Mitochondrial SHMT2 is a crucial therapeutic target in dedifferentiated thyroid cancer (2nd study)

The roles of the serine/glycine metabolic pathway (SGP) have recently been evident in certain types of tumor physiology; however, the pathological relevance of SGP in undifferentiated thyroid cancer remains unexplored. Herein, we employed a comparative transcriptome analysis of bulk RNA sequencing coupled with single-cell RNA sequencing, showing that the high expression of SHMT2 and MTHFD2 is tightly associated with a low thyroid differentiation score (TDS) and poor clinical features in thyroid cancer. In addition, unique metabolic reprogramming of SGP-relevant pathways in dedifferentiated cancer cells, and a distinct trajectory of a subpopulation of tumor cells with a high mitochondrial one-carbon pathway was observed. More importantly, such dramatic changes are functionally relevant, as inhibition of SHMT2 significantly compromises mitochondrial respiration and decreases tumor size by upregulating TDS markers. Taken together, our results highlight the importance of the mitochondrial one-carbon pathway, including SGP, in undifferentiated thyroid cancer and suggest that SHMT2 is a novel therapeutic target. RNA-seq data of 65 fresh frozen normal tissues were generated. Total RNA was isolated by RNeasy Mini Kit (Qiagen, CA, USA), according to the manufacturer's protocol. The quality and integrity of the RNA were confirmed by agarose gel electrophoresis and ethidium bromide staining, followed by visual examination under ultraviolet light. Sequencing library was prepared using TruSeq RNA Sample Preparation kit v2 (Illumina, CA, USA) according to the manufacturer’s protocols. Briefly, mRNA was purified from total RNA using poly-T oligo-attached magnetic beads, fragmented, and converted into cDNAs. Then, adapters were ligated and the fragments were amplified on a PCR. Sequencing was performed in paired end reads (2x75 bp) using NextSeq 500 platform (Illumina).