Survivin Promotes the Formation of a Microtubule-Based Glycolytic Hub
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KRAS is one of the most frequently mutated oncoproteins in cancer. Its ability to induce malignant transformation relies on metabolic reprogramming that causes cells to become dependent on aerobic glycolysis as a primary source of energy and for generating biological building blocks. Thus far, the signaling mechanism used by oncogenic KRAS to promote these changes in cancer cell metabolism has not been fully elucidated. However, through studies in pancreatic ductal adenocarcinoma (PDAC) cell lines and patient-derived organoids, we now demonstrate how oncogenic KRAS triggers an increase in glycolytic activity and identify Survivin as a newly discovered and critical KRAS-signaling partner essential for promoting these metabolic changes. We show that oncogenic KRAS potently upregulates the expression of Survivin in PDAC cells and patient-derived organoids undergoing increased glycolysis, whereas depleting Survivin expression inhibits their glycolytic activity and growth. Through a combination of cellular, biochemical, and imaging approaches, we further show that Survivin promotes the formation of unique microtubule-based structures that resemble invadosome rosettes, allowing for the recruitment of the glycolytic enzymes triose phosphate isomerase (TPI) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to these super-structures which drives the increases in glycolysis. These findings demonstrate that by directing the assembly of a microtubule-based complex of metabolic enzymes, Survivin serves as a vital link in a KRAS signaling pathway responsible for promoting the metabolic changes necessary for the accelerated growth of PDAC cells, and thus potentially highlight new therapeutic strategies for treating KRAS-dependent cancers.
Significance Statement
Oncogenic forms of the signaling protein KRAS promote the rapid growth of pancreatic cancer cells by rewiring their cellular metabolism such that they become dependent on aerobic glycolysis. However, how this metabolic adaptation is achieved has remained a critical open question in the field. In this study, we now show that there is a tight signaling connection between oncogenic KRAS and increases in the expression of the cell survival protein/cancer marker Survivin in pancreatic cancer cell lines and patient-derived organoids, with the upregulation of Survivin being essential for promoting aerobic glycolysis. The mechanism underlying this effect involves the formation of a unique Survivin-microtubule-based metabolic hub that enables the recruitment of key enzymes responsible for increasing glycolytic activity and cell growth.
