Characterization and targeting of cathepsin B and L activity in tumor-associated macrophages during pancreatic cancer development and progression.
Final Report Abstract
Macrophages have been increasingly recognized as important determinants of the inflammatory response in a wide variety of pathological states, including cancer and cardiovascular disease. In the microenvironment surrounding the tumor cells, tumorassociated macrophages have been shown to facilitate tumor progression and to mediate resistance to chemotherapy. This has been shown for many tumor types harboring a poor prognosis including pancreatic cancer. In addition to the tumor-associated context, macrophages described as foam cells have been implicated in the pathogenesis of cardiovascular disease as important players during atheroma formation. Both tumor-associated macrophages and macrophage foam cells represent a major source of secreted proteases including the family of cathepsin proteases. These proteases, when expressed in tumor-associated macrophages, have been proposed to mediate tumor progression. In addition, they have also been implicated in the modulation of macrophage foam cells during atheroma formation. However, their exact modes of action in both cellular contexts still need to be determined. In this German-Israeli collaborative project, we aimed to comparatively study the functional impact of cathepsins both in macrophages infiltrating the tumor stroma and in macrophage foam cells infiltrating vascular atheromas. For this purpose, we used novel specific pharmacological inhibitors for cathepsins cathepsin B, S and L developed by the partner laboratory in Jerusalem. As cellular models, we used human primary macrophages polarized in vitro as model of tumor-associated macrophages to study the role of cathepsins in the tumorassociated micromilieu. To study the impact of cathepsins on macrophage foam cells, we utilized an in vitro model of bone marrow-derived macrophages loaded with lipid vesicles. Our experiments in the tumor-associated macrophage model identified a novel link between cathepsin activity and metabolic reprogramming of macrophages. We found profound cathepsin-dependent changes in autophagy, a tightly regulated cellular mechanism for recycling of cellular components, and in fatty acid metabolism. Decreased cathepsin activity facilitated a pro-inflammatory micromilieu in primary human macrophages. These data provide a strong rationale for therapeutic intervention by cathepsin inhibition to overcome tumorpromoting effects of immune-evasive macrophages in the tumor micromilieu. Our data in macrophage foam cells as in vitro model for atheroma-associated macrophages confirm cathepsins as critical regulators of macrophage inflammatory activity also in this setting. Using the macrophage foam cell model, we detected distinct functional effects of cathepsin inhibition on both lysosomal function and mitochondrial dynamics. Pharmacological cathepsin inhibition resulted in mitochondrial stress, which translated into impaired oxidative metabolism, excessive production of reactive oxygen species and the activation of the cellular stress response, driven by distinct alterations in the transcriptional program. In analogy to our findings in tumor-associated macrophages, cathepsin inhibition in this cell model resulted in an inflammatory phenotype with increased expression of inflammatory cytokines. In conclusion, this project demonstrated a key role for cathepsins in regulating both tumorassociated and vascular-associated macrophage-dependent inflammation and delineated an intriguing crosstalk between cathepsin activity, autophagy, mitochondrial dysfunction and inflammation. Our data provide a clear rationale for therapeutic intervention targeting cathepsin in cancer but indicate that intracellular cathepsin activity might have a protective role in atherosclerosis.
Publications
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miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer. Oncoimmunology 2016;5(6):e1160181
Leonie Mühlberg, Benjamin Kühnemuth, Eithne Costello, Victoria Shaw, Bence Sipos, Magdalena Huber, Heidi Griesmann, Sebastian Krug, Marvin Schober, Thomas M. Gress, Patrick Michl
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Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. Gut. 2017;66(7):1278-1285
Heidi Griesmann, Christof Drexel, Nada Milosevic, Bence Sipos, Jonas Rosendahl, Thomas M Gress, Patrick Michl
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Cathepsins Drive Anti Inflammatory Activity by Regulating Autophagy and Mitochondrial Dynamics in Macrophage Foam Cells. Cellular Physiology and Biochemistry 2019;53(3):550-572
Tommy Weiss-Sadan, David Maimoun, Diana Oelschlägel, Farnusch Kaschani, Danny Misiak, Hanmant Gaikwad, Yael Ben-Nun, Emmanuelle Merquiol, Adi Anaki, Darya Tsvirkun, Markus Kaiser, Patrick Michl, Israel Gotsman, Galia Blum
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Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut. 2019;68(1):159-171
Albrecht Neesse, Christiane A. Bauer, Daniel Öhlund, Matthias Lauth, Malte Buchholz, Patrick Michl, David A. Tuveson, Thomas M. Gress
