Thymidylate synthase maintains the de-differentiated state of aggressive breast cancers

Abstract

Mechanistically, TS enzymatic activity was found essential for the maintenance of the EMT/stem-like state by fueling a DPYD-dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC (TNBC), and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.

Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer

“…We confirmed the multifaceted role of TS proliferation and chemoresistance and found a strong correlation with EMT gene signatures and prognosis, highlighting clinical, as well as biological relevance of TS in NSCLC. Interestingly, presented results clearly corroborate that different functions of TS can operate independently, as observed that TS depletion can mitigate EMT phenotypes without triggering proliferation loss (in LL/2 cells and in other previous settings (12)). This provides a strong rationale to revisit clinical and therapeutic aspects of TS in tumor biology and explore its therapeutic potential beyond proliferation.…”

“…A moderate Ts depletion ( Figure 4A) did not affect proliferation (Supp. Figure 4D), as we had previously seen that TS needs to reduce beyond a threshold to diminish proliferation (12). Furthermore, Ts knockdown did not hamper growth of primary tumors from the cells subcutaneously injected in flanks of syngeneic mice (Figure 4B), confirming our previous observation in triple negative breast cancer and NSCLC cell lines that TS must be reduced below a threshold level to effect proliferation (11,12).…”

“…Figure 4D), as we had previously seen that TS needs to reduce beyond a threshold to diminish proliferation (12). Furthermore, Ts knockdown did not hamper growth of primary tumors from the cells subcutaneously injected in flanks of syngeneic mice (Figure 4B), confirming our previous observation in triple negative breast cancer and NSCLC cell lines that TS must be reduced below a threshold level to effect proliferation (11,12). However, when injected in the tail vein, knocked down cells showed a highly significant reduction in lung metastatic colonization (Figures 4C-D), and the mice carrying cells with Ts depletion showed a significantly prolonged survival ( Figure 4E).…”

“…It is targeted by chemotherapeutic drugs, like pemetrexed, in NSCLC, and has been widely studied as a chemoresistance marker (10). Our lab recently showed a correlation between expression of TS and EMT markers in NCI-60 panel of cancer cell lines originating from different tissues (11), and established its role in maintaining the dedifferentiated mesenchymal-like state of triple negative breast cancer (12). In this study we present evidence that TS is not a mere proliferation marker in NSCLC, but also has a direct role in driving EMT phenotypes, with several biological and clinical implications.…”

Long non-coding RNAs affecting cell metabolism in cancer

“…Although serine is a nonessential amino acid, several cancer cells rely on de novo synthesis of serine, which is required for the biosynthesis of lipids, protein, nucleotide, and amino acids [72]. It has been shown that enzymes controlling nucleotides biosynthesis are also responsible for TNBC de-differentiation [73]. The first step of this pathway is the oxidation of 3-Phosphoglycerate to 3-phosphohydroxypyruvate by the enzyme Phosphoglycerate dehydrogenase [74,75].…”