2023 Grantee: Guillaume Cognet, PhD
University of Chicago
Research Project: Glycine availability in the PDAC tumor microenvironment as a driver of chemoresistance
Award: 2023 Pancreatic Cancer Action Network Fellowship, funded by the Francois Wallace Monahan Fund in loving memory of Michael Insel
Award Period: July 1, 2023 – June 30, 2025
Dr. Guillaume Cognet received his PhD in Cancer Biology and Metabolism from the Université Paul Sabatier in Toulouse in 2021. He studied acute myeloid leukemia metabolism and more specifically the impact of leukemia burden on the metabolism of the whole body with Drs. Jean-Emmanuel Sarry and Jean-Charles Portais. He developed new methods for whole tissue metabolomic analyses and worked on designing new predictors of chemotherapy resistance in leukemias.
Dr. Cognet joined Dr. Alex Muir’s lab at the University of Chicago in 2022 to work on pancreatic cancer. Dr. Muir was the recipient of a 2020 PanCAN Career Development Award. Using novel models of tumor physiological nutrients, Dr. Cognet is studying how nutrients in the microenvironment can impact chemoresistance. After gathering preliminary data on the amino acid glycine being the main nutrient driving chemoresistance, he is currently unravelling the mechanisms behind this interaction. The goal is to gain a better understanding about how pancreatic cancers resist treatments in patients as well as discover new potential therapy combinations.
Based on observations in both humans and mice that pancreatic cancer cells grown in a dish are much more sensitive to chemotherapy and other cancer drugs than cells within tumors in the body, Dr. Cognet and colleagues hypothesized that the tumor microenvironment plays a role in this chemoresistance. The tumor microenvironment is composed of cells and tissues that bring rigid structure to the tumor, evade the immune system and control the tumor’s nutrient and oxygen levels.
Dr. Cognet and colleagues observed that overall nutrient levels within the tumor and surrounding tissue in mice with pancreatic cancer are “strikingly altered” compared to healthy tissue. To better understand whether these altered nutrient levels contribute to the tumor cells’ chemoresistance, the investigators created a medium (liquid source of nutrients that cells in a dish are grown in) that replicates the nutrient composition of the tumor microenvironment. The cells grown in the altered-nutrient medium were resistant to death by chemotherapy, whereas those grown in normal-nutrient medium were killed by exposure to chemotherapy. When levels of different nutrients within the cell culture medium were systematically adjusted, Dr. Cognet and team found that elevated levels of an amino acid (building block of proteins) called glycine were necessary for the induction of chemoresistance in the cancer cells. Looking at pancreatic tumor samples directly from patients confirmed elevation of glycine compared to healthy tissues.
For his Fellowship project, generously funded by the Francois Wallace Monahan Fund in loving memory of Michael Insel, Dr. Cognet will investigate two primary aims. First, the researchers will determine how glycine accumulates in the tumor microenvironment. The three potential mechanisms by which glycine gets accumulated are: (a) dietary intake, (b) breaking down glycine-rich proteins like collagen or (c) cancer or tumor microenvironment cells producing glycine directly. By blocking each of these pathways, the researchers will identify the primary source of glycine accumulation. For his second specific aim, Dr. Cognet seeks to identify the molecular mechanism by which high levels of glycine induce resistance to chemotherapy.
Dr. Cognet wrote, “My work to determine how glycine protects pancreatic cancer cells from therapeutic challenge will provide novel insight into therapy resistance that could lead to novel targets to render pancreatic cancer tumors sensitive to treatments.”