The brain is the most cholesterol-enriched organ in our body with a cholesterol metabolism that is distinct from other organs due to the inability of peripheral cholesterol to cross the blood-brain barrier. Cholesterol that is locally synthesized by astrocytes is taken up by surrounding neurons where it is first processed at the lysosome before distribution to various compartments. Notably, brain cancer cells, including glioblastoma multiforme (GBM), take up significantly more cholesterol than normal cells, suggesting a higher dependency on lysosome cholesterol sensing and distribution mechanisms.

Indeed, GBM is characterized by aberrant lipid metabolism and high dependency on cholesterol for survival, features that have emerged as potential actionable vulnerabilities. This intriguing dependency unveils cholesterol as a master orchestrator that sculpts GBM metabolic features, its aggressiveness, and likely the crosstalk with neighboring cells. Cholesterol is also the precursor for essential molecules like hormones, oxysterols, and bile acids, which can influence the metabolism of GBM cells themselves as well as that of neighboring neurons, oligodendrocytes, and immune cells, all of which is poorly understood.

We aim to leverage current advances in organelle profiling to uncover the unique features of cholesterol uptake, trafficking, sensing, and transformation that are essential to cancer growth.

Membrane-separated organelles, including the nucleus, mitochondria, endoplasmic reticulum (ER), Golgi apparatus, and lysosomes, possess specialized structures and functions tailored to their specific tasks within the cells. Although physically separated, these organelles are not isolated but instead, work in concert and cooperate through inter-organelle communication to execute a myriad of important cellular processes. The emerging field of organelle communication has provided a new layer of complexity and profound insights into the intricate mechanisms that govern cellular function and metabolism.

Lysosomes constantly relay their status to the genome to influence downstream physiology and disease processes. Gene regulation by lysosome signaling can be particularly meaningful in the context of chronic response and subsequent disease progression, where dysregulated transporters or autophagy/lysosome functions promote long-term metabolic reprogramming. Our understanding of how the lysosome influences nuclear processes is still at its infancy. In the mammalian system, MiT/TFE transcription factors (TFs) are the only extensively validated proteins that can shuttle between the lysosome and the nucleus. However, it is tempting to speculate that a variety of TFs and/or epigenetic modulators with the ability to shuttle between the cytoplasm and the nucleus that respond to metabolite efflux from lysosomes await to be uncovered.

We hypothesize that the above example is the tip of the iceberg of a vast communication network linking the lysosome to nuclear genome regulation, and that specific nutrient input and downstream effectors mediate this communication.

Modified from Nature Chemical Biology 18, 451–460, 2022

Manipulating and measuring metabolism at the organelle and tissue levels presents a challenge with traditional small molecule drugs. To better understand the regulation of metabolism, we need a new generation of tools to measure and manipulate the levels of individual metabolites and bioenergetic ratios in compartment- and tissue-specific manner. This approach, we believe, will be complementary to genetic and biochemical approaches of manipulating one enzyme or one pathway at a time. More importantly, it holds the potential to uncover novel metabolic vulnerabilities that can be strategically targeted for therapeutic purposes.