Fifty years ago, cancer biologists were convinced that understanding cancer metabolism would lead to a cure, until discoveries about cancer genetics shifted the research focus in other directions. But now the pendulum is swinging back, renewing interest in metabolism’s role in cancer.
Dr. Jorge Moscat and Dr. Maria Diaz-Meco, who both recently arrived at Sanford-Burnham from the University of Cincinnati, have been working together for more than twenty years to understand the mechanisms that allow cancer cells to grow at such a breakneck pace. Their investigations have led them to a network of proteins characterized by having PB1 domains. This network of proteins controls inflammation, how cells communicate with each other, and how they sense nutrients—all key drivers of cancer growth.
For example, the PB1-containing scaffold protein p62 regulates an enzyme called protein kinase C zeta (PKCZ), which is often missing in human cancers. PKCZ is a tumor suppressor that prevents inflammation and ensures that cells remain sensitive to nutrient levels. Cells without PKCZ get reprogrammed to endure food scarcity.
“If they lack this gene, they don’t care if glucose is unavailable,” says Dr. Moscat, “they just use other nutrients.”
Dr. Moscat hopes that learning more about PKCZ, and other proteins regulated through PB1 domain interactions, will help him find new ways to fix these malfunctioning processes and slow tumor growth.
Dr. Diaz-Meco is also trying to understand proteins regulated by PB-1, particularly those missing in prostate cancer. She is looking at the tumor suppressors PTEN and Par-4, proteins that are commonly lost in prostate cancer. Losing PTEN alone does not lead to invasive cancer, but losing both fans the flames of inflammation and leads to full-blown, invasive carcinoma. This is significant because the PSA diagnostic test indicates the potential existence of prostate cancer but cannot determine its aggressiveness.
“One of our goals is to find biomarkers for aggressive prostate cancer,” says Dr. Diaz-Meco. “We want to determine which ones become invasive and therefore require the most aggressive treatment.”
Though Dr. Moscat and Dr. Diaz-Meco have only been at Sanford-Burnham for a few months, they have already developed fruitful collaborations. Dr. Moscat is working with Dr. Adam Richardson, a research assistant professor in Dr. Andrei Osterman’s lab, to understand the metabolic pathways in cancer cells. In other words, when a tumor cell takes up a nutrient, what happens to that nutrient during each step of the metabolic process and how is that impacted by cancer genes and tumor suppressors?
Here’s where sophisticated technologies pay off. Working with Drs. Chen Yang and David Scott at Sanford-Burnham, Dr. Richardson helped adapt a method used to study metabolism in bacteria to study human cells. He uses mass spectrometry to follow stable isotopes incorporated into various nutrients. When the cell takes up a nutrient, he can then track what happens to these molecules and the metabolites (molecules created by biochemical reactions) they ultimately produce. This method produces highly specific information about how cells process nutrition.
These studies should greatly increase our understanding of cancer metabolism by providing step-by-step snapshots of how cancer cells defy poor nutritional environments, what happens to the nutrients they take in and how we can detect that process. Ultimately, these basic discoveries will help us pinpoint and exploit vulnerabilities in cancer cells.
Read more about cancer research at Sanford-Burnham.