Cholesterol Biosynthesis Influences Subtype Specificity and Plasticity in Pancreas Cancer

Abstract

Cellular plasticity contributes to intratumoral heterogeneity, metastatic spread, and treatment resistance of cancers. In this issue of Cancer Cell, Gabitova-Cornell et al. identify the potential to inadvertently develop an undifferentiated and more aggressive pancreas cancer with agents commonly prescribed to manage heart disease risk.

Figure 1.. Cholesterol Metabolism and Differentiation State of Pancreas Cancer

Gabitova-Cornell et al. (2020) propose that inhibiting cholesterol biosynthesis (CB)—through pharmacologic blockade of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR); or genetic deletion of a key downstream enzymatic subunit, NAD(P)-dependent steroid dehydrogenase-like (Nsdhl) —relieves inhibition of sterol regulatory element binding protein 1 (SREBP1) binding to the Tgfb1 promoter. Together with an associated increase in active (H3K4me3) and decrease in repressive (H3K27me3) chromatin marks proximal to the Tgfb1 transcription start site, this results in increased gene expression. Increased autocrine TGFB1 signaling promotes conversion of classical PDA (CK⁺VIM⁻CDH1⁺) to a more basal-like PDA (VIM⁺CK⁺CDH1⁻), manifesting an increased capacity for EMT and more aggressive disease. Intermediates in the CB pathway are critical for other cellular processes that may also impact disease biology. CK, cytokeratin; VIM, vimentin; and CDH1, E-cadherin.