Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization

White-Gilbertson, Shai; Lu, Ping; Saatci, Ozge; Sahin, Ozgur; Delaney, Joe R.; Ogretmen, Besim; Voelkel-Johnson, Christina

doi:10.1016/j.jbc.2024.107136

Cited by 4 publications

(1 citation statement)

References 88 publications

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“…During polyploidization and depolyploidization, p21 is crucial upstream of acid ceramidase (ASAH1). Blocking p21 expression with UC2288 during therapy stress can inhibit ASAH1 activation, eliminating PGCCs and their daughter cells, thereby improving therapeutic efficacy ( White-Gilbertson et al, 2024 ). Therapeutic strategies to eliminate PGCCs through p21 include senolytics such as Navitoclax or drugs that disrupt depolyploidization like simvastatin or autophagy regulators ( Abbas and Dutta, 2009 ; Bowers et al, 2022 ; White-Gilbertson et al, 2022 ).…”

Section: Therapies Targeting Pgccsmentioning

confidence: 99%

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

Liu,

Wang,

2024

Front. Cell Dev. Biol.

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Polyploid giant cancer cells (PGCCs) are characterized by the presence of either a single enlarged nucleus or multiple nuclei and are closely associated with tumor progression and treatment resistance. These cells contribute significantly to cellular heterogeneity and can arise from various stressors, including radiation, chemotherapy, hypoxia, and environmental factors. The formation of PGCCs can occur through mechanisms such as endoreplication, cell fusion, cytokinesis failure, mitotic slippage, or cell cannibalism. Notably, PGCCs exhibit traits similar to cancer stem cells (CSCs) and generate highly invasive progeny through asymmetric division. The presence of PGCCs and their progeny is pivotal in conferring resistance to chemotherapy and radiation, as well as facilitating tumor recurrence and metastasis. This review provides a comprehensive analysis of the origins, potential formation mechanisms, stressors, unique characteristics, and regulatory pathways of PGCCs, alongside therapeutic strategies targeting these cells. The objective is to enhance the understanding of PGCC initiation and progression, offering novel insights into tumor biology.

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Section: Therapies Targeting Pgccsmentioning

confidence: 99%

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

Liu,

Wang,

2024

Front. Cell Dev. Biol.

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Characterization of polyploidy in cancer: Current status and future perspectives

Ghosh,

Choudhury,

Ghosh

et al. 2024

International Journal of Biological Macromolecules

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Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic

Mallin,

Rolle,

Schmidt

et al. 2024

Preprint

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There remains a large need for a greater understanding of the metastatic process within the prostate cancer field. Our research aims to understand the adaptive – ergo potentially metastatic – responses of cancer to changing microenvironments. Emerging evidence has implicated a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mountingin vitroevidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study of prostate cancer patients revealed that PACC presence in the prostate at the time of radical prostatectomy was predictive of future metastatic progression. To test for a causative relationship between PACC state biology and metastasis, we leveraged a novel method designed for flow-cytometric detection of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in subcutaneous, caudal artery, and intracardiac mouse models of metastasis. This approach provides both quantitative and qualitative information about the number and PACC-status of recovered CTCs and DTCs. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state.In vivocolonization assays proved PACC populations can regain proliferative capacity at metastatic sites following dormancy. Additional direct and indirect mechanisticin vitroanalyses revealed a PACC-specific partial Epithelial-to-Mesenchymal-Transition phenotype and a pro-metastatic secretory profile, together providing preliminary evidence that PACCs are mechanistically linked to metastasis.Statement of SignificanceWe provide the first evidence that cells in the polyaneuploid cancer cell state contribute to increased metastatic competencyin vivo.

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Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization

Cited by 4 publications

References 88 publications

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

Characterization of polyploidy in cancer: Current status and future perspectives

Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic

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