CD146 was originally identified as a melanoma cell adhesion molecule(MCAM)and highly expressed in many tumors and endothelial cells.However,the evidence that CD146 acts as an adhesion molecule to mediate a homophilic ...CD146 was originally identified as a melanoma cell adhesion molecule(MCAM)and highly expressed in many tumors and endothelial cells.However,the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking.Recent evidence revealed that CD146 is not merely an adhesion molecule,but also a cellular surface receptor of miscellaneous ligands,including some growth factors and extracellular matrixes.Through the bidirectional interactions with its ligands,CD146 is actively involved in numerous physiological and pathological processes of cells.Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers,especially vascular and lymphatic metastasis.Thus,immunotherapy against CD146 would provide a promising strategy to inhibit metastasis,which accounts for the majority of cancer-associated deaths.Therefore,to deepen the understanding of CD146,we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.展开更多
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
基金supported by the following grants:the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(No.2018ZX10101004002004)the National Natural Science Foundation of China(No.31770793)the Beijing Municipal Natural Science Foundation,China(No.7192123).
文摘CD146 was originally identified as a melanoma cell adhesion molecule(MCAM)and highly expressed in many tumors and endothelial cells.However,the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking.Recent evidence revealed that CD146 is not merely an adhesion molecule,but also a cellular surface receptor of miscellaneous ligands,including some growth factors and extracellular matrixes.Through the bidirectional interactions with its ligands,CD146 is actively involved in numerous physiological and pathological processes of cells.Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers,especially vascular and lymphatic metastasis.Thus,immunotherapy against CD146 would provide a promising strategy to inhibit metastasis,which accounts for the majority of cancer-associated deaths.Therefore,to deepen the understanding of CD146,we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.
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.
