Conditional gene targeting reveals cell type-specific roles of the lysosomal protease cathepsin L in mammary tumor progression
Abstract: Background: Cathepsin L (Ctsl) is a cysteine protease mainly located within the endosomal/lysosomal cell compartment. High expression of Ctsl indicates poor prognosis in human breast cancer. However, the cell type-specific Ctsl functions responsible for this association remain elusive. Methods: Because constitutive Ctsl−/− mice develop a complex phenotype, we developed a conditional model allowing for cell type-specific inactivation of Ctsl in mammary epithelium or myeloid cells in the transgenic mouse mammary tumor virus (MMTV)-polyoma middle T (PyMT) breast cancer model. Results: Ctsl ablation in mammary epithelial cells resulted in delayed initiation and end-stage of cancers. The latter displayed large dead cell areas. Inducible in vitro deletion of Ctsl in MMTV-PyMT-derived breast cancer cells revealed expansion of the acidic cell compartment, alteration of intracellular amino acid levels, and impaired mTOR signaling. In consequence, Ctsl-deficient cells exhibited slow growth rates and high apoptosis susceptibility. In contrast to Ctsl-deficient mammary epithelium, selective knockout of Ctsl in myeloid cells had no effects on primary tumors, but promoted lung metastasis formation. Conclusions: Our cell type-specific in vivo analysis provides strong evidence for a cancer cell-intrinsic, tumor-promoting role of Ctsl in primary breast cancer, whereas metastasis is negatively regulated by Ctsl expressed by bone marrow-derived cells
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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Cancers. - 12, 8 (2020) , 2004, ISSN: 2072-6694
- Schlagwort
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Brustkrebs
Lysosom
Proteolyse
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
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Universität
- (wann)
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2020
- Urheber
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Parigiani, María Alejandra
Ketscher, Anett
Timme-Bronsert, Sylvia
Bronsert, Peter
Schlimpert, Manuel
Kammerer, Bernd
Jacquel, Arnaud
Chaintreuil, Paul
Reinheckel, Thomas
- DOI
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10.3390/cancers12082004
- URN
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urn:nbn:de:bsz:25-freidok-1667047
- Rechteinformation
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Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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25.03.2025, 13:54 MEZ
Datenpartner
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Beteiligte
- Parigiani, María Alejandra
- Ketscher, Anett
- Timme-Bronsert, Sylvia
- Bronsert, Peter
- Schlimpert, Manuel
- Kammerer, Bernd
- Jacquel, Arnaud
- Chaintreuil, Paul
- Reinheckel, Thomas
- Universität
Entstanden
- 2020
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