From an evolutionary perspective, systemic insulin drives the intracellular PI3K signaling pathway to integrate systemic nutrient status and cellular metabolism with cellular functions, including proliferation and survival. This function enables insulin to coordinate cellular activities with systemic features, such as glucose availability , and provides a unified mechanism for the generation and utilization of key metabolites. Under normal conditions, this integration of systemic and cellular activity protects the organism by linking  metabolic requirements and cellular growth, thereby constraining cellular activities based on systemic factors. In the context of oncogenic transformation, this integration makes the insulin signaling axis a vulnerability , as activating mutations in oncogenes or inactivating mutations in tumor suppressors (p85 and PTEN) can decouple this integration.

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