Nuclear morphology predicts cell survival to cisplatin chemotherapy

Kim, Chi-Ju; Gonye, Anna L.K.; Truskowski, Kevin; Lee, Cheng‐Fan; Cho, Yoon‐Kyoung; Austin, Robert H.; Pienta, Kenneth J.; Amend, Sarah R.

doi:10.1016/j.neo.2023.100906

Cited by 17 publications

(11 citation statements)

References 39 publications

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“…First, we confirmed that this approach is sufficient to detect large cancer cells in mouse blood and bone marrow. High-ploidy cells, which we have reported to be many-fold larger than PC3 cells [ 6 ], were spiked into blood and bone marrow. Using the same gating approach, we modified the gates to be appropriate for the sample of interest.…”

Section: Resultsmentioning

confidence: 99%

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Multiparameter flow cytometric detection and analysis of rare cells in in vivo models of cancer metastasis

Mallin,

Rolle,

Pienta

et al. 2024

Biology Methods and Protocols

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Rapid and reliable circulating tumor cell (CTC) and disseminated tumor cell (DTC) detection is critical for rigorous evaluation of in vivo metastasis models. Clinical data shows that each step of the metastatic cascade presents increasing barriers to success, limiting the number of successful metastatic cells to fewer than 1 in 1,500,000,000. As such, it is critical for scientists to employ approaches that allow for evaluation of metastatic competency at each step of the cascade. Here, we present a flow cytometry-based method that enables swift and simultaneous comparison of both CTCs and DTCs from single animals, enabling evaluation of multiple metastatic steps within a single model system. We present the necessary gating strategy and optimized sample preparation conditions necessary to capture CTCs and DTCs using this approach. We also provide proof-of-concept experiments emphasizing the appropriate limits of detection of these conditions. Most importantly, we successfully recover CTCs and DTCs from murine blood and bone marrow. In supplemental materials, we expand the applicability of our method to lung tissue and exemplify a potential multi-plexing strategy to further characterize recovered CTCs and DTCs. This approach to multiparameter flow cytometric detection and analysis of rare cells in in vivo models of metastasis is reproducible, high-throughput, broadly applicable and highly adaptable to a wide range of scientific inquiries. Most notably, it simplifies the recovery and analysis of CTCs and DTCs from the same animal, allowing for a rapid first look at the comparative metastatic competency of various model systems throughout multiple steps of the metastatic cascade.

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Section: Resultsmentioning

confidence: 99%

“…Where indicated, high-ploidy PC3-GFP-Luc cells were generated as previously described [ 6 , 7 ]. Briefly, PC3-GFP-Luc cells were treated with 12 µM of cisplatin (resuspended in sterile PBS supplemented with 140 mM NaCl, according to manufacturer’s protocol) for 72 h. After 72 h, treatment was removed and replaced with complete media.…”

Section: Methodsmentioning

confidence: 99%

Multiparameter flow cytometric detection and analysis of rare cells in in vivo models of cancer metastasis

Mallin,

Rolle,

Pienta

et al. 2024

Biology Methods and Protocols

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Section: Discussionmentioning

confidence: 98%

“…Alterations to the canonical mitotic cell cycle were found in a recent study of drug-resilient, large, and primarily mononucleated prostate carcinoma cells ( 40 ). In that study, Kim and colleagues (2023) demonstrated that upon exposure to cytotoxic drugs, cells continue to replicate DNA by exiting the proliferative mitotic cycle and entering an endocycle ( 40 ). In another study of p53-mutated lymphoma cells, the cells after treatment failed to arrest in G 1 but instead at G 2 before entering an endocycle, while functional p53 stopped this ( 22 ).…”

Section: Discussionmentioning

confidence: 98%

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation

Carroll,

Manaprasertsak,

Boffelli Castro

et al. 2024

Cancer Research Communications

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Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF-2α. We found altered chromatin accessibility, ablated expression of RB1, and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF-2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF-2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF-2α in stress-response by polyploidy suggest a novel avenue for tackling chemotherapy-induced resistance in cancer.

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“…This is consistent with previously reported studies that apoptotic cells appear rounded or irregular aer treatment with cisplatin. 61,62 Povea-Cabello et al, have reported that the rounded and irregular appearance is due to the kinetics of the cytoskeleton reorganization when apoptosis is initiated. 63 The width measurement in our study is dened as the shortest distance across the cell body.…”

Section: Cisplatin Affects the Morphology Of A549 Cells Observed Usin...mentioning

confidence: 99%

Scanning ion conductance microscopy revealed cisplatin-induced morphological changes related to apoptosis in single adenocarcinoma cells

Muhammed,

Lazenby

2024

Anal. Methods

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Nuclear morphology predicts cell survival to cisplatin chemotherapy

Cited by 17 publications

References 39 publications

Multiparameter flow cytometric detection and analysis of rare cells in in vivo models of cancer metastasis

Multiparameter flow cytometric detection and analysis of rare cells in in vivo models of cancer metastasis

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation

Scanning ion conductance microscopy revealed cisplatin-induced morphological changes related to apoptosis in single adenocarcinoma cells

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