# Project 1: Polyploid giant cancer cells are central actuators of tumorigenesis, skeletal metastasis, and therapeutic resistance

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $171,063

## Abstract

Skeletal metastases associated with advanced prostate cancer (PCa) continue to kill more than 29,000 men per
year in the United States. Metastatic disease remains incurable because a population of cancer cells within a
tumor are resistant to all known natural and synthetic compounds. Resistance to a therapy may be solely cell
intrinsic, therefore present in a treatment-naïve setting, as well as be induced through external selective pressure
via therapeutic treatment. How and when drug resistance arises has profound implications to understand
tumorigenesis as well as to guide treatment and management of disease. Our preliminary data and other recent
studies have demonstrated that the appearance of a subset of morphologically distinct cancer cells, polyploid
giant cancer cells (PGCCs), is associated with therapeutic intervention, including taxane-based chemotherapy
in castrate resistant prostate cancer (CRPCa). Consistent with other studies, we further show that PGCCs are
often multinucleated, have elevated genomic content, can be found in biopsies of metastatic tumor tissue, and
are reported to possess senescent as well as stem-like properties. PGCCs also have a highly motile
mesenchymal phenotype and are enriched in metastases, suggesting that, in addition to their role in therapeutic
resistance, they may be important initiators of metastatic spread. While multiple mechanisms of drug and stress
resistance have been described, the totality of our preliminary data leads us to hypothesize that PGCCs survive
the intrinsic (microenvironment and metastasis) and extrinsic (therapeutic) stresses associated with cancer
progression in a novel manner by existing in a reversible G0 state. In Specific Aim 1 we will determine how
and when PGCCs are formed. Further, we will measure PGCCs in mouse and human PCa tissues across
clinical disease states. In Specific Aim 2 we will demonstrate that reversible senescence underlies a
common mechanism of stress resistance in PGCCs. We will also assess if PGCCs exhibit cancer stem cell
properties that permit them to reinitate proliferation. In Specific Aim 3 we will demonstrate that PGCCs are
important initiators of metastasis. In addition, we will measure circulating PGCCs in murine models and
patients in different clinical disease states. The results of our studies will fundamentally change our
understanding of how tumors develop resistance to stress as well as evolve the ability to metastasize.

## Key facts

- **NIH application ID:** 9935667
- **Project number:** 2P01CA093900-16
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** KENNETH J. PIENTA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,063
- **Award type:** 2
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935667

## Citation

> US National Institutes of Health, RePORTER application 9935667, Project 1: Polyploid giant cancer cells are central actuators of tumorigenesis, skeletal metastasis, and therapeutic resistance (2P01CA093900-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9935667. Licensed CC0.

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