Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cellular Oncology
Published in: Cellular Oncology 6/2020

Open Access 01-12-2020 | Voraxapar | Original paper

Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation

Authors: Cansu Tekin, Hella L Aberson, Cynthia Waasdorp, Gerrit K J Hooijer, Onno J de Boer, Frederike Dijk, Maarten F Bijlsma, C Arnold Spek

Published in: Cellular Oncology | Issue 6/2020

Login to get access

Abstract

Purpose

Targeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored. Here we address the PAR1-macrophage-tumor cell crosstalk and assess its contributions to tumor progression.

Methods

PAR1 expression and macrophage infiltration were correlated in primary PDAC biopsies using gene expression datasets and tissue microarrays. Medium transfer experiments were used to evaluate the functional consequences of macrophage-tumor cell crosstalk and to assess the contribution of PAR1 to the observed responses. PAR1 cleavage assays were used to identify a macrophage-secreted PAR1 agonist, and the effects of candidate proteases were assessed in medium transfer experiments with specific inhibitors and/or recombinant agonist.

Results

PAR1 expression correlates with macrophage infiltration in primary PDACs, and macrophages induce mesenchymal transition of PDAC cells through PAR1 activation. Protease profiling identified macrophage-secreted matrix metalloprotease 9 (MMP9) as the relevant PAR1 agonist in PDAC. PAR1 and/or MMP9 inhibition limited macrophage-driven mesenchymal transition. Likewise, preventing mesenchymal transition by silencing ZEB1 or by pharmacological inhibition of the MMP9/PAR1 axis significantly reduced the ability of tumor cells to survive the anti-tumor activities of macrophages.

Conclusion

Macrophages secrete MMP9, which acts upon PDAC cell PAR1 to induce mesenchymal transition. This macrophage-induced mesenchymal transition supports the tumor-promoting role of macrophage influx, explaining the dichotomous contributions of these immune cells to tumor growth.
Appendix
Available only for authorised users
Literature
1.
D. Li, K. Xie, R. Wolff, J.L. Abbruzzese, Pancreatic cancer. Lancet 363, 1049–1057 (2004)PubMed
2.
R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019)PubMed
3.
H.A. Burris 3rd, M.J. Moore, J. Andersen, M.R. Green, M.L. Rothenberg, M.R. Modiano, M.C. Cripps, R.K. Portenoy, A.M. Storniolo, P. Tarassoff, R. Nelson, F.A. Dorr, C.D. Stephens, D.D. Von Hoff, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997)PubMed
4.
T. Conroy, F. Desseigne, M. Ychou, O. Bouché, R. Guimbaud, Y. Bécouarn, A. Adenis, J.L. Raoul, S. Gourgou-Bourgade, C. de la Fouchardière, J. Bennouna, J.B. Bachet, F. Khemissa-Akouz, D. Péré-Vergé, C. Delbaldo, E. Assenat, B. Chauffert, P. Michel, C. Montoto-Grillot, M. Ducreux, Groupe Tumeurs digestives of Unicancer, and PRODIGE intergroup, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New Engl. J. Med. 364, 1817–1825 (2011)
5.
D.D. Von Hoff, T. Ervin, F.P. Arena, E.G. Chiorean, J. Infante, M. Moore, T. Seay, S.A. Tjulandin, W.W. Ma, M.N. Saleh, M. Harris, M. Reni, S. Dowden, D. Laheru, N. Bahary, R.K. Ramanathan, J. Tabernero, M. Hidalgo, D. Goldstein, E. Van Cutsem, X. Wei, J. Iglesias, M.F. Renschler, Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New Engl. J. Med. 369, 1691–1703 (2013)
6.
C. Porta, E. Riboldi, M.G. Totaro, L. Strauss, A. Sica, A. Mantovani, Macrophages in cancer and infectious diseases: The ‘good’ and the ‘bad’. Immunotherapy 3, 1185–1202 (2011)PubMed
7.
M.R. Jadus, M.R.C. Irwin, R.D. Horansky, S. Sekhon, K.A. Pepper, D.B. Kohn, H.T. Wepsic, Macrophages can recognize and kill tumor cells bearing the membrane isoform of macrophage colony-stimulating factor. Blood 87, 5232–5241 (1996)PubMed
8.
K.K. Goswami, T. Ghosh, S. Ghosh, M. Sarkar, A. Bose, R. Baral, Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell. Immunol. 316, 1–10 (2017)
9.
K.Y. Jung, S.W. Cho, Y.A. Kim, D. Kim, B.C. Oh, D.J. Park, Y.J. Park, Cancers with higher density of tumor-associated macrophages were associated with poor survival rates. J. Pathol. Transl. Med. 49, 318–324 (2015)PubMedPubMedCentral
10.
T. Lindsten, A. Hedbrant, A. Ramberg, J. Wijkander, A. Solterbeck, M. Eriksson, D. Delbro, A. Erlandsson, Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-2. Int. J. Oncol. 51, 104–114 (2017)
11.
Q. Zhang, L. Liu, C.Y. Gong, H. Shi, Y. Zeng, X. Wang, Y. Zhao, Y. Wei, Prognostic significance of tumor-associated macrophages in solid tumor: A meta-analysis of the literature. PLoS One 7, e50946 (2012)PubMedPubMedCentral
12.
S. Su, Q. Liu, J. Chen, J. Chen, F. Chen, C. He, D. Huang, W. Wu, L. Lin, W. Huang, J. Zhang, X. Cui, F. Zheng, H. Li, H. Yao, F. Su, E. Song, A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25, 605–620 (2014)PubMed
13.
Q.M. Fan, Y.Y. Jing, G.F. Yu, X.R. Kou, F. Ye, L. Gao, R. Li, Q.D. Zhao, Y. Yang, Z.H. Lu, L.X. Wei, Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 352, 160–168 (2014)PubMed
14.
C.Y. Liu, J.Y. Xu, X.Y. Shi, W. Huang, T.Y. Ruan, P. Xie, J.L. Ding, M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab. Investig. 93, 844–854 (2013)PubMed
15.
J.B. Mitchem, D.J. Brennan, B.L. Knolhoff, B.A. Belt, Y. Zhu, D.E. Sanford, L. Belaygorod, D. Carpenter, L. Collins, D. Piwnica-Worms, S. Hewitt, G.M. Udupi, W.M. Gallagher, C. Wegner, B.L. West, A. Wang-Gillam, P. Goedegebuure, D.C. Linehan, D.N. DG, Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013)
16.
N. Weizman, Y. Krelin, A. Shabtay-Orbach, M. Amit, Y. Binenbaum, R.J. Wong, Z. Gil, Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 33, 3812–3819 (2014)PubMed
17.
A. Adamska, A. Domenichini, M. Falasca, Pancreatic ductal adenocarcinoma: Current and evolving therapies. Int. J. Mol. Sci. 18, 1338 (2017)PubMedCentral
18.
A. Boire, L. Covic, A. Agarwal, S. Jacques, S. Sherifi, A. Kuliopulos, PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–303 (2005)PubMed
19.
J. Cisowski, K. O’Callaghan, A. Kuliopulos, J. Yang, N. Nguyen, Q. Deng, E. Yang, M. Fogel, S. Tressel, C. Foley, A. Agarwal, S.W. Hunt, T. McMurry, L. Brinckerhoff, L. Covic, Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. Am. J. Pathol. 179, 513–523 (2011)PubMedPubMedCentral
20.
S. Grisaru-Granovsky, Z. Salah, M. Maoz, D. Pruss, U. Beller, R. Bar-Shavit, Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int. J. Cancer 113, 372–378 (2005)PubMed
21.
L. Zhu, X. Wang, J. Wu, D. Mao, Z. Xu, Z. He, A. Yu, Cooperation of protease-activated receptor 1 and integrin alphanubeta5 in thrombin-mediated lung cancer cell invasion. Oncol. Rep. 28, 553–560 (2012)PubMed
22.
S.R. Macfarlane, M.J. Seatter, T. Kanke, G.D. Hunter, R. Plevin, Proteinase-activated receptors. Pharmacol. Rev. 53, 245 LP – 245282 (2001)
23.
K.C.S. Queiroz, K. Shi, J. Duitman, H.L. Aberson, J.W. Wilmink, C.J.M. Van Noesel, D.J. Richel, C.A. Spek, Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance. Int. J. Cancer 135, 2294–2304 (2014)PubMed
24.
Committee for Guidelines in Research (COREON), Human Tissue and Medical Research: Code of conduct for responsible use (2011)
25.
K.R. Pertiwi, A.C. Van Der Wal, D.R. Pabittei, C. Mackaaij, M.B. Van Leeuwen, X. Li, O.J. De Boer, Neutrophil extracellular traps participate in all different types of thrombotic and haemorrhagic complications of coronary atherosclerosis. Thromb. Haemost. 118, 1078–1087 (2018)PubMed
26.
M. Genin, F. Clement, A. Fattaccioli, M. Raes, C. Michiels, M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer 15, 577 (2015)PubMedPubMedCentral
27.
S. Kumar, B.I. Ratnikov, M.D. Kazanov, J.W. Smith, P. Cieplak, CleavPredict: A platform for reasoning about matrix metalloproteinases proteolytic events. PLoS One 10, e0127877 (2015)PubMedPubMedCentral
28.
J. Wang, S. Yang, P. He, A.J. Schetter, J. Gaedcke, B.M. Ghadimi, T. Ried, H.G. Yfantis, D.H. Lee, M.M. Gaida, N. Hanna, H.R. Alexander, S.P. Hussain, Endothelial nitric oxide synthase traffic inducer (NOSTRIN) is a negative regulator of disease aggressiveness in pancreatic cancer. Clin. Cancer Res. 22, 5992–6001 (2016)PubMedPubMedCentral
29.
G. Zhang, A. Schetter, P. He, N. Funamizu, J. Gaedcke, B.M. Ghadimi, T. Ried, R. Hassan, H.G. Yfantis, D.H. Lee, C. Lacy, A. Maitra, N. Hanna, H.R. Alexander, S.P. Hussain, DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma. PLoS One 7, e31507 (2012)PubMedPubMedCentral
30.
L. Badea, V. Herlea, S.O. Dima, T. Dumitrascu, I. Popescu, Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterol. 55, 2016–2027 (2008)
31.
B.J. Raphael, R.H. Hruban, A.J. Aguirre, R.A. Moffitt, et al., Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203.e13 (2017)
32.
F. Dijk, V.L. Veenstra, E.C. Soer, M.P.G. Dings, L. Zhao, J.B. Halfwerk, G.K. Hooijer, H. Damhofer, M. Marzano, A. Steins, C. Waasdorp, O.R. Busch, M.G. Besselink, J.A. Tol, L. Welling, L.B. van Rijssen, S. Klompmaker, H.W. Wilmink, H.W. van Laarhoven, J.P. Medema, L. Vermeulen, S.R. van Hooff, J. Koster, J. Verheij, M.J. van de Vijver, X. Wang, M.F. Bijlsma, Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems. Sci. Rep. 10, 1–12 (2020)
33.
L. Arnes, N. Waddell, S. Song, A.M.M. Patch, D. Miller, A. Johns, J. Wu, K.S. Kassahn, D. Wood, P. Bailey, L. Fink, S. Manning, A.N. Christ, C. Nourse, S. Kazakoff, D. Taylor, C. Leonard, D.K. Chang, M.D. Jones, M. Thomas, C. Watson, M. Pinese, M. Cowley, I. Rooman, M. Pajic, G. Butturini, A. Malpaga, V. Corbo, S. Crippa, M. Falconi, G. Zamboni, P. Castelli, R.T. Lawlor, A.J. Gill, A. Scarpa, J.V. Pearson, A.V. Biankin, S.M. Grimmond, Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma. Gut 68, 499–511 (2019)PubMed
34.
K. Nones, R.K. Sinha, L. Burnier, E.A. Bouwens, J.H. Griffin, Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int. J. Cancer 135, 1110–1118 (2014)PubMed
35.
L.O. Mosnier, R.K. Sinha, L. Burnier, E.A. Bouwens, J.H. Griffin, Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood 120, 5237–5246 (2012)PubMedPubMedCentral
36.
C. Tekin, K. Shi, J.B. Daalhuisen, M.S.T. Brink, M.F. Bijlsma, C.A. Spek, PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer. Oncotarget 9, 32010–32023 (2018)PubMedPubMedCentral
37.
38.
J.M. Florence, A. Krupa, L.M. Booshehri, T.C. Allen, A.K. Kurdowska, Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1. PLoS One 12, e0171427 (2017)PubMedPubMedCentral
39.
F. Jaffré, A.E. Friedman, Z. Hu, N. MacKman, B.C. Blaxall, β-Adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells. Circulation 125, 2993–3003 (2012)PubMedPubMedCentral
40.
N.M. Aiello, R. Maddipati, R.J. Norgard, D. Balli, J. Li, S. Yuan, T. Yamazoe, T. Black, A. Sahmoud, E.E. Furth, D. Bar-Sagi, BZ. Stanger, EMT subtype influences epithelial plasticity and mode of cell migration. Dev. Cell 45, 681–695.e4 (2018)
41.
K. Kuwada, S. Kagawa, R. Yoshida, S. Sakamoto, A. Ito, M. Watanabe, T. Ieda, S. Kuroda, S. Kikuchi, H. Tazawa, T. Fujiwara, The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer. J. Exp. Clin. Cancer Res. 37, 1–10 (2018)
42.
A. Habtezion, M. Edderkaoui, S.J. Pandol, Macrophages and pancreatic ductal adenocarcinoma. Cancer Lett 381, 211–216 (2016)PubMed
43.
M.Z. Wojtukiewicz, D. Hempel, E. Sierko, S.C. Tucker, K.V. Honn, Protease-activated receptors (PARs)-biology and role in cancer invasion and metastasis. Cancer Metastasis Rev. 34, 775–796 (2015)PubMedPubMedCentral
44.
G.N. Adams, B.K. Sharma, L. Rosenfeldt, M. Frederick, M.J. Flick, D.P. Witte, L.O. Mosnier, E. Harmel-Laws, K.A. Steinbrecher, J.S. Palumbo, Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice. J. Thromb. Haemost. 16, 2258–2269 (2018)PubMedPubMedCentral
45.
A. Pryczynicz, K. Guzinska-Ustymowicz, V. Dymicka-Piekarska, J. Czyzewska, A. Kemona, Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation. Folia Histochem. Cytobiol. 45, 37–40 (2007)PubMed
46.
K. Jakubowska, A. Pryczynicz, J. Januszewska, I. Sidorkiewicz, A. Kemona, A. Niewiński, Ł. Lewczuk, B. Kędra, K. Guzińska-Ustymowicz, Expressions of matrix metalloproteinases 2, 7, and 9 in carcinogenesis of pancreatic ductal adenocarcinoma. Dis. Markers 2016, 1–7 (2016)
47.
B. Mroczko, M. Lukaszewicz-Zajac, U. Wereszczynska-Siemiatkowska, M. Groblewska, M. Gryko, B. Kedra, G. Jurkowska, M. Szmitkowski, Clinical significance of the measurements of serum matrix metalloproteinase-9 and its inhibitor (tissue inhibitor of metalloproteinase-1) in patients with pancreatic cancer: Metalloproteinase-9 as an independent prognostic factor. Pancreas 38, 613–618 (2009)PubMed
48.
M.A. Shah, A. Starodub, S. Sharma, J. Berlin, M. Patel, Z.A. Wainberg, J. Chaves, M. Gordon, K. Windsor, C.B. Brachmann, X. Huang, G. Vosganian, J.D. Maltzman, V. Smith, J.A. Silverman, H.J. Lenz, J.C. Bendell, Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: Results from a phase I study. Clin. Cancer Res. 24, 3829–3837 (2018)PubMedPubMedCentral
Metadata
Title
Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation
Authors
Cansu Tekin
Hella L Aberson
Cynthia Waasdorp
Gerrit K J Hooijer
Onno J de Boer
Frederike Dijk
Maarten F Bijlsma
C Arnold Spek
Publication date
01-12-2020
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 6/2020
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-020-00549-x

Other articles of this Issue 6/2020

Cellular Oncology 6/2020 Go to the issue

Original paper

Reversine exerts cytotoxic effects through multiple cell death mechanisms in acute lymphoblastic leukemia

Review

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

Review

Non-coding RNAs underlying chemoresistance in gastric cancer

Original paper

Oxaliplatin induces immunogenic cell death in hepatocellular carcinoma cells and synergizes with immune checkpoint blockade therapy

Original paper

Metabolomic profiling of mouse mammary tumor-derived cell lines reveals targeted therapy options for cancer subtypes

Original Paper

NF-κB-mediated miR-650 plays oncogenic roles and activates AKT/ERK/NF-κB pathways by targeting RERG in glioma cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits