Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer
Year: 2026
Type: preprint
Abstract: Background Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2 , CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2/BrafV600E/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2 -/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.
Source: medRxiv
Authors: Mary Grace Carroll, Noha Mukhtar, Jacob Calhoun, Breaunna Garza, Matthew A. Loberg, Hua-Chang Chen, Quanhu Sheng, Alyse Staley, Tatiana L. Fonseca, Antonio C. Bianco, Matthew D. Ringel, Pamela Brock, Andrew J. Gunderson, Ahmad A. Tarhini, W. Douglas Cress, Michael J. Cavnar, Stephen Edge, Varinder Kaur, George J. Weiner, Janice L. Farlow, Robert Dood, Roman Groisberg, Abdul Rafeh Naquash, Craig Shriver, Dinesh Pal Mudaranthakam, Jose A. Oliveras, Robert J Rounbehler, Michelle L. Churchman, Vivian L. Weiss, Rebecca E. Schweppe, Nikita Pozdeyev, Bryan R Haugen
Institutions: University of Colorado Anschutz, King Faisal Specialist Hospital & Research Centre, Vanderbilt University Medical Center, University of Colorado Cancer Center, The University of Texas Medical Branch at Galveston, The Ohio State University Wexner Medical Center, Moffitt Cancer Center, University of Kentucky, Roswell Park Comprehensive Cancer Center, University of Virginia, University of Iowa, Indiana University Indianapolis, University of Utah, Rutgers, The State University of New Jersey, University of Oklahoma, Walter Reed National Military Medical Center, University of Kansas, Ponce Health Sciences University
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214107909