PMID- 33212158 OWN - NLM STAT- MEDLINE DCOM- 20210805 LR - 20240102 IS - 1872-7980 (Electronic) IS - 0304-3835 (Linking) VI - 501 DP - 2021 Mar 31 TI - Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine. PG - 210-223 LID - S0304-3835(20)30605-4 [pii] LID - 10.1016/j.canlet.2020.11.013 [doi] AB - Tumour-associated macrophages have been implicated in pancreatic ductal adenocarcinoma (PDAC) therapy response and Extracellular vesicles (EVs) shed by macrophages might have a role in this process. Here, we demonstrated that large EVs released by anti-inflammatory human macrophages decreased PDAC cellular sensitivity to gemcitabine. Using proteomic analysis, chitinase 3-like-1 (CHI3L1) and fibronectin (FN1) were identified as two of the most abundant proteins in the cargo of macrophages-derived EVs. Overexpression of CHI3L1 and FN1, using recombinant human proteins, induced PDAC cellular resistance to gemcitabine through ERK (extracellular-signal-regulated kinase) activation. Inhibition of CHI3L1 and FN1 by pentoxifylline and pirfenidone, respectively, partially reverted gemcitabine resistance. In PDAC patient samples, CHI3L1 and FN1 were expressed in the stroma, associated with the high presence of macrophages. The Cancer Genome Atlas analysis revealed an association between CHI3L1 and FN1 gene expression, overall survival of PDAC patients, gemcitabine response, and macrophage infiltration. Altogether, our data identifies CHI3L1 and FN1 as potential targets for pharmacological inhibition in PDAC. Further pre-clinical in vivo work is warranted to study the possibility of repurposing pentoxifylline and pirfenidone as adjuvant therapies for PDAC treatment. CI - Copyright (c) 2020. Published by Elsevier B.V. FAU - Xavier, Cristina P R AU - Xavier CPR AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal. FAU - Castro, Ines AU - Castro I AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal. FAU - Caires, Hugo R AU - Caires HR AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal. FAU - Ferreira, Dylan AU - Ferreira D AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Experimental Pathology and Therapeutics Group, IPO - Instituto Portugues de Oncologia, Porto, Portugal. FAU - Cavadas, Bruno AU - Cavadas B AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Genetic Diversity Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal. FAU - Pereira, Luisa AU - Pereira L AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Genetic Diversity Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal. FAU - Santos, Lucio L AU - Santos LL AD - Experimental Pathology and Therapeutics Group, IPO - Instituto Portugues de Oncologia, Porto, Portugal; ICBAS - Biomedical Sciences Institute Abel Salazar, Universidade do Porto, Porto, Portugal. FAU - Oliveira, Maria J AU - Oliveira MJ AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Tumour and Microenvironment Interactions Group, INEB - Instituto Nacional de Engenharia Biomedica, Porto, Portugal. FAU - Vasconcelos, M Helena AU - Vasconcelos MH AD - i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy of the University of Porto, Porto, Portugal. Electronic address: hvasconcelos@ipatimup.pt. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201116 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (CHI3L1 protein, human) RN - 0 (Chitinase-3-Like Protein 1) RN - 0 (FN1 protein, human) RN - 0 (Fibronectins) RN - 0 (Pyridones) RN - 0W860991D6 (Deoxycytidine) RN - D7NLD2JX7U (pirfenidone) RN - SD6QCT3TSU (Pentoxifylline) RN - 0 (Gemcitabine) SB - IM MH - Carcinoma, Pancreatic Ductal/genetics/metabolism/*mortality MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Chitinase-3-Like Protein 1/genetics/*metabolism MH - Deoxycytidine/*analogs & derivatives/pharmacology MH - *Drug Resistance, Neoplasm/drug effects MH - Extracellular Vesicles/genetics/*metabolism MH - Fibronectins/genetics/*metabolism MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Macrophages/*metabolism MH - Pancreatic Neoplasms/genetics/metabolism/*mortality MH - Pentoxifylline/pharmacology MH - Proteomics MH - Pyridones/pharmacology MH - Survival Analysis MH - Up-Regulation/drug effects MH - Gemcitabine OTO - NOTNLM OT - Anti-inflammatory macrophages OT - CHI3L1 OT - FN1 OT - Gemcitabine resistance OT - PDAC EDAT- 2020/11/20 06:00 MHDA- 2021/08/06 06:00 CRDT- 2020/11/19 20:09 PHST- 2020/08/01 00:00 [received] PHST- 2020/10/25 00:00 [revised] PHST- 2020/11/09 00:00 [accepted] PHST- 2020/11/20 06:00 [pubmed] PHST- 2021/08/06 06:00 [medline] PHST- 2020/11/19 20:09 [entrez] AID - S0304-3835(20)30605-4 [pii] AID - 10.1016/j.canlet.2020.11.013 [doi] PST - ppublish SO - Cancer Lett. 2021 Mar 31;501:210-223. doi: 10.1016/j.canlet.2020.11.013. Epub 2020 Nov 16.