Carlos Carmona-Fontaine, Ph.D.

Research

The Carmona-Fontaine laboratory (Carmofon Lab) studies how metabolic conditions within tumors determine different aspects of cancer. Solid tumors are poorly vascularized, so resources such as oxygen and nutrients are scarce. Rather than deterring tumors, these conditions select for more aggressive cancer cells and suppressing normal physiological functions such as the immune response. As a result, abnormal metabolic conditions within tumors provide an immunosuppressive niche that selects for tumor cells with adaptations to thrive under nutrient scarcity.

The lab recently demonstrated that cancer cells cooperate with one another to compensate for the lack of amino acids due to insufficient blood perfusion. They showed that while amino acids are indeed scarce in tumors, malignant cells are surrounded by large amounts of extracellular oligopeptides—short strings of amino acids derived from broken proteins. Interestingly, tumor cells do not uptake these peptides but instead cleave them into individual amino acids by secreting a peptidase named CNDP2. This extracellular digestion becomes a cooperative process because amino acids cleaved off peptides form a public good that tumor cells share. Inhibition of this cooperative process drastically reduces tumor growth in vivo, highlighting the impact that cell-cell interactions and adaptations to nutrient scarcity have on tumor growth—and why we need to better understand these kind of interactions to improve cancer treatment.

As an Innovation Fund investigator, Carlos Carmona-Fontaine, Ph.D., is teaming up with Piro Lito, M.D., Ph.D., to study the role that cell cooperation plays in the resistance to cancer therapy. The team recently discovered a noncell autonomous form of drug resistance in which tumor clones that become resistant to the sotorasib—a mutant KRAS inhibitor—protect neighboring sotorasib-sensitive cells from this treatment. By combining Carmona-Fontaine’s specialty in studying cancer cell cooperation with Lito’s expertise in the biochemical mechanisms of KRAS in cancer, the team will decipher how sotorasib-resistant tumor cells shield sensitive cells and whether this mechanism is present in other therapeutic interventions. The investigators will use quantitative live microscopy methods to examine how concurrent clones with different KRAS statuses respond to KRAS inhibitors and how they mutually influence each other during therapy. This work can reveal key aspects of cooperative resistance to sotorasib, its implications for tumor evolution, and how to refine therapies that target mutant KRAS in cancer.