Conditional gene targeting reveals cell type-specific roles of the lysosomal protease cathepsin L in mammary tumor progression

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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

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: Cancers. - 12, 8 (2020) , 2004, ISSN: 2072-6694

Keyword: Brustkrebs
Lysosom
Proteolyse

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2020

Creator: Parigiani, María Alejandra
Ketscher, Anett
Timme-Bronsert, Sylvia
Bronsert, Peter
Schlimpert, Manuel
Kammerer, Bernd
Jacquel, Arnaud
Chaintreuil, Paul
Reinheckel, Thomas

DOI: 10.3390/cancers12082004

URN: urn:nbn:de:bsz:25-freidok-1667047

Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 25.03.2025, 1:54 PM CET

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2020

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Conditional gene targeting reveals cell type-specific roles of the lysosomal protease cathepsin L in mammary tumor progression

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Other Objects (12)

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