Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming
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<sup>G12D</sup> and TP53<sup>R172H</sup> 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<sup>MUT</sup>-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<sup>MUT</sup>-dependent manner.
Authors
- Qingfeng Zhu (ORCID: https://orcid.org/0000-0001-7871-3359)
- Dwayne L. Thomas (ORCID: https://orcid.org/0000-0003-2069-310X)
- Wei‐Chih Sun (ORCID: https://orcid.org/0000-0001-8117-0359)
- Alex L. Kolodkin (ORCID: https://orcid.org/0000-0001-7562-5513)
- Stephen Q. Muth
- MacKenzie Henderson (ORCID: https://orcid.org/0000-0001-5596-1798)
- Juan Fu
- Elizabeth M. Jaffee (ORCID: https://orcid.org/0000-0003-3841-6549)
- Sanjana Davuluri (ORCID: https://orcid.org/0009-0003-4955-3255)
- Kenji Fujiwara (ORCID: https://orcid.org/0000-0001-5900-9382)
- Fengxi Meng (ORCID: https://orcid.org/0000-0002-1742-3283)
- Noelle R. J. Thielman
- Keyu Li (ORCID: https://orcid.org/0000-0002-4547-4918)
- Elizabeth D. Thompson (ORCID: https://orcid.org/0000-0003-4633-843X)
- Selina Shiqing K. Teh (ORCID: https://orcid.org/0000-0002-5281-1978)
- Lei Zheng (ORCID: https://orcid.org/0000-0003-4163-2541)
- Hector E. Ibanez (ORCID: https://orcid.org/0000-0002-8170-4127)
- Xingyi Pan
- Vanessa Funes (ORCID: https://orcid.org/0009-0002-1033-5552)
Institutions
- Bloomberg (United States) (US)
- Kyushu University (JP)
- Johns Hopkins University (US)
- Lake Erie College of Osteopathic Medicine (US)
- Sichuan University (CN)
- Discovery Institute (US)
- Johns Hopkins Medicine (US)
- West China Hospital of Sichuan University (CN)
- Kyushu University Hospital (JP)
- Eye & ENT Hospital of Fudan University (CN)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1126/sciadv.adp0684
- Citations
- 15
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.02
Funders
- Sidney Kimmel Comprehensive Cancer Center
- Japan Society for the Promotion of Science