Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling

• Published in: International Journal of Obesity Vol. 42; no. 3; pp. 334 - 343
• Main Authors: Carbone, C, Piro, G, Gaianigo, N, Ligorio, F, Santoro, R, Merz, V, Simionato, F, Zecchetto, C, Falco, G, Conti, G, Kamga, P T, Krampera, M, Di Nicolantonio, F, De Franceschi, L, Scarpa, A, Tortora, G, Melisi, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2018; Nature Publishing Group
• Subjects: 13/1; 38/39; 631/443/319/1642/393; 631/67/1504; 631/80/84/2176; 692/308/575; 692/698/690/2816; 692/699/67/1504/1713; 82/51; 82/80; 96/95; Adipocytes; Adipocytes - cytology; Aggressiveness; Biomarkers; Bone marrow; Cancer; Care and treatment; Cell Line; Cell Nucleus - metabolism; Conditioning; Development and progression; Epidemiology; Epithelial-Mesenchymal Transition - genetics; Frizzled protein; Gene expression; Genetic aspects; Genetic transformation; Genotypes; Health aspects; Health Promotion and Disease Prevention; Humans; Internal Medicine; Lesions; Medicine; Medicine & Public Health; Mesenchymal Stem Cells; Mesenchyme; Metabolic Diseases; Models, Biological; Modulators; Monoclonal antibodies; Nuclear transport; Obesity; Original; original-article; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Paracrine signalling; Phenotypes; Protein-tyrosine kinase receptors; Public Health; Receptor Tyrosine Kinase-like Orphan Receptors - genetics; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism; Signal transduction; Signal Transduction - genetics; Stromal cells; Translocation; Tyrosine; Wnt protein; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 0307-0565; 1476-5497; 1476-5497
• DOI: 10.1038/ijo.2017.285

Background: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. Methods: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS), Results: We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO CM ) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSC CM ) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPO CM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. Conclusions: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.