机构：[1]Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[2]Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA.[3]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[4]Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[5]Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[6]Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, MD 21287, USA.[7]Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[8]Department of Surgery, Kimura Hospital and Department of Surgery, Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.[9]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[10]Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.[11]Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[12]Cancer Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.[13]Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[14]Shanghai Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
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 KRASG12D and TP53R172H 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 KRASMUT-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 KRASMUT-dependent manner.
基金：
Funding was obtained from the following grants: NIH grant R01 CA169702 (L.Z.), NIH grant R01
CA197296 (L.Z.), Sidney Kimmel Comprehensive Cancer Center Support Grant P30 CA006973
(L.Z.), and JSPS Overseas Research Fellow, Japan Society for the Promotion of Science (K.F.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
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小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[2]Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA.[3]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[4]Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[5]Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
通讯作者：
通讯机构：[1]Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[3]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[4]Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[5]Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.[10]Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.[11]Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
推荐引用方式(GB/T 7714)：
Thielman Noelle R J,Funes Vanessa,Davuluri Sanjana,et al.Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming[J].Science Advances.2024,10(42):eadp0684.doi:10.1126/sciadv.adp0684.
APA：
Thielman Noelle R J,Funes Vanessa,Davuluri Sanjana,Ibanez Hector E,Sun Wei-Chih...&Zheng Lei.(2024).Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming.Science Advances,10,(42)
MLA：
Thielman Noelle R J,et al."Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming".Science Advances 10..42(2024):eadp0684
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