title: Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer.
abstract: Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild-type levels. We identified CtsZ, which is predominantly supplied by tumor-associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland.
authors.forename: Leila
authors.initials: L
authors.lastname: Akkari
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Vasilena
authors.initials: V
authors.lastname: Gocheva
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Quick
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Jemila C
authors.initials: JC
authors.lastname: Kester
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Alison K
authors.initials: AK
authors.lastname: Spencer
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Garfall
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bowman
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology
chemical_list: D002403:Cathepsins
keywords: invasion; macrophage; tumor microenvironment