The Emergence of Polyploid Giant Cancer Cells as the Reservoir of Theraputic Resistance

We demonstrate with a microfluidic stress landscape that the generation of polyploid giant cancer cells (PGCCs) is an emergent response by PC3 cancer cells under high stress chemotherapies. We tracked the emergence of polyploid cancer cells using PC3 human prostate cancer cells in a docetaxel gradient and investigated the population dynamics, morphological variations and cell motilities as a function of stress, time and space over the stress landscape. Beyond a sharp transition in cell mortality across the stress landscape, in the highest chemotherapy concentration regions, the PGCCs are the primary survivors. This implies that the PC3 cells acquired survival advantage after polyploidy emergence. We further show that the PGCCs possess stem-like properties, including the expression of cancer stem cell markers and the ability to undergo neosis during the off-drug period in the intermittent chemotherapy cycles, which reveals PGCCs' tumorigenic potential as well as their ability to drive resistance to chemotherapy. We argue that the generation of PGCCs are the adaptive response to chemotherapy on both individual and collective levels, and may be a hallmark of elevated cancer evolution dynamics and therefore could be potentially taken as the target of new treatment strategies.