Digital Spatial Profiling Identifies the Tumor Periphery as a Highly Active Biological Niche in Clear Cell Renal Cell Carcinoma
Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of intratumoral heterogeneity (ITH). Besides genomic ITH, there is considerable functional ITH, which encompasses spatial niches with distinct proliferative and signaling activities. The full extent of functional spatial heter...
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| Published in | Cancers Vol. 15; no. 20; p. 5050 |
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| Abstract | Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of intratumoral heterogeneity (ITH). Besides genomic ITH, there is considerable functional ITH, which encompasses spatial niches with distinct proliferative and signaling activities. The full extent of functional spatial heterogeneity in ccRCC is incompletely understood. In the present study, a total of 17 ccRCC tissue specimens from different sites (primary tumor, n = 11; local recurrence, n = 1; distant metastasis, n = 5) were analyzed using digital spatial profiling (DSP) of protein expression. A total of 128 regions of interest from the tumor periphery and tumor center were analyzed for the expression of 46 proteins, comprising three major signaling pathways as well as immune cell markers. Results were correlated to clinico-pathological variables. The differential expression of granzyme B was validated using conventional immunohistochemistry and was correlated to the cancer-specific patient survival. We found that a total of 37 proteins were differentially expressed between the tumor periphery and tumor center. Thirty-five of the proteins were upregulated in the tumor periphery compared to the center. These included proteins involved in cell proliferation, MAPK and PI3K/AKT signaling, apoptosis regulation, epithelial-to-mesenchymal transition, as well as immune cell markers. Among the most significantly upregulated proteins in the tumor periphery was granzyme B. Granzyme B upregulation in the tumor periphery correlated with a significantly reduced cancer-specific patient survival. In conclusion, this study highlights the unique cellular contexture of the tumor periphery in ccRCC. The correlation between granzyme B upregulation in the tumor periphery and patient survival suggests local selection pressure for aggressive tumor growth and disease progression. Our results underscore the potential of spatial biology for biomarker discovery in ccRCC and cancer in general. |
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| AbstractList | Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of intratumoral heterogeneity (ITH). Besides genomic ITH, there is considerable functional ITH, which encompasses spatial niches with distinct proliferative and signaling activities. The full extent of functional spatial heterogeneity in ccRCC is incompletely understood. In the present study, a total of 17 ccRCC tissue specimens from different sites (primary tumor, n = 11; local recurrence, n = 1; distant metastasis, n = 5) were analyzed using digital spatial profiling (DSP) of protein expression. A total of 128 regions of interest from the tumor periphery and tumor center were analyzed for the expression of 46 proteins, comprising three major signaling pathways as well as immune cell markers. Results were correlated to clinico-pathological variables. The differential expression of granzyme B was validated using conventional immunohistochemistry and was correlated to the cancer-specific patient survival. We found that a total of 37 proteins were differentially expressed between the tumor periphery and tumor center. Thirty-five of the proteins were upregulated in the tumor periphery compared to the center. These included proteins involved in cell proliferation, MAPK and PI3K/AKT signaling, apoptosis regulation, epithelial-to-mesenchymal transition, as well as immune cell markers. Among the most significantly upregulated proteins in the tumor periphery was granzyme B. Granzyme B upregulation in the tumor periphery correlated with a significantly reduced cancer-specific patient survival. In conclusion, this study highlights the unique cellular contexture of the tumor periphery in ccRCC. The correlation between granzyme B upregulation in the tumor periphery and patient survival suggests local selection pressure for aggressive tumor growth and disease progression. Our results underscore the potential of spatial biology for biomarker discovery in ccRCC and cancer in general. Simple SummaryClear cell renal cell carcinoma is characterized by a high degree of genomic intratumoral heterogeneity. The extent of spatial and functional heterogeneity, however, is much less understood. In the present study, digital spatial profiling identified the tumor periphery as a highly active biological niche with the upregulation of a number of proteins involved in tumorigenic signaling nodes. One of the most significantly upregulated proteins was granzyme B, which plays an important role in anti-cancer immune responses. Patients exhibiting such an overexpression in the tumor periphery had a significantly worse cancer-specific survival. It is possible that high granzyme B expression creates selection pressure for tumor cells to escape antitumoral host responses. Results from this study highlight the role of the tumor periphery as a hotspot for various signaling activities and tumor evolution. Our findings have important implications for the future development of predictive and prognostic biomarkers to improve patient stratification.AbstractClear cell renal cell carcinoma (ccRCC) is characterized by a high degree of intratumoral heterogeneity (ITH). Besides genomic ITH, there is considerable functional ITH, which encompasses spatial niches with distinct proliferative and signaling activities. The full extent of functional spatial heterogeneity in ccRCC is incompletely understood. In the present study, a total of 17 ccRCC tissue specimens from different sites (primary tumor, n = 11; local recurrence, n = 1; distant metastasis, n = 5) were analyzed using digital spatial profiling (DSP) of protein expression. A total of 128 regions of interest from the tumor periphery and tumor center were analyzed for the expression of 46 proteins, comprising three major signaling pathways as well as immune cell markers. Results were correlated to clinico-pathological variables. The differential expression of granzyme B was validated using conventional immunohistochemistry and was correlated to the cancer-specific patient survival. We found that a total of 37 proteins were differentially expressed between the tumor periphery and tumor center. Thirty-five of the proteins were upregulated in the tumor periphery compared to the center. These included proteins involved in cell proliferation, MAPK and PI3K/AKT signaling, apoptosis regulation, epithelial-to-mesenchymal transition, as well as immune cell markers. Among the most significantly upregulated proteins in the tumor periphery was granzyme B. Granzyme B upregulation in the tumor periphery correlated with a significantly reduced cancer-specific patient survival. In conclusion, this study highlights the unique cellular contexture of the tumor periphery in ccRCC. The correlation between granzyme B upregulation in the tumor periphery and patient survival suggests local selection pressure for aggressive tumor growth and disease progression. Our results underscore the potential of spatial biology for biomarker discovery in ccRCC and cancer in general. Clear cell renal cell carcinoma is characterized by a high degree of genomic intratumoral heterogeneity. The extent of spatial and functional heterogeneity, however, is much less understood. In the present study, digital spatial profiling identified the tumor periphery as a highly active biological niche with the upregulation of a number of proteins involved in tumorigenic signaling nodes. One of the most significantly upregulated proteins was granzyme B, which plays an important role in anti-cancer immune responses. Patients exhibiting such an overexpression in the tumor periphery had a significantly worse cancer-specific survival. It is possible that high granzyme B expression creates selection pressure for tumor cells to escape antitumoral host responses. Results from this study highlight the role of the tumor periphery as a hotspot for various signaling activities and tumor evolution. Our findings have important implications for the future development of predictive and prognostic biomarkers to improve patient stratification. Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of intratumoral heterogeneity (ITH). Besides genomic ITH, there is considerable functional ITH, which encompasses spatial niches with distinct proliferative and signaling activities. The full extent of functional spatial heterogeneity in ccRCC is incompletely understood. In the present study, a total of 17 ccRCC tissue specimens from different sites (primary tumor, n = 11; local recurrence, n = 1; distant metastasis, n = 5) were analyzed using digital spatial profiling (DSP) of protein expression. A total of 128 regions of interest from the tumor periphery and tumor center were analyzed for the expression of 46 proteins, comprising three major signaling pathways as well as immune cell markers. Results were correlated to clinico-pathological variables. The differential expression of granzyme B was validated using conventional immunohistochemistry and was correlated to the cancer-specific patient survival. We found that a total of 37 proteins were differentially expressed between the tumor periphery and tumor center. Thirty-five of the proteins were upregulated in the tumor periphery compared to the center. These included proteins involved in cell proliferation, MAPK and PI3K/AKT signaling, apoptosis regulation, epithelial-to-mesenchymal transition, as well as immune cell markers. Among the most significantly upregulated proteins in the tumor periphery was granzyme B. Granzyme B upregulation in the tumor periphery correlated with a significantly reduced cancer-specific patient survival. In conclusion, this study highlights the unique cellular contexture of the tumor periphery in ccRCC. The correlation between granzyme B upregulation in the tumor periphery and patient survival suggests local selection pressure for aggressive tumor growth and disease progression. Our results underscore the potential of spatial biology for biomarker discovery in ccRCC and cancer in general. Clear cell renal cell carcinoma is characterized by a high degree of genomic intratumoral heterogeneity. The extent of spatial and functional heterogeneity, however, is much less understood. In the present study, digital spatial profiling identified the tumor periphery as a highly active biological niche with the upregulation of a number of proteins involved in tumorigenic signaling nodes. One of the most significantly upregulated proteins was granzyme B, which plays an important role in anti-cancer immune responses. Patients exhibiting such an overexpression in the tumor periphery had a significantly worse cancer-specific survival. It is possible that high granzyme B expression creates selection pressure for tumor cells to escape antitumoral host responses. Results from this study highlight the role of the tumor periphery as a hotspot for various signaling activities and tumor evolution. Our findings have important implications for the future development of predictive and prognostic biomarkers to improve patient stratification. |
| Audience | Academic |
| Author | Schwab, Constantin Stenzinger, Albrecht Zschäbitz, Stefanie Duensing, Anette Kirchner, Martina Schneider, Felix Jäger, Dirk Kaczorowski, Adam Görtz, Magdalena Hohenfellner, Markus Schütz, Viktoria Jurcic, Christina Duensing, Stefan |
| AuthorAffiliation | 1 Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany 4 Department of Medical Oncology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany 7 Precision Oncology of Urological Malignancies, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany 3 Department of Urology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 420, D-69120 Heidelberg, Germany 2 Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany 5 Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA 6 Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA |
| AuthorAffiliation_xml | – name: 3 Department of Urology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 420, D-69120 Heidelberg, Germany – name: 7 Precision Oncology of Urological Malignancies, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany – name: 1 Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany – name: 5 Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA – name: 6 Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA – name: 2 Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany – name: 4 Department of Medical Oncology, University Hospital Heidelberg, and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany |
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| Snippet | Clear cell renal cell carcinoma (ccRCC) is characterized by a high degree of intratumoral heterogeneity (ITH). Besides genomic ITH, there is considerable... Clear cell renal cell carcinoma is characterized by a high degree of genomic intratumoral heterogeneity. The extent of spatial and functional heterogeneity,... Simple SummaryClear cell renal cell carcinoma is characterized by a high degree of genomic intratumoral heterogeneity. The extent of spatial and functional... |
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| SubjectTerms | 1-Phosphatidylinositol 3-kinase AKT protein Antibodies Antigens Apoptosis Bar codes Biomarkers Carcinoma, Renal cell Cell division Cell growth Cell proliferation Clear cell-type renal cell carcinoma Cluster analysis Ethanol Genes Genomics Granzyme B Immune response Immunohistochemistry Kidney cancer MAP kinase Metastases Metastasis Morphology Protein expression Proteins Spatial heterogeneity Tumor cells Tumors Up-regulation |
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| Title | Digital Spatial Profiling Identifies the Tumor Periphery as a Highly Active Biological Niche in Clear Cell Renal Cell Carcinoma |
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