Dihydroceramide desaturase 1 (DES1) promotes anchorage‐independent survival downstream of HER2‐driven glucose uptake and metabolism

Oncogenic reprogramming of cellular metabolism is a hallmark of many cancers, but our mechanistic understanding of how such dysregulation is linked to tumor behavior remains poor. In this study, we have identified dihydroceramide desaturase (DES1)—which catalyzes the last step in de novo sphingolipid synthesis—as necessary for the acquisition of anchorage‐independent survival (AIS), a key cancer enabling biology, and establish DES1 as a downstream effector of HER2‐driven glucose uptake and metabolism. We further show that DES1 is sufficient to drive AIS and in vitro tumorigenicity and that increased DES1 levels—found in a third of HER2+ breast cancers—are associated with worse survival outcomes. Taken together, our findings reveal a novel pro‐tumor role for DES1 as a transducer of HER2‐driven glucose metabolic signals and provide evidence that targeting DES1 is an effective approach for overcoming AIS. Results further suggest that DES1 may have utility as a biomarker of aggressive and metastasis‐prone HER2+ breast cancer.