Page 23 - SDIR5 Abstract book 21 12 2021.

CANCER AND METABOLISM

Chitinase 3-like-1 (CHI3L1) as a potential therapeutic target for pancreatic cancer

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Cristina P.R. Xavier , Sofia Sousa , Andreia Palmeira , Helena Branco , Dylan Ferreira , Lúcio L.
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Santos , Maria J. Oliveira 1,7,8 , M. Helena Vasconcelos 1,2,9,*
1 i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
2 Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal
3 Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, Portugal
4 CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Matosinhos, Portugal
5 Experimental Pathology and Therapeutics Group, IPO - Instituto Português de Oncologia, Porto, Portugal
6 ICBAS - Biomedical Sciences Institute Abel Salazar, Universidade do Porto, Portugal
7 FMUP - Faculdade de Medicina da Universidade do Porto, Portugal
8 Tumour and Microenvironment Interactions Group, INEB - Instituto Nacional de Engenharia Biomédica, Porto, Portugal
9 Department of Biological Sciences, FFUP -Faculdade de Farmácia da Universidade do Porto, Portugal
*Corresponding author: hvasconcelos@ipatimup.pt
Presenting author

The crosstalk between cancer cells and the tumor microenvironment plays an important role in resistance
to therapy. Several studies showed that tumor-associated macrophages, which are highly abundant in the
stroma of pancreatic ductal adenocarcinoma (PDAC), influence therapy response. Our previous work
demonstrated that extracellular vesicles (EVs) shed by polarized human macrophages decreased BxPC3
PDAC cellular sensitivity to gemcitabine [1]. Proteomic analysis of those EVs identified Chitinase 3-like 1
(CHI3L1) as the most abundant protein [1] and a possible therapeutic target for PDAC treatment. The aim
of the present work was to: i) validate CHI3L1 as a novel therapeutic target for PDAC treatment, and 2)
identify in silico inhibitors of CHI3L1 that could be used as adjuvants in PDAC treatment.
First, we confirmed that recombinant CHI3L1 caused resistance to gemcitabine and to gemcitabine plus
paclitaxel, in PDAC BxPC3 cells (determined by the SRB assay). Interestingly, CHI3L1 was found (by
immunohistochemistry analysis) to be expressed in the stroma of PDAC tumor patient samples and to be
associated with the presence of macrophages [1]. Then, a structure-based virtual screening was performed,
to retrieve known molecules from the DrugBank database that could potentially bind to CHI3L1. One of the
identified ligands was pentoxyfilline, a drug inhibitor of CHI3L1. Studies in PDAC cell lines confirmed that
pentoxyfilline reverted the CHI3L1-induced gemcitabine resistance [1]. Other top ranked compounds from
the molecular docking study are being tested for their potential as chemosensitizers in PDAC cells. One of
them is darifenacin, an FDA-approved drug to treat urinary incontinence. Darifenacin increased the
sensitivity of PDAC cell lines to gemcitabine treatment.
This work highlights the relevance of CHI3L1 as a therapeutic target for PDAC treatment and the possibility
of repurposing drugs, which are inhibitors of CHI3L1, as chemosensitizers to enhance response of PDAC to
conventional therapy.
References: [1] Xavier CPR, et al. Cancer Letters 2021, 501, 210-223.
Acknowledgements: CPR Xavier is supported by FCT and FSE, Portugal (SFRH/BPD/122871/2016). The work is in part
funded by "The Porto Comprehensive Cancer Center" (NORTE-01-0145-FEDER-072678).

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