Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Cancers - 12(2020), 8 vom: 22. Juli |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Parigiani, María Alejandra [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Breast cancer |
|---|
| Anmerkungen: |
Date Revised 04.11.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/cancers12082004 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM312838018 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM312838018 | ||
| 003 | DE-627 | ||
| 005 | 20231225145255.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/cancers12082004 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1042.xml |
| 035 | |a (DE-627)NLM312838018 | ||
| 035 | |a (NLM)32707827 | ||
| 035 | |a (PII)E2004 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Parigiani, María Alejandra |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 04.11.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a breast cancer | |
| 650 | 4 | |a genetically engineered mice | |
| 650 | 4 | |a lysosome | |
| 650 | 4 | |a proteolysis | |
| 700 | 1 | |a Ketscher, Anett |e verfasserin |4 aut | |
| 700 | 1 | |a Timme, Sylvia |e verfasserin |4 aut | |
| 700 | 1 | |a Bronsert, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Schlimpert, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Kammerer, Bernd |e verfasserin |4 aut | |
| 700 | 1 | |a Jacquel, Arnaud |e verfasserin |4 aut | |
| 700 | 1 | |a Chaintreuil, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Reinheckel, Thomas |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancers |d 2009 |g 12(2020), 8 vom: 22. Juli |w (DE-627)NLM198667213 |x 2072-6694 |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2020 |g number:8 |g day:22 |g month:07 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/cancers12082004 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2020 |e 8 |b 22 |c 07 | ||