Polyploid Giant Cancer Cells Actuate Prostate Cancer Tumor Resistance and Lethal Phenotype
Abstract
While advances in the treatment of localized prostate cancer have improved 5-year survival to near 100%, once cancer has spread (metastasized), it is lethal and incurable, leading to the deaths of more than 31,000 men each year in the United States. Metastatic disease is incurable because a population of cancer cells 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. Our work and other recent studies have described a morphologically distinct cancer cell that emerges upon treatment with chemotherapy called a polyploid giant cancer cell (PGCC). These cells have been recognized for more than 100 years, but are often dismissed as unimportant, thought to be technical artifacts or dying cells. As they are widely considered to be incapable of survival or proliferation, PGCCs have mostly been considered artifacts, not actuators. Based on our preliminary results, we now hypothesize that PGCCs survive by “hibernating” in what is defined as a quiescent state. In our preliminary data, we have shown that prostate cancer cells become PGCCs when treated with anti-cancer therapy. Once that stressor is released, at least a subpopulation of PGCCs, regardless of the type of stressor (e.g., different types of chemotherapy), then “awaken” and reenter cell cycle to give rise to a now-therapy-resistant proliferating population of non-PGCC cancer cells. Therefore, PGCCs could be central mediators of tumor resistance and prostate cancer lethality. To test our hypothesis, we will achieve two major aims: Aim 1. Determine how and when PGCCs are formed during prostate cancer progression. To assess when PGCCs arise during the progression of prostate cancer, we will evaluate PGCC number in clinical samples and in mouse models across the clinical spectrum of disease progression and treatment. We will also utilize cell culture in vitro modeling to determine how the initial PGCCs first emerge in the primary tumor to identify the source of intrinsic therapy resistance. Aim 2. Demonstrate that quiescence (“cell hibernation”) underlies a common mechanism for PGCCs to survive therapy. We will assess whether PGCCs enter quiescence and determine whether they reenter cell cycle to initiate a new therapy-resistant tumor. This will model what happens in prostate cancer patients who receive systemic therapy and then suffer recurrence or progression. This research will directly address the PCRP overarching challenge to define the biology of lethal prostate cancer to reduce death. The results of this research will fundamentally change our understanding of how and when therapeutic resistance arises during prostate tumorigenesis and its treatment course, specifically defining the role of polyploid giant cancer cells as mediators of therapeutic resistance in prostate tumors. Understanding when and how PGCCs arise during prostate cancer progression and how PGCCs mediate therapy resistance will provide valuable information for future therapeutic strategies, both for specific targeting of PGCCs and for altering treatment regimens to reduce the formation of PGCCs using current standard of care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010353
Entities
People
- Sarah R Amend
Organizations
- Johns Hopkins University
- United States Army