DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Wilms tumor is the most common pediatric kidney cancer, originating from embryonic renal progenitors.
• Therapeutic targeting of Wilms tumor driver mutations, including those in the microRNA processing gene DROSHA, remains a significant challenge.

Purpose of the Study:

• To elucidate the effects of DROSHA mutations in Wilms tumor using a multiomics approach.
• To define genotype-transcriptome relationships and identify potential therapeutic vulnerabilities.

Main Methods:

• Multiomics analysis of Wilms tumor samples.
• Categorization of mutations into four subclasses based on transcriptional effects.
• Inhibition of DROSHA expression in a Wilms tumor cell line.
• Investigation of redox metabolism and ferroptosis sensitivity.

Main Results:

• DROSHA mutations correlate with de-repression of microRNA targets, promoting differentiation, proliferation, and a mesenchymal state.
• Inhibition of DROSHA upregulates the cell cycle regulator cyclin D2 (CCND2).
• Wilms tumor cells with DROSHA mutations exhibit altered redox metabolism and are sensitized to ferroptosis via glutathione peroxidase 4 inhibition.

Conclusions:

• This study establishes genotype-transcriptome correlations in Wilms tumor.
• Ferroptosis represents a potential therapeutic vulnerability in a subset of Wilms tumor patients with microRNA pathway alterations.