Noelle R Jurcak1, Agnieszka A Rucki2, Stephen Muth3, Elizabeth Thompson4, Rajni Sharma5, Ding Ding3, Qingfeng Zhu5, James R Eshleman4, Robert A Anders6, Elizabeth M Jaffee7, Kenji Fujiwara8, Lei Zheng9. 1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland. 2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 3. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland. 4. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 5. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland. 7. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland; Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, Maryland. 8. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, Maryland; JSPS Overseas Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan. 9. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: lzheng6@jhmi.edu.
Abstract
BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
Authors: Phillip Jobling; Jay Pundavela; Sonia M R Oliveira; Séverine Roselli; Marjorie M Walker; Hubert Hondermarck Journal: Cancer Res Date: 2015-03-20 Impact factor: 12.701
Authors: Andrew V Biankin; Nicola Waddell; Karin S Kassahn; Marie-Claude Gingras; Lakshmi B Muthuswamy; Amber L Johns; David K Miller; Peter J Wilson; Ann-Marie Patch; Jianmin Wu; David K Chang; Mark J Cowley; Brooke B Gardiner; Sarah Song; Ivon Harliwong; Senel Idrisoglu; Craig Nourse; Ehsan Nourbakhsh; Suzanne Manning; Shivangi Wani; Milena Gongora; Marina Pajic; Christopher J Scarlett; Anthony J Gill; Andreia V Pinho; Ilse Rooman; Matthew Anderson; Oliver Holmes; Conrad Leonard; Darrin Taylor; Scott Wood; Qinying Xu; Katia Nones; J Lynn Fink; Angelika Christ; Tim Bruxner; Nicole Cloonan; Gabriel Kolle; Felicity Newell; Mark Pinese; R Scott Mead; Jeremy L Humphris; Warren Kaplan; Marc D Jones; Emily K Colvin; Adnan M Nagrial; Emily S Humphrey; Angela Chou; Venessa T Chin; Lorraine A Chantrill; Amanda Mawson; Jaswinder S Samra; James G Kench; Jessica A Lovell; Roger J Daly; Neil D Merrett; Christopher Toon; Krishna Epari; Nam Q Nguyen; Andrew Barbour; Nikolajs Zeps; Nipun Kakkar; Fengmei Zhao; Yuan Qing Wu; Min Wang; Donna M Muzny; William E Fisher; F Charles Brunicardi; Sally E Hodges; Jeffrey G Reid; Jennifer Drummond; Kyle Chang; Yi Han; Lora R Lewis; Huyen Dinh; Christian J Buhay; Timothy Beck; Lee Timms; Michelle Sam; Kimberly Begley; Andrew Brown; Deepa Pai; Ami Panchal; Nicholas Buchner; Richard De Borja; Robert E Denroche; Christina K Yung; Stefano Serra; Nicole Onetto; Debabrata Mukhopadhyay; Ming-Sound Tsao; Patricia A Shaw; Gloria M Petersen; Steven Gallinger; Ralph H Hruban; Anirban Maitra; Christine A Iacobuzio-Donahue; Richard D Schulick; Christopher L Wolfgang; Richard A Morgan; Rita T Lawlor; Paola Capelli; Vincenzo Corbo; Maria Scardoni; Giampaolo Tortora; Margaret A Tempero; Karen M Mann; Nancy A Jenkins; Pedro A Perez-Mancera; David J Adams; David A Largaespada; Lodewyk F A Wessels; Alistair G Rust; Lincoln D Stein; David A Tuveson; Neal G Copeland; Elizabeth A Musgrove; Aldo Scarpa; James R Eshleman; Thomas J Hudson; Robert L Sutherland; David A Wheeler; John V Pearson; John D McPherson; Richard A Gibbs; Sean M Grimmond Journal: Nature Date: 2012-10-24 Impact factor: 49.962
Authors: Knut Ketterer; Shyam Rao; Helmut Friess; John Weiss; Markus W Büchler; Murray Korc Journal: Clin Cancer Res Date: 2003-11-01 Impact factor: 12.531
Authors: Lei Zheng; Kelly Foley; Lanqing Huang; Ashley Leubner; Guanglan Mo; Kelly Olino; Barish H Edil; Masamichi Mizuma; Rajni Sharma; Dung T Le; Robert A Anders; Peter B Illei; Jennifer E Van Eyk; Anirban Maitra; Daniel Laheru; Elizabeth M Jaffee Journal: PLoS One Date: 2011-04-29 Impact factor: 3.240
Authors: Diana D Shi; Jimmy A Guo; Hannah I Hoffman; Jennifer Su; Mari Mino-Kenudson; Jaimie L Barth; Jason M Schenkel; Jay S Loeffler; Helen A Shih; Theodore S Hong; Jennifer Y Wo; Andrew J Aguirre; Tyler Jacks; Lei Zheng; Patrick Y Wen; Timothy C Wang; William L Hwang Journal: Lancet Oncol Date: 2022-02 Impact factor: 54.433