The overarching goal of the lab is to examine and characterize the biological mechanisms that permit cancer cell survival during tumor progression. We are especially interested in changes in cell death programs or metabolism caused by detachment of cells from the extracellular matrix (ECM). Currently, we have 3 distinct research projects all aimed at achieving this overarching goal.

1. Mitophagy and non-apoptotic mechanisms of cell death during ECM-detachment. We have discovered that the activation of RIPK1 can selectively eliminate ECM-detached cells and that cancer cells defective in RIPK1-mediated mitophagy are better able to form tumors in vivo (Hawk et al, Nat Cell Biol. 2018 Mar;20(3):272-284). Currently, we are investigating mechanisms underlying how mitophagy can kill cancer cells, studying links between ECM-detachment-mediated metabolic changes and cell death modalities, and investigating potential vulnerabilities that could be exploited to kill ECM-detached cancer cells. Our discovery of RIPK1-mediated mitophagy as a means to cause death in cancer cells has led us to investigate the importance of this new cell death pathway in additional disease contexts. We have initiated studies to assess mitophagy in Friedreich’s Ataxia (FA), a progressive, autosomal-recessive, neuro- and cardio-degenerative disorder. FA is caused by diminished expression of Frataxin (FXN), a mitochondrial matrix protein involved in iron-sulfur (Fe-S) cluster biogenesis. We are conducting pre-clinical studies aimed at understanding how changes in cell metabolism and mitophagy can impact oxidative stress that arises as a consequence of FXN deficiency.

2. Iron metabolism during ECM-detachment and ferroptosis markers. We have found that ECM-detached cells are resistant to the induction of ferroptosis, an iron-dependent form of non-apoptotic cell death. Underlying this resistance to ferroptosis is changes in iron metabolism that limit the abundance of redox-active iron necessary for ferroptotic cell death (He et al, iScience. 2023 Jun 16; 26(6):106827). Currently, we are investigating how we could sensitize ECM-detached cells to ferroptosis through modulation of iron metabolism and are studying how changes in iron metabolism might function as markers for cells dying by ferroptosis.

3. The intersection of signal transduction, metabolic reprogramming, and the tumor microenvironment. Our previous studies have found that distinct oncogenic insults can rewire metabolism during ECM-detachment to promote survival (Mason, Cockfield et al, Cell Rep. 2021 Mar 16;34(11):108821) and that stromal cells and cancer cells communicate to effectuate cell death (Hom et al, J Biol Chem. 2023 Jun 13;:104922). Our current studies are focused on understanding how metabolic changes in cancer cells can impact immune cell function.