Linchpin gene in a rare liver cancer: a new avenue toward therapy?

Cornell researchers have identified a gene that plays a crucial role in promoting tumor growth and survival in fibrolamellar carcinoma (FLC), a rare and devastating liver cancer. This discovery opens a new avenue for therapeutic development for a disease that currently has no standard of care besides surgery.

FLC predominantly affects teens and young adults with otherwise healthy livers. Being difficult to diagnose, the majority of FLC cases are detected at advanced metastatic stages, ruling out surgical options and leading to poor survival rates.

“The dire need for therapeutics is underscored by how FLC tumors are resistant to drugs currently used to treat other liver cancers,” said senior author Dr. Praveen Sethupathy ’03, professor of physiological genomics and chair of the department of Biomedical Sciences in the College of Veterinary Medicine. The work was led by Dr. Rosanna Ma, a graduate student in Sethupathy’s lab at the time, and published in the journal PLoS Genetics.

With little to start from, Sethupathy’s team cast a wide net, using advanced techniques from genomics, bioinformatics, molecular genetics and cell biology. “Our study is highly interdisciplinary and spans many different fields. We leveraged patient tissues, we developed new cell lines and we validated findings in vivo,” Sethupathy said.

Their genomic analyses led them to the gene LINC00473, the expression of which had previously been reported to be elevated in another cancer, non-small cell lung tumors. Sequencing RNA from tumor tissue from a large number of FLC patients, Sethupathy’s team discovered that LINC00473 was not only among the most upregulated genes in FLC, but also more elevated in FLC than most other cancers.

With a technology that analyzes cell metabolism in real time, the team also demonstrated how LINC00473 manipulates energy production in tumor cells in part by tweaking the function of mitochondria, the powerhouse of the cell.

Previous papers have reported on many genes whose expression levels are altered in FLC – these are called tumor markers. However, very few studies have followed up on these individual markers to determine whether they actively promote and drive disease. “Our study is one of the first to investigate a specific FLC marker gene, LINC00473, and test whether and how it promotes FLC tumor growth,” Ma said.

LINC00473 is a primate-specific gene, meaning that rodents and other non-primate mammals do not have it. Sethupathy said that “while mouse models of FLC are certainly valuable, they must be interpreted with caution because they are missing a gene that we think may be very important in shaping the way FLC tumors behave.”

Now that the team has established that LINC00473 is a key player of FLC tumor growth – and therefore potentially a candidate therapeutic target for FLC – they want to understand exactly how LINC00473 works and what other genes it interacts with.

Sethupathy explains that some genes are difficult to target with therapeutic molecules, and if LINC00473 turns out to be one of those, other genes it interacts with may be easier to target. “Our paper lays the foundation for future studies to investigate the biological pathway LINC00473 belong to, a pathway that may present other druggable targets,” Ma said.

“Understanding the molecular reasons for why a tumor behaves a certain way takes painstaking work,” Sethupathy said, “but it is extremely valuable for developing new strategies to cap the cancer at its knees.”

Written by Elodie Smith