Spatially resolved tumor-microenvironment architecture defines therapeutic response in unresectable hepatoblastoma
- 1UPMC Children's Hospital of Pittsburgh
Abstract
Background: Hepatoblastoma exhibits variable therapeutic response that is not fully explained by current risk stratification. While prior studies have characterized tumor composition, the role of spatial organization in determining outcome, particularly in unresectable disease requiring transplantation under immunosuppression, remains unclear. Methods: We integrated spatial transcriptomics using the 10x Genomics Visium platform (n = 11 tumors) with single-cell spatial molecular imaging using NanoString CosMx (n = 3 tumors) on post-chemotherapy explant specimens across clinically defined groups (relapse-prone unresectable, non-relapse unresectable, and resectable hepatoblastoma). Spatial deconvolution, module scoring, spatial co-localization, and cell-cell interaction analyses were used to define region-level transcriptional programs and their underlying cellular organization. Results: We identified three spatial architectures associated with clinical outcome. Relapse-prone tumors exhibited a centralized, TME-dominated organization enriched for progenitor-like, cycling, and stress-responsive tumor cell states co-localized with SPP1+ TAMs and CAFs, with enrichment of hypoxia response, extracellular matrix remodeling, and Midkine (MDK-LRP1) signaling. Non-relapse tumors displayed a distributed architecture with compartmentalized tumor-immune interactions, increased immune engagement, and preserved epithelial differentiation, including inflammatory hepatocyte-like states. Resection samples showed reduced tumor cell state heterogeneity and more uniform TME-immune organization. Conclusions: Integration of regional and single-cell spatial transcriptomics across two platforms reveals that the chemo-remodeled tumor architecture of hepatoblastoma encodes spatially organized tumor cell-TME interactions as central determinants of therapeutic response.
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BibTeX
@misc{mesrizadeh2026spatially,
title = {{Spatially resolved tumor-microenvironment architecture defines therapeutic response in unresectable hepatoblastoma}},
author = {Z. Mesrizadeh and M. Ningappa and S. Ranganathan and K. Mukund and C. Gestrich and J. Meade and J. H. Squires and L. A. Schmitt and G. Mazariegos and M. Malek and C. Ashokkumar and W. n. A. MacDonald and P. Morgan and S. Subramaniam and R. Sindhi},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.758234},
url = {https://www.biorxiv.org/content/10.64898/2026.10.10.758234v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Spatially resolved tumor-microenvironment architecture defines therapeutic response in unresectable hepatoblastoma
AU - Z. Mesrizadeh
AU - M. Ningappa
AU - S. Ranganathan
AU - K. Mukund
AU - C. Gestrich
AU - J. Meade
AU - J. H. Squires
AU - L. A. Schmitt
AU - G. Mazariegos
AU - M. Malek
AU - C. Ashokkumar
AU - W. n. A. MacDonald
AU - P. Morgan
AU - S. Subramaniam
AU - R. Sindhi
PY - 2026
DA - 2026/10/10
PB - bioRxiv
DO - 10.64898/2026.10.10.758234
UR - https://www.biorxiv.org/content/10.64898/2026.10.10.758234v1
AB - Background: Hepatoblastoma exhibits variable therapeutic response that is not fully explained by current risk stratification. While prior studies have characterized tumor composition, the role of spatial organization in determining outcome, particularly in unresectable disease requiring transplantation under immunosuppression, remains unclear. Methods: We integrated spatial transcriptomics using the 10x Genomics Visium platform (n = 11 tumors) with single-cell spatial molecular imaging using NanoString CosMx (n = 3 tumors) on post-chemotherapy explant specimens across clinically defined groups (relapse-prone unresectable, non-relapse unresectable, and resectable hepatoblastoma). Spatial deconvolution, module scoring, spatial co-localization, and cell-cell interaction analyses were used to define region-level transcriptional programs and their underlying cellular organization. Results: We identified three spatial architectures associated with clinical outcome. Relapse-prone tumors exhibited a centralized, TME-dominated organization enriched for progenitor-like, cycling, and stress-responsive tumor cell states co-localized with SPP1+ TAMs and CAFs, with enrichment of hypoxia response, extracellular matrix remodeling, and Midkine (MDK-LRP1) signaling. Non-relapse tumors displayed a distributed architecture with compartmentalized tumor-immune interactions, increased immune engagement, and preserved epithelial differentiation, including inflammatory hepatocyte-like states. Resection samples showed reduced tumor cell state heterogeneity and more uniform TME-immune organization. Conclusions: Integration of regional and single-cell spatial transcriptomics across two platforms reveals that the chemo-remodeled tumor architecture of hepatoblastoma encodes spatially organized tumor cell-TME interactions as central determinants of therapeutic response.
ER -