RAC1 signaling in polyploid giant cancer cells: Implications for tumorigenesis and therapy resistance.

Polyploid giant cancer cells (PGCCs) are a subpopulation of tumor cells known for driving tumor recurrence, metastasis, and therapeutic resistance. PGCCs arise mainly in response to cellular stress induced by cancer therapies and adverse microenvironmental conditions. We have recently demonstrated that a RAC1 mutation (RAC1 P34R) can induce the formation of PGCCs in aggressive thyroid cancer cells from a patient undergoing dabrafenib treatment, leading to resistance to therapy. RAC1 is a critical regulator and integrator molecule that mediates multiple cellular processes ranging from stress adaptation, metabolic regulation, cytoskeletal dynamics, motility, and cytokinesis. Importantly, RAC1's functions are highly context-dependent, varying across a cell's life cycle stages in response to dynamic biomechanical factors from the tumor microenvironment. This complexity underscores the need for precision targeting strategies that account for RAC1's dynamic roles. Therapeutic approaches aimed at modulating RAC1 must be tailored to the specific cellular context and PGCC state to effectively disrupt the mechanisms underlying tumor progression. By targeting RAC1's integrative functions, researchers may unlock new avenues for preventing PGCC-mediated recurrence and metastasis, offering a promising strategy to improve long-term outcomes in cancer treatment. This review outlines the diverse functions of RAC1 that may contribute to both the formation and sustained maintenance of PGCCs across various tumor types.