The Loss of Cholesterol Transport Enzymes Impedes Tumor Growth

Cancer cells have a voracious appetite, rapidly consuming nutrients to sustain unchecked growth. Many cancers carrying mutations in the tumor-suppressor gene TP53 are particularly dependent on cholesterol production, using the lipid as a key fuel source for proliferation.

This connection drove researchers at Sanford Burnham Prebys Medical Discovery Institute and their collaborators to investigate the mechanisms that regulate cholesterol metabolism and explore ways to disrupt these pathways—potentially starving cancer cells and slowing tumor growth.

Their findings, published in Science Advances, demonstrated that a branch of the lipid enzyme family known as phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) were required for the growth of cancers with TP53 mutations in mice.¹ These enzymes were involved in moving cholesterol from lysosomes within the cell, a process that subsequently activated a major growth pathway. “When you delete these kinases, the animals are 100 percent protected and never develop a tumor—and cholesterol turned out to be one of the missing pieces in this puzzle,” explained study coauthor Brooke Emerling in a statement. These findings offer new insights into blocking PI5P4Ks as a targeted treatment strategy for tumors that commonly have TP53 mutations, such as patients with breast cancer.

To study the role of lipid enzymes in tumor growth, the researchers used p53 knockout mice with either functional or fully deleted PI5P4Ks. Mice with functional kinases developed mammary tissue tumors, but those without them exhibited complete protection from tumorigenesis. When the team analyzed mutations in these kinases, they found that although such mutations are rare, PI5P4Ks are often overexpressed. Emerling and her team studied gene expression and related pathways of these enzymes in the context of breast cancer. They found associations with autophagy—a process triggered by nutrient deprivation—as well as cholesterol trafficking pathways and the activation of mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of cell growth.

To further investigate the role of PI5P4Ks in cholesterol homeostasis, the researchers performed experiments using cultured breast cancer cells. They measured relative cholesterol levels using staining techniques and tracked cholesterol movement within the cells.

In cancer cells with TP53 mutations and functional PI5P4Ks, the researchers observed cholesterol-laden lysosomes near the cell membrane. This localization proved important for cholesterol transport, as lysosomes positioned closer to the cell membrane were associated with activation of mTORC1 signaling. In contrast, cells lacking PI5P4Ks had lysosomes that remained near the nucleus.

“When lysosome positioning is biased towards the cell nucleus, mTORC1 activation is suppressed," added Ryan Loughran, a postdoctoral researcher in Emerling’s group. “This connects directly to our previous work, where we found that the loss of these kinases triggers starvation-like states in cancer cells.”²

These findings demonstrate the role of PI5P4Ks as the upstream mechanism that maintains lysosomal cholesterol homeostasis and mTORC1 signaling. Based on these findings, Emerling emphasized that, “If we can target mTOR activity in aggressive cancers by blocking the sensing of cholesterol, that would be a promising treatment strategy.”