Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine

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Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine

Quinta, 11.02.2021

The work recently published in the journal “Cancer Letters” by Cristina Xavier et al., in the scope of her post-doctoral research at the Cancer Drug Resistance Group, i3S, demonstrated the impact of Extracellular Vesicles released by macrophages on the response of pancreatic cancer cells to a chemotherapeutic agent. This work results from a collaboration with the Tumor and Microenvironment Interactions Group of i3S, the Experimental Pathology and Therapeutics Group of IPO-Porto and the Genetic Diversity Group of i3S.

 

Authors and Affiliations:

Cristina P R Xavier – i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal;

Inês Castro – i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal;

Hugo R Caires – i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal;

Dylan Ferreira – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Experimental Pathology and Therapeutics Group, IPO - Instituto Português de Oncologia, Porto, Portugal;

Bruno Cavadas – i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Genetic Diversity Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal;

Luísa Pereira – i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Genetic Diversity Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal;

Lúcio L Santos – Experimental Pathology and Therapeutics Group, IPO - Instituto Português de Oncologia, Porto, Portugal; ICBAS - Biomedical Sciences Institute Abel Salazar, Universidade do Porto, Porto, Portugal;

Maria J Oliveira – i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Tumour and Microenvironment Interactions Group, INEB - Instituto Nacional de Engenharia Biomédica, Porto, Portugal;

M Helena Vasconcelos – i3S - Instituto de Investigação e Inovação em Saúde, 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.

 

Abstract:

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.

 

Journal: Cancer Letters

 

Link: https://pubmed.ncbi.nlm.nih.gov/33212158/