Doxorubicin(DOx)is the most effective chemotherapeutic for breast cancer,but it is usually associated with severe cardiotoxicity.Further investigation to alleviate its side effects is essential.The present study inves...Doxorubicin(DOx)is the most effective chemotherapeutic for breast cancer,but it is usually associated with severe cardiotoxicity.Further investigation to alleviate its side effects is essential.The present study investigated the mechanism of the cross-organ communication between tumors and the heart and potential intervention targets.Morphological bubble-like protrusions were observed in both adult murine ventricular cardiomyocytes(AMvCs)and human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)cocultured with breast cancer cells(BCCs),along with elevated expression of pyroptosis-related proteins.Exosomes(EXOs)from DOX-treated BCCs aggravated DOX-induced cardiotoxicity(DOXIC)in an orthotopic mouse model of breast cancer.Blocking miRNAs by knocking down Rab27a or inhibiting the release of EXOs in cancer tissue by Dicer enzyme knockout attenuated this additional injury effect.Exosomal miRNA sequencing revealed that miR-216a-5p is especially upregulated in EXOs from DOX-induced BCCs.Mechanistically,miR-216a-5p was upregulated by enhanced transcription mediated by DOXinduced AMP-dependent transcription factor 3(ATF3)and packaged into EXOs by splicing factor 3b subunit 4(SF3B4)in BCCs.Itchy E3 ubiquitin-protein ligase(ITCH)was identified as a novel downstream target mRNA of miR-216a-5p.ITCH negatively mediated thioredoxin-interacting protein(TXNIP)ubiquitination to activate the NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)inflammasome pathway,ultimately leading to cardiomyocyte pyroptosis.Our findings revealed novel cross-organ pathogenic communication between breast cancer and the heart through the exosomal miR-216a-5p-mediated ITCH/TXNIP/NLRP3 pathway,which drives cardiomyocyte pyroptosis.These findings suggest that targeting myocardial miR-216a-5p or blocking harmful EXOs from breast cancer is a potential therapeutic strategy for alleviating DOXIC.展开更多
Substantial evidence has shown that immune-adjuvant effects associated with stimulator of interferon genes(STING)agonism play crucial roles in cancer vaccination via initiating innate immunity and priming adaptive imm...Substantial evidence has shown that immune-adjuvant effects associated with stimulator of interferon genes(STING)agonism play crucial roles in cancer vaccination via initiating innate immunity and priming adaptive immunity[1].STING binds cyclic dinucleotides(CDNs)in response to cytosolic DNA and its scaffolding function rapidly induces tank-binding kinase 1(TBK1)-interferon regulatory factor 3(IRF3)-dependent production of downstream type I interferon(IFN)and proinflammatory cytokines[2].We demonstrated a universally higher expression level of STING in pancreatic adenocarcinomas compared with normal tissues from surgical specimens,which was coordinated with the public bioinformatic data retrieved from the GEPIA website(Fig.S1 online),encouraging that STING agonists are efficient to regulate immune responses in pancreatic cancers with abundant targets.STINGstimulating therapeutics can be constructed by co-administrating adjuvants(small-molecule agonists),or by directly optimizing vaccine carriers.Of recent attention are several polymers activating the STING signaling pathway[3-5].Highly-branched poly(bamino esters)(hPBAE)is a promising nucleic acid delivery vehicle,the multiple terminal groups of which could be further modified with various end-capping amine groups,making it a highly flexible and tailorable nanoplatform[6,7].We have synthesized a series of hPBAE polymers modified with various end caps.Intriguingly,we identified a lead hPBAE candidate that possessed satisfactory mRNA translation efficiency and the highest immunogenicity via STING agonism.展开更多
基金supported by the National Key Research and Development Plan(2022YFA1104500,2022YFC3602400,2022YFA1104704)the National Nature Science Foundation of China(82470366,82270380,82470379)+2 种基金Beijing Natural Science Foundation(7232159)Beijing Nova Program(Z211100002121048)the Joint Fundof Beijing Natural Science Foundation(L241026).
文摘Doxorubicin(DOx)is the most effective chemotherapeutic for breast cancer,but it is usually associated with severe cardiotoxicity.Further investigation to alleviate its side effects is essential.The present study investigated the mechanism of the cross-organ communication between tumors and the heart and potential intervention targets.Morphological bubble-like protrusions were observed in both adult murine ventricular cardiomyocytes(AMvCs)and human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)cocultured with breast cancer cells(BCCs),along with elevated expression of pyroptosis-related proteins.Exosomes(EXOs)from DOX-treated BCCs aggravated DOX-induced cardiotoxicity(DOXIC)in an orthotopic mouse model of breast cancer.Blocking miRNAs by knocking down Rab27a or inhibiting the release of EXOs in cancer tissue by Dicer enzyme knockout attenuated this additional injury effect.Exosomal miRNA sequencing revealed that miR-216a-5p is especially upregulated in EXOs from DOX-induced BCCs.Mechanistically,miR-216a-5p was upregulated by enhanced transcription mediated by DOXinduced AMP-dependent transcription factor 3(ATF3)and packaged into EXOs by splicing factor 3b subunit 4(SF3B4)in BCCs.Itchy E3 ubiquitin-protein ligase(ITCH)was identified as a novel downstream target mRNA of miR-216a-5p.ITCH negatively mediated thioredoxin-interacting protein(TXNIP)ubiquitination to activate the NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)inflammasome pathway,ultimately leading to cardiomyocyte pyroptosis.Our findings revealed novel cross-organ pathogenic communication between breast cancer and the heart through the exosomal miR-216a-5p-mediated ITCH/TXNIP/NLRP3 pathway,which drives cardiomyocyte pyroptosis.These findings suggest that targeting myocardial miR-216a-5p or blocking harmful EXOs from breast cancer is a potential therapeutic strategy for alleviating DOXIC.
基金supported by the National Natural Science Foundation of China(U20A20378,82100645,32301165,82188102,and 2273488)the Natural Science Foundation of Zhejiang Province(LY22E030009 and LQ20H160039)the China National Postdoctoral Program for Innovative Talents(BX20230312)。
文摘Substantial evidence has shown that immune-adjuvant effects associated with stimulator of interferon genes(STING)agonism play crucial roles in cancer vaccination via initiating innate immunity and priming adaptive immunity[1].STING binds cyclic dinucleotides(CDNs)in response to cytosolic DNA and its scaffolding function rapidly induces tank-binding kinase 1(TBK1)-interferon regulatory factor 3(IRF3)-dependent production of downstream type I interferon(IFN)and proinflammatory cytokines[2].We demonstrated a universally higher expression level of STING in pancreatic adenocarcinomas compared with normal tissues from surgical specimens,which was coordinated with the public bioinformatic data retrieved from the GEPIA website(Fig.S1 online),encouraging that STING agonists are efficient to regulate immune responses in pancreatic cancers with abundant targets.STINGstimulating therapeutics can be constructed by co-administrating adjuvants(small-molecule agonists),or by directly optimizing vaccine carriers.Of recent attention are several polymers activating the STING signaling pathway[3-5].Highly-branched poly(bamino esters)(hPBAE)is a promising nucleic acid delivery vehicle,the multiple terminal groups of which could be further modified with various end-capping amine groups,making it a highly flexible and tailorable nanoplatform[6,7].We have synthesized a series of hPBAE polymers modified with various end caps.Intriguingly,we identified a lead hPBAE candidate that possessed satisfactory mRNA translation efficiency and the highest immunogenicity via STING agonism.
