Abstract

The Polyaneuploid Cancer Cell (PACC) State Promotes Therapeutic Resistance Through Extracellular Vesicles (EVs)

Chi-Ju Kim, Postdoctoral Research Fellow, Johns Hopkins University School of Medicine

The Johns Hopkins Cancer Ecology Center recently discovered a novel form of cancer therapeutic resistance achieved through the polyaneuploid cancer cell (PACC) state. The PACC state is triggered through a conserved evolutionary program that results in sustained polyploidization of the aneuploid genome. Cells in the PACC state are resistant to all therapies, not only the stressor that induced entry into the PACC state, and that the cell population that arises from the induced PACC state likewise shows reduced sensitivity to multiple agents. Clinically, the presence of cells in the PACC state in radical prostatectomy specimens of prostate cancer (PCa) patients increases the risk of progression. Utilizing a novel extracellular vesicle (EV) isolation platform, combined with development of a 3D imaging-based cellular EV uptake assay as well as a multiplexed EV RNA cargo profiling method, it was discovered that PACCs release significantly larger numbers of EVs. It is hypothesized that EVs contain factors (i.e., multidrug resistance proteins) that transmit resistance to adjacent cancer cells. An understanding of PACC-derived EVs and the impact of the transferred EV cargo on the phenotype of therapeutic-sensitive cells will provide critical insight into the acquisition of therapy resistance in lethal cancer.