Overview

Cell death is a fundamental biological process necessary for development and to maintain homeostasis in adulthood. When the normal regulation of cell death is lost this can cause diseases such as cancer. In medicine, the goal of many treatments is to induce cell death (e.g. chemotherapy or radiation treatment for cancer), or to prevent cell death when it is not wanted (e.g. during stroke or heart attack). Understanding the biochemical and genetic regulation of cell death therefore has substantial basic and clinical importance. We currently have a broad interest in the regulation of non-apoptotic and apoptotic cell death. In particular, we want to understand how the perturbation of intracellular metabolism causes different forms of cell death. We also would like to discover new small molecules that can induce or inhibit cell death. Our work combines cell biology, metabolism, chemical biology and biochemical approaches, along with extensive use of advanced chemical and genetic screening. Our studies are enriched by collaborations with labs all over the world.

NEW projects fall into TWO major areas:

Project 1. Analysis of Glioblastoma Cell Death
Glioblastoma is a deadly form of brain cancer with few effective treatment options. Together with colleagues at UCLA, we are working with patient-derived glioblastoma, which are grown in suspension culture as spheroids (see the beautiful images, below). We are searching for new ways to kill these cells. Recent and ongoing projects include analyzing how these cells undergo ferroptosis, and deciphering interactions between the cancer cells and surrounding cells in the brain that may modulate cell death responses. For this project we are making extensive use of high-throughput imaging techniques we have developed in the lab.

Project 2. Investigating a Novel Form of Cell Death
Many cancers are resistant to the best-known form of cell death, apoptosis. It therefore seems logical to try and find ways that can kill cancer cells without needing to activate the apoptosis pathway. Towards this goal, we have shown that the small molecule CIL56 triggers an unconventional form of non-apoptotic cell death in a variety of cancer cells. This form of cell death is characterized by “ballooning” of the Golgi apparatus (seen in the images, below). Moreover, this type of cells death depends on a protein palmitoylation complex that we discovered that contains the palmitoyltransferase ZDHHC5 and the accessory subunit GOLGA7. Ongoing projects include discovering the molecular target of CIL56, assessing how protein palmitoylation is involved in cell death, and searching for new small molecules that can induce this mechanism.