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

被引：2

作者：

Thielman, Noelle R. J. ^{[1
,2
,3
,4
,5
]}

Funes, Vanessa ^{[1
,3
,5
]}

Davuluri, Sanjana ^{[1
,3
,5
,6
]}

Ibanez, Hector E. ^{[1
,3
,5
]}

Sun, Wei-Chih ^{[1
,3
,5
]}

Fu, Juan ^{[1
,3
,5
]}

Li, Keyu ^{[1
,3
,5
,7
]}

Muth, Stephen ^{[1
,3
,5
]}

Pan, Xingyi ^{[1
,3
,4
,5
]}

Fujiwara, Kenji ^{[1
,3
,5
,8
,9
]}

Henderson, Mackenzie ^{[1
,3
,5
]}

Teh, Selina Shiqing ^{[4
,10
]}

Zhu, Qingfeng ^{[1
,3
,5
,10
]}

Thompson, Elizabeth ^{[1
,3
,5
,10
]}

Jaffee, Elizabeth M. ^{[1
,3
,4
,5
,11
,12
,13
]}

Kolodkin, Alex ^{[4
,14
]}

Meng, Fengxi ^{[1
,15
]}

Zheng, Lei ^{[1
,3
,4
,5
,11
,12
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA

[2] Lake Erie Coll Osteopath Med, Erie, PA 16509 USA

[3] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Sch Med, Grad Program Cellular & Mol Med, Baltimore, MD 21287 USA

[5] Johns Hopkins Univ, Sch Med, Pancreat Canc Precis Med Program, Baltimore, MD 21287 USA

[6] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Sch Publ Hlth, Baltimore, MD 21287 USA

[7] Sichuan Univ, West China Hosp, Dept Gen Surg, Div Pancreat Surg, Chengdu, Sichuan, Peoples R China

[8] Kyushu Univ, Kimura Hosp, Dept Surg, Fukuoka, Japan

[9] Kyushu Univ, Grad Sch Med Sci, Dept Surg, Oncol, Fukuoka, Japan

[10] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA

[11] Johns Hopkins Univ, Sch Med, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD 21231 USA

[12] Johns Hopkins Univ, Skip Viragh Ctr Pancreat Canc, Sch Med, Baltimore, MD 21287 USA

[13] Johns Hopkins Univ, Canc Convergence Inst, Sch Med, Baltimore, MD 21231 USA

[14] Johns Hopkins Univ, Kavli Neurosci Discovery Inst, Dept Neurosci, Sch Med, Baltimore, MD 21287 USA

[15] Fudan Univ, Shanghai Eye & ENT Hosp, Shanghai 200031, Peoples R China

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 42期

基金：

日本学术振兴会;

关键词：

TUMOR-ASSOCIATED MACROPHAGES; PERINEURAL INVASION; CANCER; EXPRESSION; PROLIFERATION; COOPERATE; GROWTH; KRAS;

D O I：

10.1126/sciadv.adp0684

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

共 61 条

[61] Tyrosine 23 Phosphorylation-Dependent Cell-Surface Localization of Annexin A2 Is Required for Invasion and Metastases of Pancreatic Cancer [J].

Zheng, Lei ;

Foley, Kelly ;

Huang, Lanqing ;

Leubner, Ashley ;

Mo, Guanglan ;

Olino, Kelly ;

Edil, Barish H. ;

Mizuma, Masamichi ;

Sharma, Rajni ;

Le, Dung T. ;

Anders, Robert A. ;

Illei, Peter B. ;

Van Eyk, Jennifer E. ;

Maitra, Anirban ;

Laheru, Daniel ;

Jaffee, Elizabeth M. .

PLOS ONE, 2011, 6 (04)

← 1 2 3 4 5 6 7 →