Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mec...Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression,and to identify a novel prognosis marker and treatment target of breast malignant PTs.Methods The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing(scRNA-seq),immunostaining,real-time PCR and other methodologies.Functional experiments including proliferation assay,colony formation assay,transwell assay,and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs.The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft(PDX)model.Transcriptome sequencing,proteomic analysis,co-immunoprecipitation,and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism.Results In this study,the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in theα-SMA+fibroblast subset.Furthermore,a progressive elevation in the level of CD146 was observed with the malignant progression of PTs.More importantly,CD146 was found to serve as an independent predictor for recurrence in PT patients.Furthermore,CD146 was found to augment the viability and invasion of PTs.Mechanistically,CD146 acted as a protective“shield”to prevent the degradation of Discoidin,CUB,and LCCL domain-containing protein 2(DCBLD2),thereby activating the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and enhancing malignant behaviors of PT cells.In the malignant PT organoid and PDX model,a significant suppression of malignant PT growth was observed after the application of AA98.Conclusions These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs.The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.展开更多
Phyllodes tumor is a rare breast tumor. A 45-year-old woman who underwent left mastectomy 12 years ago was found to have infiltrates in both lungs in a health examination. Combining histological examinations of the lu...Phyllodes tumor is a rare breast tumor. A 45-year-old woman who underwent left mastectomy 12 years ago was found to have infiltrates in both lungs in a health examination. Combining histological examinations of the lung and breast samples the diagnosis of borderline phyllodes tumor metastases to the lung was made. It is the longest interval to our knowledge that the metastases occurred 12 years after primary phyllodes tumor.展开更多
Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant behavior.Long non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely...Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant behavior.Long non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely unexplored.In this study,microarray was leveraged for the first time to investigate the role of lncRNA in PT.We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT,and its overexpression endowed PT with high tumor grade and adverse prognosis.Furthermore,we elucidated that ZFPM2-AS1 promotes the proliferation,migration,and invasion of malignant PT in vitro.Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft(PDX)model could effectively inhibit tumor progression in vivo.Mechanistically,our findings showed that ZFPM2-AS1 is competitively bound to CDC42,inhibiting ACK1 and STAT1 activation,thereby launching the transcription of TNFRSF19.In conclusion,our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT,and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.展开更多
基金Natural Science Foundation of China.Grant Numbers:82173054,81621004,81720108029,82002782 Basic and Applied Basic Research Foundation of Guangdong Province.Grant Number:2022A1515110069 Strategic Priority Research Program of Chinese Academy of Sciences.Grant Number:XDB29040100 Guangdong Science and Technology Department.Grant Number:2022B1515020048 Clinical Innovation Research Program of Bioland Laboratory.Grant Number:2018GZR0201004 Guangzhou Science Technology and Innovation Commission.Grant Number:202102010148 Bureau of Science and Technology of Guangzhou.Grant Number:20212200003 Program for Guangdong Introducing Innovative and Enterpreneurial Teams.Grant Number:2019BT02Y198。
文摘Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression,and to identify a novel prognosis marker and treatment target of breast malignant PTs.Methods The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing(scRNA-seq),immunostaining,real-time PCR and other methodologies.Functional experiments including proliferation assay,colony formation assay,transwell assay,and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs.The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft(PDX)model.Transcriptome sequencing,proteomic analysis,co-immunoprecipitation,and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism.Results In this study,the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in theα-SMA+fibroblast subset.Furthermore,a progressive elevation in the level of CD146 was observed with the malignant progression of PTs.More importantly,CD146 was found to serve as an independent predictor for recurrence in PT patients.Furthermore,CD146 was found to augment the viability and invasion of PTs.Mechanistically,CD146 acted as a protective“shield”to prevent the degradation of Discoidin,CUB,and LCCL domain-containing protein 2(DCBLD2),thereby activating the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and enhancing malignant behaviors of PT cells.In the malignant PT organoid and PDX model,a significant suppression of malignant PT growth was observed after the application of AA98.Conclusions These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs.The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.
文摘Phyllodes tumor is a rare breast tumor. A 45-year-old woman who underwent left mastectomy 12 years ago was found to have infiltrates in both lungs in a health examination. Combining histological examinations of the lung and breast samples the diagnosis of borderline phyllodes tumor metastases to the lung was made. It is the longest interval to our knowledge that the metastases occurred 12 years after primary phyllodes tumor.
基金supported by the National Natural Science Foundation of China(82173054,82222029,82203085)the Guangdong Basic and Applied Basic Research Foundation(2022B1515020048,2022B1515020101,China)Guangzhou Science,Technology and Innovation Commission(202102010148,China).
文摘Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant behavior.Long non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely unexplored.In this study,microarray was leveraged for the first time to investigate the role of lncRNA in PT.We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT,and its overexpression endowed PT with high tumor grade and adverse prognosis.Furthermore,we elucidated that ZFPM2-AS1 promotes the proliferation,migration,and invasion of malignant PT in vitro.Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft(PDX)model could effectively inhibit tumor progression in vivo.Mechanistically,our findings showed that ZFPM2-AS1 is competitively bound to CDC42,inhibiting ACK1 and STAT1 activation,thereby launching the transcription of TNFRSF19.In conclusion,our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT,and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.