Scientists led by a team at Duke-NUS Medical School have made a breakthrough in understanding the mechanisms of cholesterol synthesis that influence the growth and development of cancer cells. Researchers highlight the previously hidden role of a new enzyme, called fatty acid hydroxylase domain-containing 2 (FAXDC2), revealing its critical role in cholesterol synthesis and the progression of cancer.
The results of research were published in the Journal of Clinical Investigation.
The fundamental role of cholesterol synthesis in cancer progression
The study details the cascade of molecular events ranging from suppression of FAXDC2 to disruption of normal cholesterol synthesis to alteration of cancer fate, highlighting a potential vulnerability in tumor cells that could be targeted for therapeutic intervention .
“Our journey into cellular drivers of cancer began with the exploration of the Wnt signaling pathway, a crucial player in cell growth and development,” explained Assistant Professor Babita Madan, first author of the Cancer & Stem Cell study Duke-NUS Biology. (CSCB) Program.
“It was during these studies that we came across the enzyme FAXDC2, which has emerged as a central figure in the control of cancer and stem cells. Our finding suggests that FAXDC2 activity, or its suppression, has profound implications for cell growth and differentiation, painting a complex picture of the relationship between cancer biology and cholesterol synthesis.”
The research began with an in-depth analysis of the Wnt signaling pathway, known for its critical role in regulating the growth of normal and tumor cells. Wnt signaling is a key signaling pathway that regulates the growth, development, and maintenance of brain, skin, hair, and gut cells.
However, overactive Wnt signaling, present in the cancer models used in the study, impairs cell differentiation and maintains tumors in a stem cell-like state. These undifferentiated cancer stem cells proliferate rapidly and uncontrollably, promoting faster tumor progression and are resistant to anticancer therapies.
A study by scientists at Duke-NUS Medical School has identified the critical but previously unknown role of an enzyme, called FAXDC2, that is suppressed in tumors with overactive Wnt signaling. FAXDC2 regulates the production of cholesterol and cell signaling molecules, and its suppression causes abnormal cell growth. Restoring FAXDC2 function could potentially normalize cellular behavior in these tumors.
Using cutting-edge genomic technologies to unravel this complex biological process, scientists' attention was drawn to the FAXDC2 enzyme when they found that it dramatically increased after pancreatic cancer models were treated with a Wnt inhibitor made in Singapore, ETC -159 .
In-depth analyzes of colorectal tumor tissue samples confirmed this finding, showing a consistent pattern of suppression of FAXDC2 and subsequent accumulation of cholesterol precursors, including a cholesterol building block called lophenol. The lower the expression of FAXDC2, the higher the lophenol level.
“FAXDC2 is a previously unknown enzyme that helps produce cholesterol from the precursor lophenol. Importantly, the amount of FAXDC2 present in the cells modifies the amount of lophenol present,” explained Professor David Virshup, director of the CSCB program and senior author of the study.
“Lophenol appears to modulate the activity of the differentiation pathway and, therefore, we believe it helps maintain tumor cells in a more stem cell-like state.”
Professor Virshup highlighted the wider implications of these insights, saying: “This study provides a fascinating insight into the molecular machinery of cancer cells. The role of FAXDC2 in regulating cholesterol synthesis opens new avenues for future therapies. Understanding these complex mechanisms paves the way for innovative approaches to fight cancer, underlining the importance of cholesterol biosynthesis intermediates as important signaling molecules and potential drugs.”
The discovery of the role of FAXDC2 in cancer biology marks only the beginning of a longer scientific journey. Further research is needed to fully understand how FAXDC2 suppression and resulting changes in cholesterol metabolism can be exploited to develop new cancer therapies.
The research team is interested in exploring the therapeutic potential of targeting FAXDC2 in the treatment of cancer, considering it as a possible avenue for the development of drugs that could inhibit cancer growth by modulating cholesterol synthesis pathways.
Furthermore, the findings stimulate interest in preventative strategies that could mitigate the risk of cancer development by maintaining the balance of cholesterol precursors in the body. Understanding the triggers that lead to FAXDC2 suppression in tumor cells could pave the way for new prevention methodologies, potentially offering new hope in the fight against cancer.
“These results reflect our ongoing commitment to improving patient care through critical discoveries,” commented Professor Patrick Tan, senior vice president for research at Duke-NUS.
“The way forward involves rigorous research and collaboration across disciplines, all aimed at translating these fundamental insights into tangible medical breakthroughs that could one day transform cancer treatment and prevention strategies.”
Scientists at Cold Spring Harbor Laboratory (CSHL) have found that they can stop the growth of pancreatic cancer cells by interfering with how the cells store cholesterol. Their findings in mice and lab-grown pancreas models point to a new strategy for treating the deadly disease.
The study, reported in the Journal of Experimental Medicine, was led by Professor David Tuveson of CSHL. Tuveson's team wanted to know why pancreatic cancer cells, like many cancer cells, produce abundant amounts of c.
Cholesterol is an essential component of cell membranes, but the research team determined that pancreatic cancer cells produce far more than they need to support their growth. “This is unusual, because the cholesterol pathway is one of the most regulated pathways in metabolism,” says Tobiloba Oni, a graduate student in Tuveson's lab.
Most cells produce only as much cholesterol as they need, quickly shutting down the synthesis pathway once they have enough, Oni explains. But he and his colleagues, including Giulia Biffi, a former postdoctoral researcher in Tuveson's lab, found that tumor cells convert most of the cholesterol they produce into a form that can be stored inside the cell. The c. free never accumulates and the synthesis path continues to produce more.
Cancer cells in the pancreas appear to thrive on this overactive synthesis of cholesterol. The team believes this is likely because they are taking advantage of other molecules generated by the same pathway. They are able to keep the pathway active and maintain their supply thanks to an enzyme called sterol O-acyltransferase 1 (SOAT1), which converts c. free in its stored form and which pancreatic cancer cells have in abundance.
When the researchers eliminated the SOAT1 enzyme through genetic manipulation, preventing the cells from converting to and storing cholesterol, the cancer cells stopped proliferating. In animal experiments, deletion of the enzyme blocked tumor growth.
Importantly, the team found that deleting SOAT1 only impacted cells that contained mutations in both copies of a tumor suppressor gene known as p53.
This genetic alteration promotes cancer growth and is extremely common in patients' tumors. Normal pancreatic cells functioned perfectly without the enzyme in the team's experiments, making SOAT1 a promising therapeutic target, Oni says.
The hope, he says, is that researchers can develop a drug that selectively blocks the enzyme, damaging cancer cells but leaving normal cells healthy.
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