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 gutjnl-2021-325564
DO 10.1136/gutjnl-2021-325564
A1 Marta Alonso-Nocelo
A1 Laura Ruiz-Cañas
A1 Patricia Sancho
A1 Kıvanç Görgülü
A1 Sonia Alcalá
A1 Coral Pedrero
A1 Mireia Vallespinos
A1 Juan Carlos López-Gil
A1 Marina Ochando
A1 Elena García-García
A1 Sara Maria David Trabulo
A1 Paola Martinelli
A1 Patricia Sánchez-Tomero
A1 Carmen Sánchez-Palomo
A1 Patricia Gonzalez-Santamaría
A1 Lourdes Yuste
A1 Sonja Maria Wörmann
A1 Derya Kabacaoğlu
A1 Julie Earl
A1 Alberto Martin
A1 Fernando Salvador
A1 Sandra Valle
A1 Laura Martin-Hijano
A1 Alfredo Carrato
A1 Mert Erkan
A1 Laura García-Bermejo
A1 Patrick C Hermann
A1 Hana Algül
A1 Gema Moreno-Bueno
A1 Christopher Heeschen
A1 Francisco Portillo
A1 Amparo Cano
A1 Bruno Sainz, Jr
YR 2022
UL http://gut.bmj.com/content/early/2022/04/14/gutjnl-2021-325564.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;Trp53LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras+/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2KI/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.