TY - JOUR
T1 - Serum levels of iCAF-derived osteoglycin predict favorable outcome in pancreatic cancer
AU - Dings, Mark P. G.
AU - Manoukian, Paul
AU - Waasdorp, Cynthia
AU - Quik, Judith S. E.
AU - Strijker, Marin
AU - Lodestijn, Sophie C.
AU - van Neerven, Sanne M.
AU - Moreno, Leandro F.
AU - de Oliveira, Rodrigo Leite
AU - Bonsing, Bert A.
AU - Bruno, Marco J.
AU - Busch, Olivier R.
AU - Doukas, Michael
AU - van Eijck, Casper H.
AU - Mohammad, Nadia Haj
AU - de Hingh, Ignace H.
AU - Molenaar, Quintus I.
AU - Besselink, Marc G.
AU - Vermeulen, Louis
AU - Medema, Jan Paul
AU - van Laarhoven, Hanneke W. M.
AU - Bijlsma, Maarten F.
N1 - Funding Information: Maarten F. Bijlsma has received research funding from Celgene, Frame Therapeutics and LeadPharma, and has acted as a consultant to Servier. Hanneke W. M. van Laarhoven has served as a consultant for BMS, Dragonfly, Lilly, Merck, Nordic Pharma and Servier, and has received unrestricted research funding and/or study medication from Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche and Servier, and has been a speaker for Astellas and Novartis. Jan Paul Medema has acted as a consultant to AbbVie. Louis Vermeulen received consultancy fees from Bayer, MSD, Genentech, Servier and Pierre Fabre. None of these parties were involved in the design of our study or drafting of the study. The other authors have no conflict of interest to declare. Funding Information: The authors would like to thank the patients for participating, and to the Liquid Biopsy Center, Mai Tran, Melissa Fidder, Dr Michiel Pegtel for sample acquisition and logistical support. Funding was provided by KWF Dutch Cancer Society, the AMC Foundation, the CCA Foundation, H2020‐MSCA‐ITN 861196 PRECODE and Oncode. Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Stroma-targeting agents have been proposed to improve the poor outcome of current treatments. However, clinical trials using these agents showed disappointing results. Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and tumor-suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. RNA-sequencing reads from patient-derived xenografts (PDXs) were mapped to the human and mouse genome to allocate the expression of genes to the tumor or stroma. Survival meta-analysis for stromal genes was performed and applied to human protein atlas data to identify circulating biomarkers. The candidate protein was perturbed in co-cultures and assessed in existing and novel single-cell gene expression analysis from control, pancreatitis, pancreatitis-recovered and PDAC mouse models. Serum levels of the candidate biomarker were measured in two independent cohorts totaling 148 PDAC patients and related them to overall survival. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis indicated that Ogn is derived from a subgroup of inflammatory CAFs. Ogn-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts (HR = 0.47, P =.042 and HR = 0.53, P =.006). Altogether, we conclude that high circulating OGN levels inform on a previously unrecognized subgroup of CAFs and predict favorable outcomes in resectable PDAC.
AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Stroma-targeting agents have been proposed to improve the poor outcome of current treatments. However, clinical trials using these agents showed disappointing results. Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and tumor-suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. RNA-sequencing reads from patient-derived xenografts (PDXs) were mapped to the human and mouse genome to allocate the expression of genes to the tumor or stroma. Survival meta-analysis for stromal genes was performed and applied to human protein atlas data to identify circulating biomarkers. The candidate protein was perturbed in co-cultures and assessed in existing and novel single-cell gene expression analysis from control, pancreatitis, pancreatitis-recovered and PDAC mouse models. Serum levels of the candidate biomarker were measured in two independent cohorts totaling 148 PDAC patients and related them to overall survival. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis indicated that Ogn is derived from a subgroup of inflammatory CAFs. Ogn-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts (HR = 0.47, P =.042 and HR = 0.53, P =.006). Altogether, we conclude that high circulating OGN levels inform on a previously unrecognized subgroup of CAFs and predict favorable outcomes in resectable PDAC.
KW - CAF subtypes
KW - liquid biopsy center
KW - pancreatic ductal adenocarcinoma
KW - stroma
UR - http://www.scopus.com/inward/record.url?scp=85138278433&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ijc.34276
DO - https://doi.org/10.1002/ijc.34276
M3 - Article
C2 - 36069222
SN - 0020-7136
VL - 152
SP - 511
EP - 523
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -