Gabrielle T Parkinson1, Simona Salerno1, Parmida Ranji1, Joakim Håkansson2,3, Yalda Bogestål2, Yvonne Wettergren4, Anders Ståhlberg1,5,6, Elinor Bexe Lindskog4, Göran Landberg1. 1. Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 2. Research Institutes of Sweden (RISE), Division Biosciences and Materials, Section for Medical Device Technology, Borås, Sweden. 3. Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. 4. Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden. 5. Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden. 6. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.
Abstract
BACKGROUND: Colorectal cancer is the second most common cause of cancer-related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from the surrounding tumor microenvironment (TME) contribute to the complexity of the disease and large variability in clinical outcomes. METHODS: To model the heterogeneous nature of colorectal cancer, we used patient-derived scaffolds (PDS), which were obtained via decellularization of surgically resected tumor material, as a growth substrate for standardized cell lines. RESULTS: After confirmation of native cell absence and validation of the structural and compositional integrity of the matrix, 89 colorectal PDS were repopulated with colon cancer cell line HT29. After 3 weeks of PDS culture, HT29 cells varied their gene and protein expression profiles considerably compared to 2D-grown HT29 cells. Markers associated with proliferation were consistently decreased, while markers associated with pluripotency were increased in PDS-grown cells compared to their 2D counterparts. When comparing the PDS-induced changes in HT29 cells with clinically relevant tumor information from individual patients, we observed significant associations between stemness/pluripotency markers and tumor location, and between epithelial-to-mesenchymal transition (EMT) markers and cancer mortality. Kaplan-Meier analysis revealed that low PDS-induced EMT correlated with worse cancer-specific survival. CONCLUSIONS: The colorectal PDS model can be used as a simplified personalized tool that can potentially reveal important diagnostic and pathophysiological information related to the TME.
BACKGROUND:Colorectal cancer is the second most common cause of cancer-related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from the surrounding tumor microenvironment (TME) contribute to the complexity of the disease and large variability in clinical outcomes. METHODS: To model the heterogeneous nature of colorectal cancer, we used patient-derived scaffolds (PDS), which were obtained via decellularization of surgically resected tumor material, as a growth substrate for standardized cell lines. RESULTS: After confirmation of native cell absence and validation of the structural and compositional integrity of the matrix, 89 colorectal PDS were repopulated with colon cancer cell line HT29. After 3 weeks of PDS culture, HT29 cells varied their gene and protein expression profiles considerably compared to 2D-grown HT29 cells. Markers associated with proliferation were consistently decreased, while markers associated with pluripotency were increased in PDS-grown cells compared to their 2D counterparts. When comparing the PDS-induced changes in HT29 cells with clinically relevant tumor information from individual patients, we observed significant associations between stemness/pluripotency markers and tumor location, and between epithelial-to-mesenchymal transition (EMT) markers and cancer mortality. Kaplan-Meier analysis revealed that low PDS-induced EMT correlated with worse cancer-specific survival. CONCLUSIONS: The colorectal PDS model can be used as a simplified personalized tool that can potentially reveal important diagnostic and pathophysiological information related to the TME.
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