Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2
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gc
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male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.

AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation

Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifunctional protein 1(AIMP1)participates in several steps during cancer development and osteoclast differentiation.This study aimed to explore its role in MM.Methods:The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis.Enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting were used to detect AIMP1 expression.Protein chip analysis,RNA-sequencing,and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1.The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay in vitro and a xenograft model in vivo.Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro.A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.Results:AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes.Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase(MAPK)signaling pathway.Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A(ANP32A)to regulate histone H3 acetylation.In addition,AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2(GAREM2)to increase the phosphorylation of extracellular-regulated kinase 1/2(p-ERK1/2).Furthermore,AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1(NFATc1)in vitro.In contrast,exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Conclusions:Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM,which accelerates MM malignancy via activation of the MAPK signaling pathway.