RT Journal Article
SR Electronic
T1 Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 345
OP 359
DO 10.1136/gutjnl-2021-325564
VO 72
IS 2
A1 Alonso-Nocelo, Marta
A1 Ruiz-Cañas, Laura
A1 Sancho, Patricia
A1 Görgülü, Kıvanç
A1 Alcalá, Sonia
A1 Pedrero, Coral
A1 Vallespinos, Mireia
A1 López-Gil, Juan Carlos
A1 Ochando, Marina
A1 García-García, Elena
A1 David Trabulo, Sara Maria
A1 Martinelli, Paola
A1 Sánchez-Tomero, Patricia
A1 Sánchez-Palomo, Carmen
A1 Gonzalez-Santamaría, Patricia
A1 Yuste, Lourdes
A1 Wörmann, Sonja Maria
A1 Kabacaoğlu, Derya
A1 Earl, Julie
A1 Martin, Alberto
A1 Salvador, Fernando
A1 Valle, Sandra
A1 Martin-Hijano, Laura
A1 Carrato, Alfredo
A1 Erkan, Mert
A1 García-Bermejo, Laura
A1 Hermann, Patrick C
A1 Algül, Hana
A1 Moreno-Bueno, Gema
A1 Heeschen, Christopher
A1 Portillo, Francisco
A1 Cano, Amparo
A1 Sainz, Bruno
YR 2023
UL http://gut.bmj.com/content/72/2/345.abstract
AB Objective The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.Design Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.Results Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment.Conclusion Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.Data from datasets used in this manuscript are available in a public, open access repository. Other data are available upon reasonable request. https://www.nature.com/articles/ng.3398; https://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2540-6; https://gut.bmj.com/content/66/9/1665.