Twelve researchers at Weill Cornell, along with numerous colleagues from across the United States, published a study earlier this month identifying a critical metabolic difference between human and mouse lung tumor cells, which explains a discrepancy in previous findings and suggests new pathways for developing cancer treatments.
Their work focuses on lung adenocarcinoma, a common cancer that affects the outer edges of the lungs and is difficult to treat because of its aggression. Researchers have traditionally used mouse models to study lung adenocarcinoma pathology. However, previous work found that tumor growth in mouse models does not always align with clinical observations in human patients. This study explains the divergence by identifying a specific gene mutation with different effects on tumor development in humans and mice.
In patients with lung adenocarcinoma, the three most common independent mutations that occur are in genes called LKB1, KRAS and TP53. Benjamin Stein — a cancer biology instructor at Weill Cornell and co-lead author of the paper — found a disconnect in the role that these genes play in regulating lung cancer metabolism in humans versus mice. Metabolism is the process by which cells create energy to fuel growth, signaling and other functions. In cancer cells, metabolism is dramatically increased to support rapid proliferation.
Clinical data showed that LKB1, KRAS and TP53 mutations rarely co-occurred in humans. Two of the mutations would commonly occur together but rarely all three at once. This led scientists to believe that once a tumor acquired two of the mutations, acquiring a third would be disadvantageous for rapid growth.
When testing this hypothesis on mice models, researchers discovered that the combination of all three mutations created a highly aggressive cancer, which contradicted the initial hypothesis. This discrepancy influenced Stein to begin a new project at Weill Cornell.
Stein partnered with co-lead author Dr. John Ferrarone, a medical oncology instructor at Weill Cornell, to further study the effects of LKB1, KRAS and TP53 mutations in mouse models and human cell cultures.
Specifically, Stein and Ferrarone focused on LKB1, a master kinase that regulates how a cell responds to metabolic stress. A kinase is a protein that phosphorylates other proteins, creating a signaling cascade. They looked at tumors with natural KRAS and TP53 mutations and then disrupted LKB1 to study the LKB1-signaling pathway.
The researchers applied a variety of scientific technologies to study the effects of LKB1 — such as CRISPR-Cas9, a genetic engineering tool, and mass spectrometry, an analytic technique for observing changes in a set of proteins in a cell.
“The power of mass spectrometry is that you can ask very broad questions with high precision. We looked globally at the proteome and substrates of kinases in metabolism,” Stein said. “Using genetic tools like CRISPR-Cas9 in concert with these global technologies allows us to control the biology and make precise changes to specific cells and ask how that single change is affecting metabolism globally.”
The methods revealed a critical difference in the LKB1-driven regulation of metabolism in humans and mice, which can be attributed to differences in how humans and mice regulate the metabolic enzyme triose phosphate isomerase. This enzyme catalyzes glycolysis, a process that creates energetic compounds from sugar in the early stages of metabolism.
In mouse models, mutating LKB1 had a positive effect on the regulation of TPI1, offering a metabolic advantage that accelerated proliferation. In human cell cultures, however, mutating LKB1 in the same context inhibited the ability of tumor cells to regulate TPI1 and metabolism.
These findings explain why the LKB1, KRAS and TP53 mutations rarely co-occur in human cancer — the co-occurrence of all three mutations is detrimental to rapid cell growth.
According to Stein and Ferrarone, the study results point to methods for improving the accuracy of mouse models and novel pathways to treat lung adenocarcinoma by targeting the LKB1 signaling cascade.
“Our study highlights that either LKB1 or its downstream proteins, which are called the salt-inducible kinases, can be therapeutically targeted,” Ferrarone said. “The next step is to develop small molecule inhibitors for both targets to further test their therapeutic potential.”