Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases...Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.展开更多
Plasma fibrinogen(F1)and fibronectin(pFN)polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing.About 90%of plasma F1 has a homodimeric pair ofγchains(γγF1),and 10%has a...Plasma fibrinogen(F1)and fibronectin(pFN)polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing.About 90%of plasma F1 has a homodimeric pair ofγchains(γγF1),and 10%has a heterodimeric pair ofγand more acidicγ′chains(γγ′F1).We have synthesized a novel fibrin matrix exclusively from a 1:1(molar ratio)complex ofγγ′F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII(rFXIIIa).In this matrix,the fibrin nanofibers were decorated with pFN nanoclusters(termedγγ′F1:pFN fibrin).In contrast,fibrin made from 1:1 mixture ofγγF1 and pFN formed a sporadic distribution of“pFN droplets”(termedγγF1+pFN fibrin).Theγγ′F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells(HUVECs)relative to theγγF1+FN fibrin.Three dimensional(3D)culturing showed that theγγ′F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human fibroblasts.HUVECs in the 3Dγγ′F1:pFN fibrin exhibited a starkly enhanced vascular morphogenesis while an apoptotic growth profile was observed in theγγF1+pFN fibrin.Relative toγγF1+pFN fibrin,mouse dermal wounds that were sealed byγγ′F1:pFN fibrin exhibited accelerated and enhanced healing.This study suggests that a 3D pFN presentation on a fibrin matrix promotes wound healing.展开更多
The recent report by Slabicki et al.in Nature used an array of techniques including cryo-electron microscopy to elucidate the mechanism of action of BI-3802,a molecular glue.1 The discovery of small molecules that hig...The recent report by Slabicki et al.in Nature used an array of techniques including cryo-electron microscopy to elucidate the mechanism of action of BI-3802,a molecular glue.1 The discovery of small molecules that highjack cellular quality control machinery to selectively degrade proteins has generated considerable excitement in the drug discovery community,particularly toward targets often deemed"undruggable".Whether its proteolysis targeting chimeras(PROTACs),consisting of heterobifunctional molecules connected by a linker that facilitates the recruitment of an E3 ligase to the protein of interest(POI)or small molecules that function as molecular glues2 to induce a novel interaction between an E3 ligase and the POI,the ultimate goal is to tag the POI for destruction in cells.PROTAC design is relatively straight forward,wherein a POI binding small molecule,and an E3 ligase binding ligand are connected through a linker that enables stable ternary complex formation(POI:PROTAC:E3 ligase)followed by POI degradation.展开更多
基金supported by grants from the National Institutes of Health (NIH) U01 CA185148, DOD W81XWH-18-10308 (SKB), DOD W81XWH-21-1-0640 (JAS), and R01 CA218545, R01 CA241752 (MWN)
文摘Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.
基金supported by the National Cancer Institute/the National Institute of Health(1R01CA197976,1R01CA201500)Vincent Memorial Hospital Foundation+6 种基金the Vincent Center for Reproductive Biologythe Olson Center for Women’s HealthUniversity of Nebraska Medical Center Graduate Studies Fellowshipthe Fred&Pamela Buffett Cancer Center(LB595)Colleen’s Dream FoundationMarsha Rivkin Center for Ovarian Cancer Research(the Barbara Learned Bridge Funding Award)the Co BRE grant from the Nebraska Center for Cellular Signaling/the National Institute of General Medical Science/the National Institute of Health(5P30GM106397)。
基金supported by the University of Nebraska Research Initiative 2018–2019(YL and WV)the University of Nebraska-Lincoln start-up(YL)+3 种基金the Nebraska DHHS Stem Cell Grant 2019(YL and WV)the U.S.Army GRANT10824516(WV)the Department of Defense,USA,W81XWH-BAA-11-1(WV)This study was financed in part by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior–Brasil(CAPES)–Finance Code 88882.434714/2019–01(EPA and LAV)。
文摘Plasma fibrinogen(F1)and fibronectin(pFN)polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing.About 90%of plasma F1 has a homodimeric pair ofγchains(γγF1),and 10%has a heterodimeric pair ofγand more acidicγ′chains(γγ′F1).We have synthesized a novel fibrin matrix exclusively from a 1:1(molar ratio)complex ofγγ′F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII(rFXIIIa).In this matrix,the fibrin nanofibers were decorated with pFN nanoclusters(termedγγ′F1:pFN fibrin).In contrast,fibrin made from 1:1 mixture ofγγF1 and pFN formed a sporadic distribution of“pFN droplets”(termedγγF1+pFN fibrin).Theγγ′F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells(HUVECs)relative to theγγF1+FN fibrin.Three dimensional(3D)culturing showed that theγγ′F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human fibroblasts.HUVECs in the 3Dγγ′F1:pFN fibrin exhibited a starkly enhanced vascular morphogenesis while an apoptotic growth profile was observed in theγγF1+pFN fibrin.Relative toγγF1+pFN fibrin,mouse dermal wounds that were sealed byγγ′F1:pFN fibrin exhibited accelerated and enhanced healing.This study suggests that a 3D pFN presentation on a fibrin matrix promotes wound healing.
文摘The recent report by Slabicki et al.in Nature used an array of techniques including cryo-electron microscopy to elucidate the mechanism of action of BI-3802,a molecular glue.1 The discovery of small molecules that highjack cellular quality control machinery to selectively degrade proteins has generated considerable excitement in the drug discovery community,particularly toward targets often deemed"undruggable".Whether its proteolysis targeting chimeras(PROTACs),consisting of heterobifunctional molecules connected by a linker that facilitates the recruitment of an E3 ligase to the protein of interest(POI)or small molecules that function as molecular glues2 to induce a novel interaction between an E3 ligase and the POI,the ultimate goal is to tag the POI for destruction in cells.PROTAC design is relatively straight forward,wherein a POI binding small molecule,and an E3 ligase binding ligand are connected through a linker that enables stable ternary complex formation(POI:PROTAC:E3 ligase)followed by POI degradation.
