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

C. Carbone, G. Piro, N. Gaianigo, F. Ligorio, R. Santoro, V. Merz, F. Simionato, C. Zecchetto, G. Falco, G. Conti, P. T. Kamga, M. Krampera, F. Di Nicolantonio, L. De Franceschi, A. Scarpa, G. Tortora, D. Melisi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)334-343
Number of pages10
JournalInternational Journal of Obesity
Volume42
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

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Pancreatic Neoplasms
Adipocytes
Epithelial-Mesenchymal Transition
Mesenchymal Stromal Cells
Epithelial Cells
Conditioned Culture Medium
Paracrine Communication
Chemoprevention
Early Detection of Cancer
Cultured Cells
Obesity
Biomarkers
Monoclonal Antibodies
Phenotype
Cell Line
Survival
Incidence

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

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

In: International Journal of Obesity, Vol. 42, No. 3, 01.03.2018, p. 334-343.

Research output: Contribution to journalArticle

Carbone, C, Piro, G, Gaianigo, N, Ligorio, F, Santoro, R, Merz, V, Simionato, F, Zecchetto, C, Falco, G, Conti, G, Kamga, PT, Krampera, M, Di Nicolantonio, F, De Franceschi, L, Scarpa, A, Tortora, G & Melisi, D 2018, 'Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling', International Journal of Obesity, vol. 42, no. 3, pp. 334-343. https://doi.org/10.1038/ijo.2017.285
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. / Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling. In: International Journal of Obesity. 2018 ; Vol. 42, No. 3. pp. 334-343.
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abstract = "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.",
author = "C. Carbone and G. Piro and N. Gaianigo and F. Ligorio and R. Santoro and V. Merz and F. Simionato and C. Zecchetto and G. Falco and G. Conti and Kamga, {P. T.} and M. Krampera and {Di Nicolantonio}, F. and {De Franceschi}, L. and A. Scarpa and G. Tortora and D. Melisi",
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T1 - Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling

AU - Carbone, C.

AU - Piro, G.

AU - Gaianigo, N.

AU - Ligorio, F.

AU - Santoro, R.

AU - Merz, V.

AU - Simionato, F.

AU - Zecchetto, C.

AU - Falco, G.

AU - Conti, G.

AU - Kamga, P. T.

AU - Krampera, M.

AU - Di Nicolantonio, F.

AU - De Franceschi, L.

AU - Scarpa, A.

AU - Tortora, G.

AU - Melisi, D.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

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