Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells
Background: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. Methods: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of C...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/6/1908 |
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| author | Gregory T. Gallanis Ghada M. Sharif Marcel O. Schmidt Benjamin N. Friedland Rohith Battina Raneen Rahhal John E. Davis Irfan S. Khan Anton Wellstein Anna T. Riegel |
| author_facet | Gregory T. Gallanis Ghada M. Sharif Marcel O. Schmidt Benjamin N. Friedland Rohith Battina Raneen Rahhal John E. Davis Irfan S. Khan Anton Wellstein Anna T. Riegel |
| author_sort | Gregory T. Gallanis |
| collection | DOAJ |
| description | Background: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. Methods: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. Results: Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. Conclusions: These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche. |
| first_indexed | 2024-03-11T06:48:53Z |
| format | Article |
| id | doaj.art-a9f0e4c652a747e1bfa84e3bf07e4a72 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T06:48:53Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a9f0e4c652a747e1bfa84e3bf07e4a722023-11-17T10:08:53ZengMDPI AGCancers2072-66942023-03-01156190810.3390/cancers15061908Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer CellsGregory T. Gallanis0Ghada M. Sharif1Marcel O. Schmidt2Benjamin N. Friedland3Rohith Battina4Raneen Rahhal5John E. Davis6Irfan S. Khan7Anton Wellstein8Anna T. Riegel9Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USALombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USABackground: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. Methods: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. Results: Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. Conclusions: These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.https://www.mdpi.com/2072-6694/15/6/1908CDK4/6 inhibitorspalbociclibabemacicliblung metastasismammary cancersenescence |
| spellingShingle | Gregory T. Gallanis Ghada M. Sharif Marcel O. Schmidt Benjamin N. Friedland Rohith Battina Raneen Rahhal John E. Davis Irfan S. Khan Anton Wellstein Anna T. Riegel Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells Cancers CDK4/6 inhibitors palbociclib abemaciclib lung metastasis mammary cancer senescence |
| title | Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells |
| title_full | Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells |
| title_fullStr | Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells |
| title_full_unstemmed | Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells |
| title_short | Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells |
| title_sort | stromal senescence following treatment with the cdk4 6 inhibitor palbociclib alters the lung metastatic niche and increases metastasis of drug resistant mammary cancer cells |
| topic | CDK4/6 inhibitors palbociclib abemaciclib lung metastasis mammary cancer senescence |
| url | https://www.mdpi.com/2072-6694/15/6/1908 |
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