Alonso-Nocelo M, Ruiz-Cañas L,..., Cano A, Sainz B Jr. Macrophages direct cancer cells through a LOXL2- mediated metastatic cascade in pancreatic ductal adenocarcinoma
"Understanding the fibroinflammatory microenvironment of pancreatic cancer is essential for designing new therapies for patients suffering from this devastating cancer" - Dr. Bruno Sainz Anding -
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.
Keywords: CELL MATRIX INTERACTION; MACROPHAGES; MOLECULAR ONCOLOGY; PANCREATIC CANCER; PANCREATIC FIBROSIS.
Why do you highlight this publication?
Importantly, this study shows in a pioneering way that Loxl2 expression plays an important role in PDAC metastasis, and that compounds blocking Loxl2 in combination with inhibitors of TAMs or OSM-mediated signaling may represent a new therapeutic approach to reduce the metastatic potential of PDAC tumor cells.
Publication commented by:
Dr. Bruno Sainz
Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM
Autónoma University of Madrid (UAM), Department of Biochemistry