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effective at inhibiting breast and lung cancer respectively [126,127] . Serine is converted to glycine in the
cytoplasm via serine hydroxymethyltransferase 1 (SHMT1) to donate a methylene group to tetrahydrofolate
[35]
(THF), forming 5,10 m-THF in the process . SHMT1 is high in PTC and ATC and can be inhibited with
SHIN1, which has a high affinity for both isoforms of SHMT [124,128] . The 5,10 m-THF is then used for dTMP
generation via TYMS, forming dihydrofolate (DHF) in the process. DHF is converted back to THF via
DHFR, which requires NADPH to be re-oxidized [15,35] .

GLUTAMINE METABOLISM
[129]
Glutamine is recognized as one of the most important amino acids in cancer metabolism . It acts as a
carbon and nitrogen source for a variety of important biosynthetic pathways. Glutamine is the most
abundant amino acid in serum and is taken up by the cell by a few transporters, most notably alanine,
serine, cysteine transporter 2 (ASCT2) [Figure 5] . ASCT2 expression is correlated with BRAF V600E and is
[130]
[131]
expressed the highest in PDTC tumors . Small molecules such as L-γ-Glutamyl-p-nitroanilide,
phenylacetate, and V-9302 are selective inhibitors for blocking ASCT2-mediated glutamine transport [132-135] .
Notably, phenylacetate inhibited PTC and FTC growth in vitro . Once in the cell, glutamine can
[136]
immediately be used in several steps of nucleotide synthesis to donate nitrogen atoms to the ribose
base [35,111,129] . In the cytoplasm, glutamine can be exchanged for neutral non-branched amino acids via LAT1
[137]
which was highly expressed in PTC and ATC . JPH203, a LAT1 inhibitor, slowed TC growth in vitro and
inhibited ATC growth in xenograft models [137,138] . Glutamine can also be converted to glutamate by
glutaminase (GLS1/2), which is highly expressed in PTC, FTC, and ATC [131,139] . Glutaminase inhibitors such
as CB-839 and BPTES have already demonstrated success at inhibiting PTC and ATC growth in vitro [140,141] .
Glutamate and aspartate can be transaminated to αKG and OAA via aspartate aminotransferase. These
anaplerotic reactions are essential for replenishing TCA cycle intermediates from excess glutamate and
aspartate [15,35] . Glutamate can directly be converted to αKG in the mitochondria via glutamate
dehydrogenase (GDH), which is overexpressed in PTC, FTC, and ATC . GDH is inhibited by
[131]
epigallocatechin gallate, which worked well in PTC and FTC to slow growth .
[142]
THYROID CANCER METABOLISM AND CELL SIGNALING INTEGRATION
It is important to understand the metabolic landscape of an individual tumor to strategically inhibit
aberrant metabolic pathways [Figure 6]. PTC and ATC tumors typically exhibit overactive MAPK signaling
due to BRAF V600E[1] . Hyperphosphorylation of the downstream targets of BRAF, MEK and ERK, leads to
increased cell proliferation, survival, and inhibition of apoptosis by regulating oncogene transcription .
[143]
Constitutively activated BRAF strongly correlates with enhanced expression of all three serine synthesis
[124]
genes . Whether this observation is simply a correlation, or if these genes are directly regulated by MAPK
signaling is unknown. At least in PTC, PKM2 is highly expressed, which increases the rate of glycolysis, and
PKM2 is further activated by high serine levels [45,46,49] . Low serine levels cause PKM2 to adopt a dimer
configuration to support serine and nucleotide synthesis. This is further promoted by ERK-mediated
phosphorylation, and p-PKM2 can phosphorylate ERK in return to enhance oncogenic signaling [42,44,46] . This
serine-PKM2-ERK axis may represent an unexplored metabolic switch in TC tumors driven by BRAF V600E .
In contrast to PTC, FTC (and ATC) tumors demonstrate highly active PI3K signaling. The tumor
promoters Akt and mTORC1 are phosphorylated as a result of aberrant PI3K activity and have major roles
in macromolecule synthesis. Akt stimulates fatty acid and glycogen synthesis while mTORC1 promotes
protein synthesis by regulating translation factors and inhibits autophagy [1,6,144-146] . Accordingly, FTC tumors
have been shown to upregulate fatty acid metabolism via ACC and CACT [102,105] , the glycogen buildup and
[31]
breakdown enzyme PGM1 , and enzymes for amino acid metabolism such as ASCT2, GLS, and
GDH [131,139] . There may be a connection between the aberrant signaling landscape in FTC tumors and these
specific metabolic pathways. FTC tumors may be primed to store carbon in the form of glycogen and fatty