9.5 million people worldwide and more than 600,000 in the US alone died due to cancer in 2018. By 2040, projections estimate that annual cancer-specific mortality will rise to 16.3 million deaths. Once cancer has spread, or metastasizes, it is lethal and incurable. Metastatic disease remains incurable because a population of cancer cells within a tumor are resistant to all known natural and synthetic compounds, including anti-cancer therapies. Optimal foraging theory describes how cancer cells adopt a foraging strategy to balance predation risk, resource reward, and individual cell ability. This dynamic foraging requires individual cells to respond to a variety of changing environments in space and in time. Under high stress, adopting a motile foraging strategy is adaptive. In addition to increasing opportunity and reward at the local level of the cancer cell’s primary tumor microenvironment, mobile foraging also likely selects for cancer cells with high metastatic potential and with increased resilience to other microenvironmental stressors such as systemic therapy. By in vitro modeling the characteristics of a resource-poor “cancer swamp” (e.g., hypoxia, overcrowding) and by increasing the resource “bads” (e.g., chemotherapy), our preliminary data and that of others have demonstrated the appearance of a motile foraging phenotype. These motile foragers are morphologically distinct cancer cells with high DNA content: poly-aneuploid cancer cells (PACCs).
Results/Conclusions
While first described more than 130 years ago, the significance of PACCs has remained largely unexplored as they are frequently discounted as dying cells or artifact of cell culture. We have found that PACCs are a rare but stable subpopulation in cancer cell lines. Our preliminary data show that modulating resource availability by decreasing “goods” (hypoxia), increasing “bads” (multiple different classes of chemotherapy) leads to a striking emergence of PACCs. After treating prostate cancer cell lines with [LD90] therapy for 72 hours, >90% of the surviving cells are PACCs. Our data suggest that while PACCs persist outside of cell-cycle, eventually, all non-PACC cells die. After allowing the cultures to recover in the absence of chemotherapeutic stress, PACCs will give rise to a “typical” cancer cell population that has increased therapy resistance. These data present a compelling evo-ecological model of metastasis, therapy resistance, and disease recurrence.