Category: Publications
El-Kenawi, et al., 2019, Cancer likes it sour!
In his early work, the great Otto Warburg was the first to describe preference of cancer cells to metabolize glucose into lactate even in the presence of oxygen, a phenomenon termed aerobic glycolysis. Although, aerobic glycolysis is an inefficient way to generate cellular energy (produce 2 ATP molecules) it may provide cancer cells with proliferative privilege more than the normal metabolic pathway, oxidative phosphorylation (produce 36 ATP molecules). The proliferative advantage of glycolytic phenotype may be because:
-It facilitates the uptake and incorporation of nutrients into the growing biomass (Reference).
-The metabolic products of glycolysis, such as hydrogen ions and lactate, cause a heterogeneous but consistent acidification of the extracellular space, which results in harsh conditions that kills normal cells allowing more space for tumor to grow (Gatenby and Gillies, 2004).
In El-Kenawi, et al., 2019, we demonstrated that acids released by cancer cells can convert a type of immune cells called macrophage towards tumor-loving phenotype. Macrophage are multi-functional immune cells and their phenotype can shift depending on their surroundings. Thus, by dumping acids into the extracellular space, cancer cells avoid the tough side of macrophages functionality “being cytotoxic”. Education of macrophages by prostate cancer cells was associated by the release of cytokines and upregulation of CD206, ARG1 and the cholesterol transporter ABCA1. This motivated me to tackle the function of macrophage cholesterol in Next Publication.
El-Kenawi et al., 2023 Persisters: the story of cells left behind!
Evolution of resistance is a major barrier to prolonged tumor control. Growing evidence suggests that resistance can be driven by few number of cells which remains after treatment, known as persisters or residual tumor cells. How these cells resist anti-cancer treatment? It depends on the way they die with or what we call “cell death pathways”!
There are many types of cell death pathway: such as apoptosis, necroptosis, pyroptosis and necrosis.
In this paper, we focus on mechanism which enable resistance to pyroptosis, a type of inflammatory cell death which usually occur in macrophages, a type of innate immune cells. To decipher the molecular mechanisms of resistance to pyroptosis, we combined time-lapse imaging with longitudinal DNA/RNA sequencing and metabolomics. We found that these persisters lap up methionine to counteract the detrimental impact of pyroptosis signaling on plasma membrane integrity. However, this will also increase the methylation capacity leading to various epigenetic changes.
Read More on the Cancer Research Website Here
El-Kenawi et al., 2021, Macrophages feed cancer cells!
Do you remember my highlight for El-Kenawi, et al., 2019? During working on this project, I observed accumulation of cholesterol in prostate cancer associated-macrophage. We also observed that acidity skyrocketed intracellular lipid in macrophages.
And why is this important?
Cholesterol is used to make the 5 main classes of steroid hormones.
Cancers such as prostate, breast and ovarian cancers use steroidal hormones to proliferate. Therapies that stop these hormones from working are effective but resistance eventually occur. One path to resistance results from tumors utilizing an increasing amount of cholesterol to make local steroids.
Thus, I asked a couple of simple questions:
Does macrophage regulate response to therapies targeting the steroid hormone receptors such as androgen receptor (AR) antagonists?
Does cholesterol exchange play a role?
In this study, El-Kenawi et al., 2021 utilized immune assays, mouse models, RNA sequencing and metabolomics to investigate how macrophage cholesterol regulates response to hormonal therapies and androgen receptor blockade. We also validated our findings using ex vivo prostate cancer tissues isolated from patients.
