Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma

Biswas, A and Sahoo, S and Riedlinger, GM and Ghodoussipour, S and Jolly, MK and De, S (2023) Transcriptional state dynamics lead to heterogeneity and adaptive tumor evolution in urothelial bladder carcinoma. In: Communications Biology, 6 (1).

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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. © 2023, The Author(s).

Item Type:	Journal Article
Publication:	Communications Biology
Publisher:	Nature Research
Additional Information:	The copyright for this article belongs to authors.
Keywords:	peroxisome proliferator activated receptor gamma, bladder; bladder tumor; disease exacerbation; human; pathology; transitional cell carcinoma, Carcinoma, Transitional Cell; Disease Progression; Humans; PPAR gamma; Urinary Bladder; Urinary Bladder Neoplasms
Department/Centre:	Others
Date Deposited:	16 Nov 2024 15:35
Last Modified:	16 Nov 2024 15:35
URI:	http://eprints.iisc.ac.in/id/eprint/85321

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