PT  - JOURNAL ARTICLE
AU  - Marta Alonso-Nocelo
AU  - Laura Ruiz-Cañas
AU  - Patricia Sancho
AU  - Kıvanç Görgülü
AU  - Sonia Alcalá
AU  - Coral Pedrero
AU  - Mireia Vallespinos
AU  - Juan Carlos López-Gil
AU  - Marina Ochando
AU  - Elena García-García
AU  - Sara Maria David Trabulo
AU  - Paola Martinelli
AU  - Patricia Sánchez-Tomero
AU  - Carmen Sánchez-Palomo
AU  - Patricia Gonzalez-Santamaría
AU  - Lourdes Yuste
AU  - Sonja Maria Wörmann
AU  - Derya Kabacaoğlu
AU  - Julie Earl
AU  - Alberto Martin
AU  - Fernando Salvador
AU  - Sandra Valle
AU  - Laura Martin-Hijano
AU  - Alfredo Carrato
AU  - Mert Erkan
AU  - Laura García-Bermejo
AU  - Patrick C Hermann
AU  - Hana Algül
AU  - Gema Moreno-Bueno
AU  - Christopher Heeschen
AU  - Francisco Portillo
AU  - Amparo Cano
AU  - Bruno Sainz, , Jr
TI  - Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
AID  - 10.1136/gutjnl-2021-325564
DP  - 2023 Feb 01
TA  - Gut
PG  - 345--359
VI  - 72
IP  - 2
4099  - http://gut.bmj.com/content/72/2/345.short
4100  - http://gut.bmj.com/content/72/2/345.full
SO  - Gut2023 Feb 01; 72
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.