title: The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer.
abstract: Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non-small cell lung cancer (NSCLC) cell lines, transforming growth factor-β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)-induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus-interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to-mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFβ and correlated with tumor progression in patients.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gemmill
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nasarre
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Nair-Menon
authors.affiliation: Azienda Unità Sanitaria Locale della Romagna, Ravenna 48100, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile di Livorno, Viale Alfieri 36, Leghorn 57100, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Landi
authors.affiliation: Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile di Livorno, Viale Alfieri 36, Leghorn 57100, Italy.
authors.forename: Armida
authors.initials: A
authors.lastname: D'Incecco
authors.affiliation: Division of Thoracic Surgery, Kanazawa Medical University, 1-1 Daigaku, Uchinada 920-0293, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.affiliation: Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Armeson
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. drabkin@musc.edu.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Drabkin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D039943:Neuropilin-2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D039943:Neuropilin-2; D016212:Transforming Growth Factor beta; C581308:neuropilin-2, human