Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma
Abstract Intra-tumor heterogeneity contributes to treatment failure and poor survival in urothelial bladder carcinoma (UBC). Analyzing transcriptome from a UBC cohort, we report that intra-tumor transcriptomic heterogeneity indicates co-existence of tumor cells in epithelial and mesenchymal-like tra...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05668-3 |
| _version_ | 1797376873603268608 |
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| author | Antara Biswas Sarthak Sahoo Gregory M. Riedlinger Saum Ghodoussipour Mohit K. Jolly Subhajyoti De |
| author_facet | Antara Biswas Sarthak Sahoo Gregory M. Riedlinger Saum Ghodoussipour Mohit K. Jolly Subhajyoti De |
| author_sort | Antara Biswas |
| collection | DOAJ |
| description | Abstract Intra-tumor heterogeneity contributes to treatment failure and poor survival in urothelial bladder carcinoma (UBC). Analyzing transcriptome from a UBC cohort, we report that intra-tumor transcriptomic heterogeneity indicates co-existence of tumor cells in epithelial and mesenchymal-like transcriptional states and bi-directional transition between them occurs within and between tumor subclones. We model spontaneous and reversible transition between these partially heritable states in cell lines and characterize their population dynamics. SMAD3, KLF4 and PPARG emerge as key regulatory markers of the transcriptional dynamics. Nutrient limitation, as in the core of large tumors, and radiation treatment perturb the dynamics, initially selecting for a transiently resistant phenotype and then reconstituting heterogeneity and growth potential, driving adaptive evolution. Dominance of transcriptional states with low PPARG expression indicates an aggressive phenotype in UBC patients. We propose that phenotypic plasticity and dynamic, non-genetic intra-tumor heterogeneity modulate both the trajectory of disease progression and adaptive treatment response in UBC. |
| first_indexed | 2024-03-08T19:44:51Z |
| format | Article |
| id | doaj.art-da760c2ba979429ea0c8f52471d43aa0 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-08T19:44:51Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-da760c2ba979429ea0c8f52471d43aa02023-12-24T12:26:32ZengNature PortfolioCommunications Biology2399-36422023-12-016111810.1038/s42003-023-05668-3Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinomaAntara Biswas0Sarthak Sahoo1Gregory M. Riedlinger2Saum Ghodoussipour3Mohit K. Jolly4Subhajyoti De5Rutgers Cancer Institute of New Jersey, Rutgers the State University of New JerseyIndian Institute of ScienceRutgers Cancer Institute of New Jersey, Rutgers the State University of New JerseyRutgers Cancer Institute of New Jersey, Rutgers the State University of New JerseyIndian Institute of ScienceRutgers Cancer Institute of New Jersey, Rutgers the State University of New JerseyAbstract Intra-tumor heterogeneity contributes to treatment failure and poor survival in urothelial bladder carcinoma (UBC). Analyzing transcriptome from a UBC cohort, we report that intra-tumor transcriptomic heterogeneity indicates co-existence of tumor cells in epithelial and mesenchymal-like transcriptional states and bi-directional transition between them occurs within and between tumor subclones. We model spontaneous and reversible transition between these partially heritable states in cell lines and characterize their population dynamics. SMAD3, KLF4 and PPARG emerge as key regulatory markers of the transcriptional dynamics. Nutrient limitation, as in the core of large tumors, and radiation treatment perturb the dynamics, initially selecting for a transiently resistant phenotype and then reconstituting heterogeneity and growth potential, driving adaptive evolution. Dominance of transcriptional states with low PPARG expression indicates an aggressive phenotype in UBC patients. We propose that phenotypic plasticity and dynamic, non-genetic intra-tumor heterogeneity modulate both the trajectory of disease progression and adaptive treatment response in UBC.https://doi.org/10.1038/s42003-023-05668-3 |
| spellingShingle | Antara Biswas Sarthak Sahoo Gregory M. Riedlinger Saum Ghodoussipour Mohit K. Jolly Subhajyoti De Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma Communications Biology |
| title | Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma |
| title_full | Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma |
| title_fullStr | Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma |
| title_full_unstemmed | Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma |
| title_short | Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma |
| title_sort | transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma |
| url | https://doi.org/10.1038/s42003-023-05668-3 |
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