2. Academic Validation
  3. CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway

CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway

  • Cancer Commun (Lond). 2023 Nov;43(11):1244-1266. doi: 10.1002/cac2.12495.
Jiewen Chen 1 2 3,  Qingji Xu 4 5,  Dan Liu 4,  Xun Li 1 2,  Mingyan Guo 6,  Xuehui Chen 4,  Jianyou Liao 1,  Rong Lei 1 2,  Wende Li 7,  Hongyan Huang 8,  Phei Er Saw 1,  Erwei Song 1 2,  Xiyun Yan 4 5 9,  Yan Nie 1 2
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
  • 2 Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
  • 3 Department of Breast Medicine, Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong, P. R. China.
  • 4 Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China.
  • 5 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P. R. China.
  • 6 Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
  • 7 Guangdong Laboratory Animal Monitoring Institute, Guangdong Key Laboratory of Laboratory Animal, Guangzhou, Guangdong, P. R. China.
  • 8 Department of Breast Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China.
  • 9 Joint Laboratory of Nanozymes in Zhengzhou University, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P. R. China.
PMID: 37856423 DOI: 10.1002/cac2.12495
Abstract

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 the α-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.

Keywords

CD146; DCBLD2; PI3K/AKT signaling pathway; phyllodes tumor of breast; tumor target.

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