ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β

Andreia Vaqueirinho de Pinho, Mathias Van Bulck, Lorraine A. Chantrill, Mehreen Arshi, David Herrmann, Claire Vennin, Australian Pancreatic Cancer Genome Initiative, Anthony Gill, Paul Timpson, Andrew Biankin, Jianmin Wu, Ilse Rooman

Research output: Contribution to journalMeeting abstractResearch

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, being predicted to become the second leading cause of cancer-related death by 2030. Chronic pancreatitis is a risk factor for PDAC and both diseases are characterized by a strong desmoplastic response, comprised of activated myofibroblasts and immune cell infiltrates. Genomic aberrations in the SLIT-ROBO pathway are frequent in PDAC. Nevertheless, their role in the pancreas is unclear. We have used an integrative approach combining the study of murine models and PDAC patients with the objective of unraveling the function of the SLIT-ROBO signaling pathway in pancreatic disease. RNA expression of SLIT-ROBO genes was analyzed in murine normal pancreas, pancreatitis and PDAC. Primary cell cultures and experimental pancreatitis were studied using pancreas-specific Robo2 (Pdx1-Cre;Robo2F/F) and whole-body Slit1 (Slit1-/-) knockout mice. Gene and protein expression were assessed in a cohort of PDAC patients (n=109). In mouse pancreatitis and PDAC, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Pdx1Cre;Robo2F/F pancreatic cell cultures showed increased activation of Robo1-positive myofibroblasts and induction of TGF-β and Wnt pathways. Likewise, induction of pancreatitis in Pdx1Cre;Robo2F/F mice enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. Similar results were obtained using Slit1-/- animals. Moreover, TGF-β inhibition using galunisertib treatment suppressed Robo2-mediated effects in the microenvironment. In patients, ROBO2 expression is overall low in PDAC, while ROBO1 is variably expressed in epithelium and high in the stroma. ROBO1 expression is correlated with markers of activated stroma, Wnt and TGF-β pathways. ROBO2low;ROBO1high subpopulation of patients present the poorest survival rates. In conclusion, Robo2 acts nonautonomously as a stroma suppressor gene by restraining myofibroblast activation and inflammation in the pancreatic microenvironment. ROBO1/2 expression is prognostic in PDAC patients and may guide therapy with TGF-β inhibitors or immunotherapies, currently being tested in clinical trials for advanced pancreatic cancer.

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Suppressor Genes
Transforming Growth Factor beta
Pancreas
Adenocarcinoma
Myofibroblasts
Pancreatitis
LY-2157299
Pancreatic Diseases
Wnt Signaling Pathway
Primary Cell Culture
Chronic Pancreatitis
Pancreatic Neoplasms
Knockout Mice
Immunotherapy
Collagen
Survival Rate
Epithelium
Cell Culture Techniques
Biomarkers
Clinical Trials

Cite this

Vaqueirinho de Pinho, A., Van Bulck, M., Chantrill, L. A., Arshi, M., Herrmann, D., Vennin, C., ... Rooman, I. (2019). ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β. Cancer immunology research, Volume 7(Issue 2 Supplement), [Abstract A100]. https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A100
Vaqueirinho de Pinho, Andreia ; Van Bulck, Mathias ; Chantrill, Lorraine A. ; Arshi, Mehreen ; Herrmann, David ; Vennin, Claire ; Australian Pancreatic Cancer Genome Initiative ; Gill, Anthony ; Timpson, Paul ; Biankin, Andrew ; Wu, Jianmin ; Rooman, Ilse. / ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β. In: Cancer immunology research. 2019 ; Vol. Volume 7, No. Issue 2 Supplement.
@article{5330df18ff0b4aa3a24cfaf1082a9d7e,
title = "ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, being predicted to become the second leading cause of cancer-related death by 2030. Chronic pancreatitis is a risk factor for PDAC and both diseases are characterized by a strong desmoplastic response, comprised of activated myofibroblasts and immune cell infiltrates. Genomic aberrations in the SLIT-ROBO pathway are frequent in PDAC. Nevertheless, their role in the pancreas is unclear. We have used an integrative approach combining the study of murine models and PDAC patients with the objective of unraveling the function of the SLIT-ROBO signaling pathway in pancreatic disease. RNA expression of SLIT-ROBO genes was analyzed in murine normal pancreas, pancreatitis and PDAC. Primary cell cultures and experimental pancreatitis were studied using pancreas-specific Robo2 (Pdx1-Cre;Robo2F/F) and whole-body Slit1 (Slit1-/-) knockout mice. Gene and protein expression were assessed in a cohort of PDAC patients (n=109). In mouse pancreatitis and PDAC, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Pdx1Cre;Robo2F/F pancreatic cell cultures showed increased activation of Robo1-positive myofibroblasts and induction of TGF-β and Wnt pathways. Likewise, induction of pancreatitis in Pdx1Cre;Robo2F/F mice enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. Similar results were obtained using Slit1-/- animals. Moreover, TGF-β inhibition using galunisertib treatment suppressed Robo2-mediated effects in the microenvironment. In patients, ROBO2 expression is overall low in PDAC, while ROBO1 is variably expressed in epithelium and high in the stroma. ROBO1 expression is correlated with markers of activated stroma, Wnt and TGF-β pathways. ROBO2low;ROBO1high subpopulation of patients present the poorest survival rates. In conclusion, Robo2 acts nonautonomously as a stroma suppressor gene by restraining myofibroblast activation and inflammation in the pancreatic microenvironment. ROBO1/2 expression is prognostic in PDAC patients and may guide therapy with TGF-β inhibitors or immunotherapies, currently being tested in clinical trials for advanced pancreatic cancer.",
author = "{Vaqueirinho de Pinho}, Andreia and {Van Bulck}, Mathias and Chantrill, {Lorraine A.} and Mehreen Arshi and David Herrmann and Claire Vennin and {Australian Pancreatic Cancer Genome Initiative} and Anthony Gill and Paul Timpson and Andrew Biankin and Jianmin Wu and Ilse Rooman",
year = "2019",
doi = "10.1158/2326-6074.CRICIMTEATIAACR18-A100",
language = "English",
volume = "Volume 7",
journal = "Cancer immunology research",
issn = "2326-6066",
publisher = "AMER ASSOC CANCER RESEARCH",
number = "Issue 2 Supplement",

}

Vaqueirinho de Pinho, A, Van Bulck, M, Chantrill, LA, Arshi, M, Herrmann, D, Vennin, C, Australian Pancreatic Cancer Genome Initiative, Gill, A, Timpson, P, Biankin, A, Wu, J & Rooman, I 2019, 'ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β', Cancer immunology research, vol. Volume 7, no. Issue 2 Supplement, Abstract A100. https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A100

ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β. / Vaqueirinho de Pinho, Andreia; Van Bulck, Mathias; Chantrill, Lorraine A.; Arshi, Mehreen; Herrmann, David; Vennin, Claire; Australian Pancreatic Cancer Genome Initiative; Gill, Anthony; Timpson, Paul; Biankin, Andrew; Wu, Jianmin; Rooman, Ilse.

In: Cancer immunology research, Vol. Volume 7, No. Issue 2 Supplement, Abstract A100, 2019.

Research output: Contribution to journalMeeting abstractResearch

TY - JOUR

T1 - ROBO2 is a stroma suppressor gene in the pancreas through regulation of TGF-β

AU - Vaqueirinho de Pinho, Andreia

AU - Van Bulck, Mathias

AU - Chantrill, Lorraine A.

AU - Arshi, Mehreen

AU - Herrmann, David

AU - Vennin, Claire

AU - Australian Pancreatic Cancer Genome Initiative

AU - Gill, Anthony

AU - Timpson, Paul

AU - Biankin, Andrew

AU - Wu, Jianmin

AU - Rooman, Ilse

PY - 2019

Y1 - 2019

N2 - Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, being predicted to become the second leading cause of cancer-related death by 2030. Chronic pancreatitis is a risk factor for PDAC and both diseases are characterized by a strong desmoplastic response, comprised of activated myofibroblasts and immune cell infiltrates. Genomic aberrations in the SLIT-ROBO pathway are frequent in PDAC. Nevertheless, their role in the pancreas is unclear. We have used an integrative approach combining the study of murine models and PDAC patients with the objective of unraveling the function of the SLIT-ROBO signaling pathway in pancreatic disease. RNA expression of SLIT-ROBO genes was analyzed in murine normal pancreas, pancreatitis and PDAC. Primary cell cultures and experimental pancreatitis were studied using pancreas-specific Robo2 (Pdx1-Cre;Robo2F/F) and whole-body Slit1 (Slit1-/-) knockout mice. Gene and protein expression were assessed in a cohort of PDAC patients (n=109). In mouse pancreatitis and PDAC, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Pdx1Cre;Robo2F/F pancreatic cell cultures showed increased activation of Robo1-positive myofibroblasts and induction of TGF-β and Wnt pathways. Likewise, induction of pancreatitis in Pdx1Cre;Robo2F/F mice enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. Similar results were obtained using Slit1-/- animals. Moreover, TGF-β inhibition using galunisertib treatment suppressed Robo2-mediated effects in the microenvironment. In patients, ROBO2 expression is overall low in PDAC, while ROBO1 is variably expressed in epithelium and high in the stroma. ROBO1 expression is correlated with markers of activated stroma, Wnt and TGF-β pathways. ROBO2low;ROBO1high subpopulation of patients present the poorest survival rates. In conclusion, Robo2 acts nonautonomously as a stroma suppressor gene by restraining myofibroblast activation and inflammation in the pancreatic microenvironment. ROBO1/2 expression is prognostic in PDAC patients and may guide therapy with TGF-β inhibitors or immunotherapies, currently being tested in clinical trials for advanced pancreatic cancer.

AB - Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, being predicted to become the second leading cause of cancer-related death by 2030. Chronic pancreatitis is a risk factor for PDAC and both diseases are characterized by a strong desmoplastic response, comprised of activated myofibroblasts and immune cell infiltrates. Genomic aberrations in the SLIT-ROBO pathway are frequent in PDAC. Nevertheless, their role in the pancreas is unclear. We have used an integrative approach combining the study of murine models and PDAC patients with the objective of unraveling the function of the SLIT-ROBO signaling pathway in pancreatic disease. RNA expression of SLIT-ROBO genes was analyzed in murine normal pancreas, pancreatitis and PDAC. Primary cell cultures and experimental pancreatitis were studied using pancreas-specific Robo2 (Pdx1-Cre;Robo2F/F) and whole-body Slit1 (Slit1-/-) knockout mice. Gene and protein expression were assessed in a cohort of PDAC patients (n=109). In mouse pancreatitis and PDAC, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Pdx1Cre;Robo2F/F pancreatic cell cultures showed increased activation of Robo1-positive myofibroblasts and induction of TGF-β and Wnt pathways. Likewise, induction of pancreatitis in Pdx1Cre;Robo2F/F mice enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. Similar results were obtained using Slit1-/- animals. Moreover, TGF-β inhibition using galunisertib treatment suppressed Robo2-mediated effects in the microenvironment. In patients, ROBO2 expression is overall low in PDAC, while ROBO1 is variably expressed in epithelium and high in the stroma. ROBO1 expression is correlated with markers of activated stroma, Wnt and TGF-β pathways. ROBO2low;ROBO1high subpopulation of patients present the poorest survival rates. In conclusion, Robo2 acts nonautonomously as a stroma suppressor gene by restraining myofibroblast activation and inflammation in the pancreatic microenvironment. ROBO1/2 expression is prognostic in PDAC patients and may guide therapy with TGF-β inhibitors or immunotherapies, currently being tested in clinical trials for advanced pancreatic cancer.

U2 - 10.1158/2326-6074.CRICIMTEATIAACR18-A100

DO - 10.1158/2326-6074.CRICIMTEATIAACR18-A100

M3 - Meeting abstract

VL - Volume 7

JO - Cancer immunology research

T2 - Cancer immunology research

JF - Cancer immunology research

SN - 2326-6066

IS - Issue 2 Supplement

M1 - Abstract A100

ER -