Signaling networks dictating cancer cell fate: From death to adaptation through the lens of proteomics

Abstract

Cancer can be read through many lenses: genetic, metabolic, and immunological. However, the story that most faithfully captures its behavior is about choice: the continuous, contested decisions that cells make between survival and death. In healthy tissues these decisions are disciplined, computed through layered signaling networks that weigh cytokines, growth factors, and cell-cell contact to preserve form and function. Malignancy begins when this calculus is bent. Tumor cells learn to reinterpret danger as permission to mutate the signals that would normally force them into elimination, and to rewire their behavior under pressure. This thesis follows the behavior of cancer cells from surviving immune cell-mediated cell death to adapting through competition or resistance and asks how those choices are encoded in protein signaling through the lens of mass spectrometry-based proteomics. Through the chapters of this thesis, we observe cancer cell fate being computed through protein-protein interactions (PPI), post-translational modification (PTM) regulation and complex formation, and we aim to uncover where that computation can be tipped back towards immune control and irreversible death. We demonstrate how discovery proteomics can illuminate the molecular strategies tumors use to survive immune attack, evade regulated cell death, compete within tissue niches, and resist targeted therapies. By integrating MS-based proteomics with mechanistic interventions across diverse experimental systems, this work uncovers actionable vulnerabilities and offers a framework for understanding how we can reshape tumor fate.