Researchers uncover how prostate cancer cells build up cholesterol and fuel tumor growth

Researchers at Texas A&M Health have identified a molecular mechanism that increases cholesterol levels inside prostate cancer cells — an important process that may help explain how some tumors progress and become resistant to treatment.

The study, led by Ziying Liu ’25,  a former student in the lab of Fen Wang at the Institute of Biosciences and Technology and the Naresh K. Vashisht College of Medicine, found that a cell-signaling receptor called fibroblast growth factor receptor 1 (FGFR1) helps prostate cancer cells increase their internal supply of cholesterol. Cholesterol is a key building block for steroid hormones and cell membrane that can fuel tumor growth.

When the research team removed FGFR1 from prostate cancer cells, cholesterol levels dropped. Genes responsible for taking up low-density lipoprotein (LDL) — often called “bad cholesterol” — and producing cholesterol within the cell became less active.

Understanding prostate cancer progression

Prostate cancer is the most commonly diagnosed cancer among men and the second leading cause of cancer-related deaths in men. The standard first-line treatment is androgen deprivation therapy (ADT), which lowers the levels of male hormones that drive tumor growth.

Although many patients initially respond to this therapy, most cases progress within one to three years to a more aggressive form known as castration-resistant prostate cancer as tumors develop resistance to treatment.

One of the biological processes contributing to this transition is steroidogenesis — the production of steroid hormones derived from cholesterol. Because these hormones can fuel tumor growth even when androgen levels are suppressed, understanding how cancer cells obtain and regulate cholesterol has become an important focus of prostate cancer research.

Key molecular findings

In the study, Liu and colleagues found that FGFR1 activates sterol regulatory element-binding protein 2 (SREBP2), a major regulator of cholesterol metabolism. This activation occurs through ERK-dependent phosphorylation and cleavage of SREBP2 to switch on genes involved in cholesterol uptake and production.

Once activated, SREBP2 increases the expression of the low-density lipoprotein receptor (LDLR) and several enzymes involved in cholesterol synthesis. Together, these changes allow prostate cancer cells to import more LDL particles and produce additional cholesterol internally.

Computational analyses of clinical datasets also found that higher FGFR1 expression was associated with increased LDLR expression and with disease features linked to prostate cancer progression.

Revealing how cancer cells acquire cholesterol

Using bulk RNA sequencing, the researchers determined that genes involved in regulating intracellular cholesterol levels were among the most significantly affected targets of ectopic FGFR1 in prostate cancer cells.

These findings provide new insight into how prostate cancer cells regulate LDL-mediated cholesterol uptake — a key pathway that supplies cells with cholesterol needed for tumor growth and hormone production.

“Our study reveals how prostate cancer cells hijack the FGFR1 signaling pathway to boost their cholesterol supply, highlighting new opportunities to target cholesterol metabolism in advanced prostate cancer,” Liu said.

By clarifying the molecular mechanisms that control cholesterol metabolism in prostate cancer cells, the research may help identify potential targets for future therapies aimed at slowing or preventing disease progression.

“Cancer cells frequently rewire metabolic pathways to sustain growth, and evade therapeutic treatment,” Wang said. “Our group has previously shown that aberrant FGFR1 signaling drives several metabolic programs in prostate cancer, including glycolysis, choline metabolism and iron metabolism. This study adds cholesterol metabolism to that list and further highlights FGFR1 as a multifunctional pathway that could be exploited for future immunotherapy strategies.”

Funding for the study was provided by the Cancer Prevention and Research Institute of Texas, the National Institutes of Health, the Welch Foundation, Texas A&M Seedling Grants and the Internal Grants Program of the Texas A&M University Division of Research.