Abstract A018: Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival and metastasis of HER2-positive and basal breast cancer through regulation of caspase 14

Abstract

Abstract Despite improvements in therapies, metastasis still leads to high mortality rates in breast cancer (BC). Consequently, discovering new therapies that are effective at targeting metastatic disease remains a critical need, particularly for the aggressive HER2+ and basal BC subtypes. The ability of cancer cells to survive in the absence of an extracellular matrix – termed anchorage-independent survival (AIS) – is central to the metastatic cascade and has emerged as a target biology of interest for reducing metastatic burden. Previously, we identified the SL enzyme dihydroceramide desaturase 1 (DES1) as a critical node for AIS of HER2+ BC cells. Here, we have extended these data to show that targeting DES1 through pharmacological inhibitors (4HPR), siRNA, or CRISPR-cas9 knockout was able to overcome AIS in basal BC cells as well as HER2+ BC cells that, functionally, led to a reduction of in vitro colony formation in soft agar. Extending these findings in vivo, we found that DES1 knockout led to a significant reduction in lung metastasis of both HER2+ and basal BC cells in murine models of experimental metastasis. Moreover, treatment of PyMT mice with the DES1 inhibitor 4HPR was able to reduce metastatic burden. To define downstream effectors of DES1 required for AIS, we performed a microarray analysis of control and DES1 knockout cells in suspension, leading us to identify caspase 14 as a downstream effector of DES1 in HER2+ and basal BC. Consistent with these findings, siRNA knockdown of caspase 14 led to a striking decrease in cell viability in colony formation assays. Finally, analysis of publicly available data found that high levels of DES1 and Caspase 14 were associated with poor clinical outcomes in both HER2+ and basal BC. Taken together, these data establish DES1 as a mediator of BC metastasis, likely through promoting AIS, and define caspase 14 as a target of DES1-driven signaling. Furthermore, results suggest that both DES1 and caspase 14 expression may be useful as biomarkers of metastasis-prone tumors. Citation Format: Deanna M Peperno, Danielle Lambadis, Victoria Alvarado, Andrew E Resnick, Christopher J Clarke. Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival and metastasis of HER2-positive and basal breast cancer through regulation of caspase 14 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A018.