Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
Creators: name: Alonso-Nocelo, Marta
name: Ruiz-Cañas, Laura
name: Sancho, Patricia
name: Görgülü, Kıvanç
name: Alcalá, Sonia
name: Pedrero, Coral
name: Vallespinos, Mireia
name: López-Gil, Juan Carlos
name: Ochando, Marina
name: García-García, Elena
name: David Trabulo, Sara Maria
name: Martinelli, Paola
name: Sánchez-Tomero, Patricia
name: Sánchez-Palomo, Carmen
name: Gonzalez-Santamaría, Patricia
name: Yuste, Lourdes
name: Wörmann, Sonja Maria
name: Kabacaoğlu, Derya
name: Earl, Julie
name: Martin, Alberto
name: Salvador, Fernando
name: Valle, Sandra
name: Martin-Hijano, Laura
name: Carrato, Alfredo
name: Erkan, Mert
name: García-Bermejo, Laura
name: Hermann, Patrick C
name: Algül, Hana
name: Moreno-Bueno, Gema
name: Heeschen, Christopher
name: Portillo, Francisco
name: Cano, Amparo
name: Sainz, Bruno
Publisher: name: Universität Ulm
Year: 2022
Subjects: subject: Pancreatic cancer
subject: Cell matrix interaction
subject: Molecular oncology
subject: Pancreatic fibrosis
subject: DDC 610 / Medicine &amp; health
subject: Pancreas; Cancer
subject: Pancreatic neoplasms
subject: Molecular targeted therapy
subject: Cystic fibrosis
subject: Macrophages
subject: Cell communication
subject: Bauchspeicheldrüsenkrebs
subject: Tumorassoziierter Makrophage

description: ObjectiveThe 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.DesignTowards 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.ResultsUsing 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.ConclusionTaken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.