IN SILICO INVESTIGATION OF SIGNALING PATHWAYS ACTIVATED UPON NUTRIENT RESTRICTION IN CANCER CELLS

2025-4-21
Nehri, Leman Nur
Acquisition of a metastatic phenotype requires many transcriptional, translational, and metabolic changes; computational approaches can facilitate detailed evaluation of cellular mechanisms. In this study, a role of organelle crosstalk was hypothesized to address our observation of a remarkable change of cellular shape from cobblestone to elongated in Caco-2 cells undergoing nutrient restriction and lysosomal alkalinization. These cells were also undergoing partial EMT and were highly motile in vivo. To address our hypothesis, RNA sequencing data generated in our lab from Caco-2 cells was analyzed. A systems biology approach using multiple in silico approaches including computational and statistical methods such as the detection of differentially expressed genes, protein-protein and lipid-protein interactions were used. The synergistic effects of starvation and lysosomal alkalinization on various cellular phenomena were examined. A probabilistic graphical model (PGM) was created to explain how starvation and lysosomal alkalinization could lead to the acquisition of a metastatic phenotype in starved cells. Finally, plant-derived saposins were identified as potential therapeutic options for metastatic cells. Our data suggest that Caco-2 cells under starvation and lysosomal alkalinization could activate vi apoptosis, fatty acid oxidation, mitochondrial ROS and mitophagy, all of which could support cell survival. Under the same conditions, the lysosomes could release calcium ions, which increased lysosomal exocytosis, potentially leading to extracellular matrix remodeling and cellular motility. Thus, although many cancer cells die under starvation, the ones that survive continue to acquire signals for survival and motility via a crosstalk between the mitochondria and lysosomes. The framework created by this study and the resulting data may form the basis for a systems biology approach to understand metastatic phenotype in cancer cells.
Citation Formats
L. N. Nehri, “IN SILICO INVESTIGATION OF SIGNALING PATHWAYS ACTIVATED UPON NUTRIENT RESTRICTION IN CANCER CELLS,” Ph.D. - Doctoral Program, Middle East Technical University, 2025.