Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming.

Autor:	Thielman NRJ; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Funes V; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Davuluri S; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, MD 21287, USA., Ibanez HE; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Sun WC; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Fu J; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Li K; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China., Muth S; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Pan X; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Fujiwara K; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Surgery, Kimura Hospital and Department of Surgery; Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Dwayne L Thomas Ii; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Henderson M; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Teh SS; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Zhu Q; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Thompson E; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Jaffee EM; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.; Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Cancer Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Kolodkin A; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Meng F; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Shanghai Eye and ENT Hospital, Fudan University, Shanghai 200031, China., Zheng L; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.; Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2024 Oct 18; Vol. 10 (42), pp. eadp0684. Date of Electronic Publication: 2024 Oct 16.
DOI:	10.1126/sciadv.adp0684
Abstrakt:	Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRAS G12D and TP53 R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRAS MUT -dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRAS MUT -dependent manner.
Databáze:	MEDLINE
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