Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression.
María Alejandra ParigianiAnett KetscherSylvia TimmePeter BronsertManuel SchlimpertBernd KammererArnaud JacquelPaul ChaintreuilThomas ReinheckelPublished in: Cancers (2020)
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.
Keyphrases
- poor prognosis
- cell cycle arrest
- induced apoptosis
- single cell
- cell death
- long non coding rna
- oxidative stress
- magnetic resonance
- bone marrow
- cell therapy
- gene expression
- mesenchymal stem cells
- endothelial cells
- metabolic syndrome
- dendritic cells
- magnetic resonance imaging
- signaling pathway
- cell proliferation
- transcription factor
- adipose tissue
- immune response
- copy number
- genome wide
- radiofrequency ablation
- reactive oxygen species
- contrast enhanced