Summary
A medRxiv preprint reports that DIO2 is concentrated in cancer-associated fibroblasts across several solid tumours. In a genetically engineered mouse model, loss of Dio2 in the tumour microenvironment significantly reduced tumour growth.
A medRxiv preprint reports that the enzyme DIO2 is concentrated in cancer-associated fibroblasts (CAFs) across thyroid cancer and six other solid tumour types. In a genetically engineered mouse model of thyroid cancer, genetic loss of Dio2 in the tumour microenvironment significantly reduced tumour growth. The findings point to a possible role for DIO2 in tumour-supporting tissue, but the growth result is preclinical rather than evidence from a treatment study in people.
DIO2 was concentrated in a stromal cell population
CAFs are connective-tissue cells found within tumours. They are part of the tumour microenvironment—the cells and structures surrounding cancer cells—and can occur in different states, including myofibroblastic and inflammatory forms. DIO2, also called type 2 deiodinase or D2, converts thyroxine (T4) into the active thyroid hormone triiodothyronine (T3).
The researchers analysed single-cell RNA-sequencing data from primary thyroid tumours, an integrated thyroid-cancer atlas and publicly available datasets for six other solid tumour types. These analyses found DIO2 expression largely restricted to CAFs, with little expression in cancer cells, immune cells or endothelial cells. Within thyroid cancer, DIO2 was more prominent in myofibroblastic CAFs than in inflammatory CAFs. Analyses of bulk tumour RNA data also found stronger correlations between DIO2 and markers of myofibroblastic CAFs than with inflammatory CAF markers across multiple cancers.
Bulk RNA sequencing measures gene expression across mixed tissue, while single-cell sequencing can help assign expression to particular cell populations. That distinction matters here: the authors report that thyroid cancer showed an inverse relationship between DIO2 and outcomes, which they attribute to loss of DIO2 expression in epithelial tumour cells as cancers become less differentiated. In bulk samples, expression from different cell types can contribute to the overall measurement.
Mouse experiments provide a functional signal
The study also used a genetically engineered thyroid-cancer mouse model, called TBP, to examine Dio2 in the tumour stroma. The authors report that the model reproduced key features relevant to their analysis, including Dio2 expression in CAFs and stromal fibrosis. D2 enzyme activity was measurable and was suppressed by cefuroxime and lenvatinib in the model.
When the researchers crossed TBP mice with mice lacking Dio2, tumour growth was significantly reduced. This result gives the expression findings a functional dimension: Dio2 loss in the tumour microenvironment affected tumour growth in this model. The abstract does not specify the size of that reduction or establish which downstream process caused it.
The human-data analyses found that higher DIO2 expression was associated with worse overall survival in pancreatic and bladder cancers, in a pattern that paralleled the reported adverse association with greater myofibroblastic CAF abundance. These are associations in transcriptomic data, not evidence that DIO2 itself caused poorer outcomes.
Together, the study identifies DIO2 as a recurring marker of CAFs and reports a tumour-growth effect from its loss in a mouse model. The evidence combines analyses of human tumour data with preclinical experiments; it is not a clinical trial of a DIO2-targeted treatment. The preprint frames further work on DIO2’s role in CAF biology and therapeutic strategies as the next step.