Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells
Metastatic prostate cancer (PCa) cells soiling in the bone require a metabolic adaptation. Here, we identified the metabolic genes fueling the seeding of PCa in the bone niche. Using a transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3 or Raw264.7), we assessed the transcripto...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/9/2083 |
| _version_ | 1797505468364488704 |
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| author | Pablo Sanchis Nicolas Anselmino Sofia Lage-Vickers Agustina Sabater Rosario Lavignolle Estefania Labanca Peter D. A. Shepherd Juan Bizzotto Ayelen Toro Antonina Mitrofanova Maria Pia Valacco Nora Navone Elba Vazquez Javier Cotignola Geraldine Gueron |
| author_facet | Pablo Sanchis Nicolas Anselmino Sofia Lage-Vickers Agustina Sabater Rosario Lavignolle Estefania Labanca Peter D. A. Shepherd Juan Bizzotto Ayelen Toro Antonina Mitrofanova Maria Pia Valacco Nora Navone Elba Vazquez Javier Cotignola Geraldine Gueron |
| author_sort | Pablo Sanchis |
| collection | DOAJ |
| description | Metastatic prostate cancer (PCa) cells soiling in the bone require a metabolic adaptation. Here, we identified the metabolic genes fueling the seeding of PCa in the bone niche. Using a transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3 or Raw264.7), we assessed the transcriptome of PC3 cells modulated by soluble factors released from bone precursors. In a Principal Component Analysis using transcriptomic data from human PCa samples (GSE74685), the altered metabolic genes found in vitro were able to stratify PCa patients in two defined groups: primary PCa and bone metastasis, confirmed by an unsupervised clustering analysis. Thus, the early transcriptional metabolic profile triggered in the in vitro model has a clinical correlate in human bone metastatic samples. Further, the expression levels of five metabolic genes (<i>VDR, PPARA, SLC16A1, GPX1</i> and <i>PAPSS2</i>) were independent risk-predictors of death in the SU2C-PCF dataset and a risk score model built using this lipid-associated signature was able to discriminate a subgroup of bone metastatic PCa patients with a 23-fold higher risk of death. This signature was validated in a PDX pre-clinical model when comparing MDA-PCa-183 growing intrafemorally vs. subcutaneously, and appears to be under the regulatory control of the Protein Kinase A (PKA) signaling pathway. Secretome analyses of conditioned media showcased fibronectin and type-1 collagen as critical bone-secreted factors that could regulate tumoral PKA. Overall, we identified a novel lipid gene signature, driving PCa aggressive metastatic disease pointing to PKA as a potential hub to halt progression. |
| first_indexed | 2024-03-10T04:19:01Z |
| format | Article |
| id | doaj.art-7f3e5d12d2ba488893597ef8758111a8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:19:01Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7f3e5d12d2ba488893597ef8758111a82023-11-23T07:54:35ZengMDPI AGCancers2072-66942022-04-01149208310.3390/cancers14092083Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer CellsPablo Sanchis0Nicolas Anselmino1Sofia Lage-Vickers2Agustina Sabater3Rosario Lavignolle4Estefania Labanca5Peter D. A. Shepherd6Juan Bizzotto7Ayelen Toro8Antonina Mitrofanova9Maria Pia Valacco10Nora Navone11Elba Vazquez12Javier Cotignola13Geraldine Gueron14Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaDepartment of Genitourinary Medical Oncology and The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USALaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaLaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaLaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaDepartment of Genitourinary Medical Oncology and The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Genitourinary Medical Oncology and The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USALaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaLaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaDepartment of Biomedical and Health Informatics, Rutgers School of Health Professions, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 07101, USALaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaDepartment of Genitourinary Medical Oncology and The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USALaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaLaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaLaboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, ArgentinaMetastatic prostate cancer (PCa) cells soiling in the bone require a metabolic adaptation. Here, we identified the metabolic genes fueling the seeding of PCa in the bone niche. Using a transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3 or Raw264.7), we assessed the transcriptome of PC3 cells modulated by soluble factors released from bone precursors. In a Principal Component Analysis using transcriptomic data from human PCa samples (GSE74685), the altered metabolic genes found in vitro were able to stratify PCa patients in two defined groups: primary PCa and bone metastasis, confirmed by an unsupervised clustering analysis. Thus, the early transcriptional metabolic profile triggered in the in vitro model has a clinical correlate in human bone metastatic samples. Further, the expression levels of five metabolic genes (<i>VDR, PPARA, SLC16A1, GPX1</i> and <i>PAPSS2</i>) were independent risk-predictors of death in the SU2C-PCF dataset and a risk score model built using this lipid-associated signature was able to discriminate a subgroup of bone metastatic PCa patients with a 23-fold higher risk of death. This signature was validated in a PDX pre-clinical model when comparing MDA-PCa-183 growing intrafemorally vs. subcutaneously, and appears to be under the regulatory control of the Protein Kinase A (PKA) signaling pathway. Secretome analyses of conditioned media showcased fibronectin and type-1 collagen as critical bone-secreted factors that could regulate tumoral PKA. Overall, we identified a novel lipid gene signature, driving PCa aggressive metastatic disease pointing to PKA as a potential hub to halt progression.https://www.mdpi.com/2072-6694/14/9/2083prostate cancerbone metastasismetabolismgene signaturelipid metabolismPKA |
| spellingShingle | Pablo Sanchis Nicolas Anselmino Sofia Lage-Vickers Agustina Sabater Rosario Lavignolle Estefania Labanca Peter D. A. Shepherd Juan Bizzotto Ayelen Toro Antonina Mitrofanova Maria Pia Valacco Nora Navone Elba Vazquez Javier Cotignola Geraldine Gueron Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells Cancers prostate cancer bone metastasis metabolism gene signature lipid metabolism PKA |
| title | Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells |
| title_full | Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells |
| title_fullStr | Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells |
| title_full_unstemmed | Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells |
| title_short | Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells |
| title_sort | bone progenitors pull the strings on the early metabolic rewiring occurring in prostate cancer cells |
| topic | prostate cancer bone metastasis metabolism gene signature lipid metabolism PKA |
| url | https://www.mdpi.com/2072-6694/14/9/2083 |
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