Your browser doesn't support javascript.
loading
ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures.
Li, Jiaoduan; Cao, Dongyan; Jiang, Lixin; Zheng, Yiwen; Shao, Siyuan; Zhuang, Ai; Xiang, Dongxi.
Afiliação
  • Li J; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.
  • Cao D; Department of Biliary-Pancreatic Surgery, the Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • Jiang L; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.
  • Zheng Y; Department of Biliary-Pancreatic Surgery, the Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • Shao S; Department of Ultrasound, the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • Zhuang A; Department of Ultrasound, the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • Xiang D; Shanghai OneTar Biomedicine, Shanghai, China.
Cell Oncol (Dordr) ; 47(3): 951-965, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38150154
ABSTRACT

PURPOSE:

Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, but the mechanism behind BAP1 deficiency driving UM metastasis is unknown.

METHODS:

We analyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations (MUTs) to reveal inter- and intra-tumor heterogeneity among different groups. Then, an immune-competent mouse liver metastatic model was used to explore the role of ITGB2-ICAM1 in BAP1-associated UM metastasis.

RESULTS:

Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1A, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8+ T cells and GDF15hiATF3hiCDKN1Ahi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM1 was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, CAV2, ENO1, PGK1, LOXL2, ITGA5, and VCAN. etc.

CONCLUSION:

This study suggested that the ITGB2-ICAM1 axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures, which provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Uveais / Proteínas Supressoras de Tumor / Ubiquitina Tiolesterase / Neoplasias Hepáticas / Melanoma / Mutação Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Uveais / Proteínas Supressoras de Tumor / Ubiquitina Tiolesterase / Neoplasias Hepáticas / Melanoma / Mutação Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article