Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

Area of Science:

• Biochemistry
• Oncology
• Genetics

Background:

• Mutations in tricarboxylic acid (TCA) cycle enzymes are linked to various human cancers.
• Succinate dehydrogenase (SDH) complex mutations are recently implicated in differentiated thyroid cancer.

Purpose of the Study:

• To investigate the mechanistic role of SDH subunit D (SDHD) in thyroid tumorigenesis.
• To explore the metabolic alterations and cellular changes associated with SDHD deficiency in thyroid cells.

Main Methods:

• Generation of mice lacking SDHD specifically in the thyroid.
• In vitro studies using human thyroid cell lines with SDHD knockdown.
• Analysis of cellular proliferation, migration, and stem-like features.
• Assessment of the effect of α-ketoglutarate on cellular characteristics.

Main Results:

• Mice lacking Sdhd developed enlarged thyroid glands with hypercellularity and increased proliferation.
• SDHD-knockdown thyroid cells showed enhanced migration but not proliferation.
• These cells acquired stem-like features, observed in both cell lines and mouse tumors.
• α-ketoglutarate reversed the stem-like characteristics.

Conclusions:

• SDH-associated thyroid tumorigenesis is driven by dedifferentiation due to TCA cycle metabolic imbalance.
• SDHD deficiency leads to stem-like cell acquisition and altered cellular behavior.
• Metabolic reprogramming targeting the TCA cycle presents a potential therapeutic vulnerability for SDH-associated neoplasia.