Although traditional AR-targeted therapies have shown initial success,acquired resis-tance remains a significant clinical challenge,often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency(HRD).Approximately 20%of advanced prostate cancer cases exhibit HRD,resulting in substantial genomic instability and complicating treatment.Fortunately,Food and Drug Administration–approved poly(ADP-ribose)polymerase inhibitors,in-cluding olaparib and rucaparib,exploit synthetic lethality to target prostate cancer with HRD,and additional drugs targeting DNA dam-age response(DDR)proteins are under development.Emerging evidence suggests that AR activity enhances DDR gene expression,with multiple DDR proteins localized near androgen-regulated regions,highlighting a close interaction between AR and DDR pathways.Consequently,recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage,such as radiation therapy,or inhibit DNA repair mechanisms.This review discusses AR's role in cellular processes,the interplay between AR and DDR,and recent advances in prostate cancer treatment strategies.
基金This work was supported by grants from Indiana Center for Technology and Science Innovation(CTSl),USA(No.2286230 to TL)and Indiana Drug Discovery Alliance(IDDA),USA(No.2286233 to TL),both are funded in part by National Institutes of Health,USA(No.UL1TR002529)National Institutes of Health,USA(No.1R01GM120156-01A1 to TL+5 种基金No.R03 CA223906-01 to TL)This work was also supported by National Institutes of Health,USA(No.P41-GM103426 and DP20D007237 to REA),National Science Foundation,USA(No.CHE060073N to REA)National Institutes of Health,USA(No.R01 CA069202 to ZYZ)MLF and MRK were supported by IUSCCC Cancer Center,USA(No.P30 CA082709),National Institutes of Health,USA(No.R01CA167291and R01CA254110).MRK was also supported by National Institutes of Health,USA(No.R01CA205166,R01CA231267,and R01HL140961)MLF was also supported by National Institutes of Health,USA(No.R01CA211098,U01HL143403,and NF180045)MLF and MRK were additionally supported by the Riley Children's Foundation,USA.
文摘Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.
文摘Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment.These plastic cells can transdifferentiate into Tregs during inflammation resolution,in allogenic heart transplantation models,or in cancer through mechanisms that remain poorly understood.Here,we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism.In the absence of NLRP3,Th17 cells produce more inflammatory cytokines(IFNγ,Granzyme B,TNFα)and exhibit reduced immunosuppressive activity toward CD8+cells.Moreover,the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost.Mechanistically,NLRP3 in Th17 cells interacts with the TGF-βreceptor,enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions.Consequently,the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8+T-cell effectiveness,ultimately inhibiting tumor growth.
基金the National Institute of Diabetes and Digestive and Kidney Diseases(R01DK120689,R01DK121925,P30DK097512)the National Institute on Alcohol Abuse and Alcoholism(R01AA028506),the National Institute on Aging(R21AG072288)the National Cancer Institute(P30CA082709 and P30CA023168),the Walther Cancer Foundation and the Ricks Family Foundation.
文摘Background Autophagy is critical for cellular homeostasis.Autophagy related 14(ATG14)is a key regulator of autophagy initiation;however,its role in hepatocyte survival remains poorly understood.This study aimed to investigate the hepatocyte-specific function of ATG14 in vivo.Methods We generated Atg14 hepatocyte-specific knockout(HepKO)mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into Atg14 floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet.Blood and tissue samples were collected for biochemical and histological analyses.Results Atg14 HepKO mice develop severe hepatomegaly under normal dietary conditions.ATG14 deficiency leads to hepatic injury,inflammation and fibrosis.Multiple forms of cell death,including apoptosis and pyroptosis,increase significantly.When challenged with a Western diet for 4 weeks,Atg14 HepKO mice exhibit exacerbated hepatic injury,inflammation and fibrosis despite no significant lipid droplet accumulation in the liver.Transcriptomic analysis reveals upregulation of several cell death pathways,including pyroptosis,apoptosis and necroptosis.Further biochemical and microscopic analyses validate the induction of multiple cell death pathways.In addition,NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in Atg14 HepKO mouse livers and ATG14-deficient hepatocytes.Conclusion Our data suggest that ATG14 is required for maintaining hepatocyte identity,survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly,tissue injury,inflammation and fibrosis.
基金This work was partly supported by the NCI grants(1RO1CA231349,1RO1CA262798)the Brown Center for Immunotherapy at Indiana University Melvin and Bren Simon Comprehensive Cancer Center.
文摘Glioblastoma(GBM)is one of the most immunosuppressive and heterogeneous tumors with limited treatment options.Most studies relied on treatment-experienced patient samples to elucidate the origins of tumor heterogeneity,introducing bias into the analysis.The analysis of samples from multifocal GBM patients,in which independent lesions arise from the same progenitor and undergo parallel evolution,enables the study of the natural evolution of GBM while removing the effect of therapy on the emergence of heterogeneity.This enables the identification of critical events in the evolution of GBM and the unbiased study of subtype progression,diversity,and invasive potential.The tumor microenvironment of GBM undergoes significant changes throughout tumor progression.Recent studies have highlighted the switch from an abundance of resident microglia-derived macrophages in earlier stages to the prevalence of blood-derived macrophages in later stages of GBM.There is conclusive evidence that these alterations cannot be viewed in isolation and that the tumor microenvironment co-evolves with tumor cells during cancer progression.Together with an increasingly hypoxic environment,this culminates in highly immunosuppressive conditions,resulting in a feedback loop further reinforcing evolutionary changes in the tumor.A new study now provides a unique look at the natural evolution of GBM,identifies critical events in its development,and has the potential to help improve the diagnosis and therapy of this deadly disease.
基金supported by National Cancer Institute grants R00CA175189,R01AI155499(both to SHO),R01CA205246(to EAR),R01CA121044(to KPL),T32CA085183(to GAH and MML),and P30CA016056,involving the use of the Roswell Park Comprehensive Cancer Center Flow and Image Cytometry,Genomics,Laboratory Animal,and Immune Analysis Shared Resourcesby the Roswell Park Alliance Foundation.NMR experiments were carried out at the Center for Environmental and Systems Biochemistry Shared Resource Facility funded in part by the Markey Cancer Center(P30CA177558).
文摘Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.
基金supported by The Biomechanics and Bio-materials Research Center at Indiana University-Purdue University Indianapolis,USA(No.2201-01)The NIH/Eunice Kennedy Shriver NICHD,USA(No.P50HD090215)+2 种基金The NIH/NCI Cancer Center Support Grant,USA(No.P30CA082709)The Tyler Trent Cancer Research Endowment for the Riley Hospital for Children IU-Health,USAThe Indiana University Grand ChallengeePrecision Health Initiative,USA.
文摘Cancer cells tend to develop resistance to chemotherapy and enhance aggressive-ness.A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents.Based on this strategy,induced tumor-suppressing cells(iTSCs)have been generated from tumor cells and mesenchymal stem cells.Here,we examined the possi-bility of generating iTSCs from lymphocytes by activating PKA signaling for suppressing the pro-gression of osteosarcoma(OS).While lymphocyte-derived CM did not present anti-tumor capabilities,the activation of PKA converted them into iTSCs.Inhibiting PKA conversely gener-ated tumor-promotive secretomes.In a mouse model,PKA-activated CM suppressed tumorinduced bone destruction.Proteomics analysis revealed that moesin(MSN)and calreticulin(Calr),which are highly expressed intracellular proteins in many cancers,were enriched in PKA-activated CM,and they acted as extracellular tumor suppressors through CD44,CD47,and CD91.The study presented a unique option for cancer treatment by generating iTSCs that secret tumor-suppressive proteins such as MSN and Calr.We envision that identifying these tu-mor suppressors and predicting their binding partners such as CD44,which is an FDA-approved oncogenic target to be inhibited,may contribute to developing targeted protein therapy.
基金This study was partly supported by the National Natural Science Foundation of China(82122069,82073869,30900650,81372501,81572260,81773299,and H2808/82330065)Guangdong Basic and Applied Basic Research Foundation(2021B1515020004,2020B1515120032,2021B1212040017,and 2023B03J0106,China)+1 种基金the Fundamental Research Funds for the Central Universities(23yxqntd001,China)the Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation(2020B1212060034,China).
文摘Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.
