Cargando…

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

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 dat...

Descripción completa

Detalles Bibliográficos
Autores principales: Alonso-Nocelo, Marta, Ruiz-Cañas, Laura, Sancho, Patricia, Görgülü, Kıvanç, Alcalá, Sonia, Pedrero, Coral, Vallespinos, Mireia, López-Gil, Juan Carlos, Ochando, Marina, García-García, Elena, David Trabulo, Sara Maria, Martinelli, Paola, Sánchez-Tomero, Patricia, Sánchez-Palomo, Carmen, Gonzalez-Santamaría, Patricia, Yuste, Lourdes, Wörmann, Sonja Maria, Kabacaoğlu, Derya, Earl, Julie, Martin, Alberto, Salvador, Fernando, Valle, Sandra, Martin-Hijano, Laura, Carrato, Alfredo, Erkan, Mert, García-Bermejo, Laura, Hermann, Patrick C, Algül, Hana, Moreno-Bueno, Gema, Heeschen, Christopher, Portillo, Francisco, Cano, Amparo, Sainz, Bruno
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9872246/
https://www.ncbi.nlm.nih.gov/pubmed/35428659
http://dx.doi.org/10.1136/gutjnl-2021-325564
_version_ 1784877363768590336
author Alonso-Nocelo, Marta
Ruiz-Cañas, Laura
Sancho, Patricia
Görgülü, Kıvanç
Alcalá, Sonia
Pedrero, Coral
Vallespinos, Mireia
López-Gil, Juan Carlos
Ochando, Marina
García-García, Elena
David Trabulo, Sara Maria
Martinelli, Paola
Sánchez-Tomero, Patricia
Sánchez-Palomo, Carmen
Gonzalez-Santamaría, Patricia
Yuste, Lourdes
Wörmann, Sonja Maria
Kabacaoğlu, Derya
Earl, Julie
Martin, Alberto
Salvador, Fernando
Valle, Sandra
Martin-Hijano, Laura
Carrato, Alfredo
Erkan, Mert
García-Bermejo, Laura
Hermann, Patrick C
Algül, Hana
Moreno-Bueno, Gema
Heeschen, Christopher
Portillo, Francisco
Cano, Amparo
Sainz, Bruno
author_facet Alonso-Nocelo, Marta
Ruiz-Cañas, Laura
Sancho, Patricia
Görgülü, Kıvanç
Alcalá, Sonia
Pedrero, Coral
Vallespinos, Mireia
López-Gil, Juan Carlos
Ochando, Marina
García-García, Elena
David Trabulo, Sara Maria
Martinelli, Paola
Sánchez-Tomero, Patricia
Sánchez-Palomo, Carmen
Gonzalez-Santamaría, Patricia
Yuste, Lourdes
Wörmann, Sonja Maria
Kabacaoğlu, Derya
Earl, Julie
Martin, Alberto
Salvador, Fernando
Valle, Sandra
Martin-Hijano, Laura
Carrato, Alfredo
Erkan, Mert
García-Bermejo, Laura
Hermann, Patrick C
Algül, Hana
Moreno-Bueno, Gema
Heeschen, Christopher
Portillo, Francisco
Cano, Amparo
Sainz, Bruno
author_sort Alonso-Nocelo, Marta
collection PubMed
description 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 (Loxl2(Exon2) (fl/fl)) or conditional Loxl2 overexpressing mice (R26Loxl2 (KI/KI)) to generate KPCL2(KO) or KCL2(KO) and KPCL2(KI) or KCL2(KI) 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.
format Online
Article
Text
id pubmed-9872246
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-98722462023-01-25 Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma Alonso-Nocelo, Marta Ruiz-Cañas, Laura Sancho, Patricia Görgülü, Kıvanç Alcalá, Sonia Pedrero, Coral Vallespinos, Mireia López-Gil, Juan Carlos Ochando, Marina García-García, Elena David Trabulo, Sara Maria Martinelli, Paola Sánchez-Tomero, Patricia Sánchez-Palomo, Carmen Gonzalez-Santamaría, Patricia Yuste, Lourdes Wörmann, Sonja Maria Kabacaoğlu, Derya Earl, Julie Martin, Alberto Salvador, Fernando Valle, Sandra Martin-Hijano, Laura Carrato, Alfredo Erkan, Mert García-Bermejo, Laura Hermann, Patrick C Algül, Hana Moreno-Bueno, Gema Heeschen, Christopher Portillo, Francisco Cano, Amparo Sainz, Bruno Gut Pancreas 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 (Loxl2(Exon2) (fl/fl)) or conditional Loxl2 overexpressing mice (R26Loxl2 (KI/KI)) to generate KPCL2(KO) or KCL2(KO) and KPCL2(KI) or KCL2(KI) 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. BMJ Publishing Group 2023-02 2022-04-15 /pmc/articles/PMC9872246/ /pubmed/35428659 http://dx.doi.org/10.1136/gutjnl-2021-325564 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Pancreas
Alonso-Nocelo, Marta
Ruiz-Cañas, Laura
Sancho, Patricia
Görgülü, Kıvanç
Alcalá, Sonia
Pedrero, Coral
Vallespinos, Mireia
López-Gil, Juan Carlos
Ochando, Marina
García-García, Elena
David Trabulo, Sara Maria
Martinelli, Paola
Sánchez-Tomero, Patricia
Sánchez-Palomo, Carmen
Gonzalez-Santamaría, Patricia
Yuste, Lourdes
Wörmann, Sonja Maria
Kabacaoğlu, Derya
Earl, Julie
Martin, Alberto
Salvador, Fernando
Valle, Sandra
Martin-Hijano, Laura
Carrato, Alfredo
Erkan, Mert
García-Bermejo, Laura
Hermann, Patrick C
Algül, Hana
Moreno-Bueno, Gema
Heeschen, Christopher
Portillo, Francisco
Cano, Amparo
Sainz, Bruno
Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
title Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
title_full Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
title_fullStr Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
title_full_unstemmed Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
title_short Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
title_sort macrophages direct cancer cells through a loxl2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
topic Pancreas
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9872246/
https://www.ncbi.nlm.nih.gov/pubmed/35428659
http://dx.doi.org/10.1136/gutjnl-2021-325564
work_keys_str_mv AT alonsonocelomarta macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT ruizcanaslaura macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT sanchopatricia macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT gorgulukıvanc macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT alcalasonia macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT pedrerocoral macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT vallespinosmireia macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT lopezgiljuancarlos macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT ochandomarina macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT garciagarciaelena macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT davidtrabulosaramaria macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT martinellipaola macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT sancheztomeropatricia macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT sanchezpalomocarmen macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT gonzalezsantamariapatricia macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT yustelourdes macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT wormannsonjamaria macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT kabacaogluderya macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT earljulie macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT martinalberto macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT salvadorfernando macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT vallesandra macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT martinhijanolaura macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT carratoalfredo macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT erkanmert macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT garciabermejolaura macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT hermannpatrickc macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT algulhana macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT morenobuenogema macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT heeschenchristopher macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT portillofrancisco macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT canoamparo macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma
AT sainzbruno macrophagesdirectcancercellsthroughaloxl2mediatedmetastaticcascadeinpancreaticductaladenocarcinoma