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Bladder cancer subtypes exhibit limited plasticity across different microenvironments and in metastases

Bernardo, Carina LU orcid ; Chattopadhyay, Subhayan LU orcid ; Andersson, Natalie LU orcid ; Eriksson, Pontus LU ; Medle, Benjamin LU ; Tran, Lena LU ; Marzouka, Nour-Al-Dain LU ; Mattsson, Adam LU ; Zadoroznyj, Aymeric LU and Larsson, Malin , et al. (2025) In Experimental Hematology and Oncology 14(91).
Abstract
Background
Transcriptomic and genomic analyses of bladder cancer (BC) reveal a highly diverse disease stratified into molecular subtypes with distinct molecular features and biological behaviors. Intratumor heterogeneity (ITH) and plasticity can significantly impact diagnosis and patient management, yet their extent in BC remains highly debated. Here, we investigated whether the three main bladder cancer subtypes maintain or alter their identity in response to changes in the microenvironment and during metastatic colonization.

Methods
Seven patient-derived xenograft (PDX) models representing the major BC subtypes were propagated into three distinct tissue microenvironments: subcutaneous, mammary fat pad and under the... (More)
Background
Transcriptomic and genomic analyses of bladder cancer (BC) reveal a highly diverse disease stratified into molecular subtypes with distinct molecular features and biological behaviors. Intratumor heterogeneity (ITH) and plasticity can significantly impact diagnosis and patient management, yet their extent in BC remains highly debated. Here, we investigated whether the three main bladder cancer subtypes maintain or alter their identity in response to changes in the microenvironment and during metastatic colonization.

Methods
Seven patient-derived xenograft (PDX) models representing the major BC subtypes were propagated into three distinct tissue microenvironments: subcutaneous, mammary fat pad and under the kidney capsule. Metastatic lesions were generated via systemic injection of tumor cells. Tumor samples were analysed using RNA- and exome sequencing, SNP-arrays and histopathology to assess subtype fidelity, genomic evolution, and clonal dynamics.

Results
A comprehensive, longitudinal multiomics analysis showed that tumors consistently maintain their molecular subtype, as well as their transcriptomic and genomic profiles, across different environments. No evidence of emerging ITH or subtype transitions was observed, regardless of the microenvironment. The transcriptomic adaptations observed in metastases and different implantation sites are limited and are associated primarily with hypoxia, epithelial-mesenchymal transition (EMT), and invasion.

Conclusions
Our results suggest that invasive bladder cancers have a strong intrinsic tumor identity that is not easily reprogrammed by the microenvironment. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology and Oncology
volume
14
issue
91
article number
91
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40605119
ISSN
2162-3619
DOI
10.1186/s40164-025-00682-z
language
English
LU publication?
yes
id
068fdb6c-2ea7-4e06-ae67-6cba327cf020
date added to LUP
2025-07-07 08:59:19
date last changed
2025-07-08 03:22:13
@article{068fdb6c-2ea7-4e06-ae67-6cba327cf020,
  abstract     = {{Background<br/>Transcriptomic and genomic analyses of bladder cancer (BC) reveal a highly diverse disease stratified into molecular subtypes with distinct molecular features and biological behaviors. Intratumor heterogeneity (ITH) and plasticity can significantly impact diagnosis and patient management, yet their extent in BC remains highly debated. Here, we investigated whether the three main bladder cancer subtypes maintain or alter their identity in response to changes in the microenvironment and during metastatic colonization.<br/><br/>Methods<br/>Seven patient-derived xenograft (PDX) models representing the major BC subtypes were propagated into three distinct tissue microenvironments: subcutaneous, mammary fat pad and under the kidney capsule. Metastatic lesions were generated via systemic injection of tumor cells. Tumor samples were analysed using RNA- and exome sequencing, SNP-arrays and histopathology to assess subtype fidelity, genomic evolution, and clonal dynamics.<br/><br/>Results<br/>A comprehensive, longitudinal multiomics analysis showed that tumors consistently maintain their molecular subtype, as well as their transcriptomic and genomic profiles, across different environments. No evidence of emerging ITH or subtype transitions was observed, regardless of the microenvironment. The transcriptomic adaptations observed in metastases and different implantation sites are limited and are associated primarily with hypoxia, epithelial-mesenchymal transition (EMT), and invasion.<br/><br/>Conclusions<br/>Our results suggest that invasive bladder cancers have a strong intrinsic tumor identity that is not easily reprogrammed by the microenvironment.}},
  author       = {{Bernardo, Carina and Chattopadhyay, Subhayan and Andersson, Natalie and Eriksson, Pontus and Medle, Benjamin and Tran, Lena and Marzouka, Nour-Al-Dain and Mattsson, Adam and Zadoroznyj, Aymeric and Larsson, Malin and Liedberg, Fredrik and Höglund, Mattias and Sjödahl, Gottfrid}},
  issn         = {{2162-3619}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{91}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Experimental Hematology and Oncology}},
  title        = {{Bladder cancer subtypes exhibit limited plasticity across different microenvironments and in metastases}},
  url          = {{http://dx.doi.org/10.1186/s40164-025-00682-z}},
  doi          = {{10.1186/s40164-025-00682-z}},
  volume       = {{14}},
  year         = {{2025}},
}