The Polyaneuploid Cancer Cell State Mediates Multitherapy Resistance in Cancer
Abstract
While advances in the treatment of localized prostate cancer have improved five-year survival to near 100%, once cancer has spread (metastasized), it is lethal and incurable, leading to the deaths of more than 34,000 men each year in the United States. Metastatic disease is incurable because tumors develop resistance to all known natural and synthetic compounds, including all standard-of-care systemic therapy (e.g., chemotherapy, hormone therapy). Despite decades of dedicated work by researchers worldwide, the fundamental barrier to prostate cancer survivorship remains unsolved: therapeutic resistance. Therapy resistance has classically been attributed to genetic tumor cell heterogeneity: that among the billions of cancer cells in a tumor, some cells have accumulated resistance mechanisms to a particular agent through chance genetic variation. Our data suggest that this model is incomplete. Our preliminary data indicate a previously underrecognized but critical cell state that represents the lynchpin of resistance, regardless of mutation status or therapy class: the polyaneuploid cancer cell (PACC) state. To better understand therapy resistance in prostate cancer, we cultured prostate cancer cell lines with lethal doses of hormone therapy or chemotherapy (two different classes: docetaxel and cisplatin). While we observed cell death as expected (clinically observed as decreased tumor burden), we also observed the only surviving cells were morphologically distinct large cells with doubled DNA content (polyaneuploidy): what we now know as cells in the PACC state. After a period of recovery, we have shown that the cells in the PACC state undergo depolyploidization and repopulate a typical cancer cell population. Importantly, the PACC-derived population of cancer cells has increased therapy resistance, both to the same therapy initially used to induce the PACC state (e.g., docetaxel) as well as a different class of therapy (e.g., cisplatin). Taken together, we now hypothesize that that the PACC transition facilitates underlying therapy resistance. Therefore, unless the PACC transition is eliminated, cancer will recur in treated patients. To test this hypothesis, we will achieve the following Aims. Specific Aim 1. Map the life history of the therapy-induced polyaneuploid transition. The mechanisms of cancer cell entry into the PACC state and exit from the PACC state to seed a recurrent tumor remain unknown. We will comprehensively map the life history of the PACC state induced by three different therapy classes using ultra-deep genetic lineage tracing in vitro and in vivo. We will demonstrate that PACCs are enriched following therapy in PCa patients and mouse models of PCa. We hypothesize that the cells that arise following exit of the PACC state will have memory of the PACC transition that will endow therapy resistance. We will directly test this using live cell imaging, genetic lineage tracing, and transcriptional analysis. Specific Aim 2. Targeting the polyaneuploid transition state to overcome therapy resistance. Standard-of-care systemic therapies rarely cure metastatic PCa patients. Our data argue that this is the result of the therapy-induced PACC state actuating resistance. We hypothesize that, if the PACC state can be eliminated, therapy-resistant recurrence will be eliminated. The PACC state can be targeted in three ways: (1) prevent formation of PACCs, (2) kill PACCs outright, and (3) prevent PACC depolyploidization. We will perform transcriptomic and proteomic profiling to identify targetable vulnerabilities at each of these three PACC life stages. We will also test a novel treatment strategy: evolutionary double bind. We will perform proof-of-principle evolutionary double-bind studies that combine traditional debulking chemohormonal therapies (Step 1) with residual PACC-directed treatment (Step 2) to eradicate all cancer cells and prevent recurrence in vitro and in vivo. A
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210680
Entities
People
- Sarah R Amend
Organizations
- Johns Hopkins University
- United States Army