Sphingolipids in Cancer Biology and Therapy

ABSTRACT The overall organizing hypothesis of this Program posits that the highly integrated sphingolipid (SL) metabolism regulates important cancer functions, especially in anchorage-independent growth (AIG), DNA damage response, and cytotoxic responses. As a consequence, enzymes of SL metabolism are emerging as clear targets for specific intervention as well as for modulation of adverse effects of chemotherapeutics. Unfortunately, the study of bioactive lipids encounters significant complexities, both conceptual and technical and thus the study of lipids necessitates the collaborative interactions of various disciplines and specialized cores. Thus, we have evolved 3 distinct projects that collaborate to investigate the overall hypothesis, focusing on breast cancer. These projects address highly interrelated metabolic pathways with important functions. Each project has identified a key node in these pathways that constitutes a specific vulnerability in the target cancer under study. Thus, Project 1 will test the hypothesis that neutral sphingomyelinase 2 is an important tumor suppressor enzyme, acting through ceramide and downstream signaling pathways to prevent the progression and metastasis of breast cancer. Project 2 will test the hypothesis that the p53-dependent upregulation of ACER2 mediates chemotherapy-induced myelosuppression. Clinically, inhibiting the ACER2/SPH pathway should mitigate CIM and thereby improve the efficacy of chemotherapy against p53-mutant cancers. Project 3 will test the hypothesis that targeting critical nodes of SL metabolism to mimic the SL response observed with cytotoxic chemotherapy doses will sensitize BC cells to low doses, while also overcoming dangerous prometastatic functions. These 3 projects will be supported by two unique research cores: The Lipidomics Shared Resource which will provide advanced analytical lipid chemistry with new and novel capabilities for flux analysis and tissue imaging of lipids, and by a Sphingolipid Animal Cancer Pathobiology Shared Resource that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and models of in vivo carcinogenesis. It has recently introduced biobanking and CRISPR-mediated nock outs. This Program group has been highly integrated and productive (having published in the past 5 years 80 manuscripts, 45 of which were in collaboration) and has advanced significantly our understanding of sphingolipids (one of the last frontiers of basic research) in caner biology and therapeutics. We are now poised to advance pre-clinical studies and translational research based on our understanding of these novel pathways. These studies continue to identify novel targets and strategies for cancer therapeutics.