Lipid droplet evolution gives insight into polyaneuploid cancer cell lipid droplet functions

Kostecka, Laurie G.; Pienta, Kenneth J.; Amend, Sarah R.

doi:10.1007/s12032-021-01584-w

Cited by 16 publications

(21 citation statements)

References 80 publications

(140 reference statements)

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“…In support with this notion, lipid metabolism of cancer cells has recently received considerable attention; Siros et.al showed the importance of lipids and mitochondria in survival of the chemo-resistant cancer cells and reported that PGCCs shift their metabolism to higher dependence on fatty acids and oxidative phosphorylation [41]. The increment of lipid droplets in these cells has also been observed [41,42]. Indeed, lipids as energy stores enable cancer cells to e ciently endure long-term stress condition [43].…”

Section: Discussionmentioning

confidence: 94%

Bisphosphonates Fight Against Cancer Roots: Zoledronic Acid Targets Chemo-Resistant Polyploid Giant Cancer Cells

Adibi

Moein

Gheisari

2022

Preprint

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Although polyploid giant cancer cells (PGCCs) are known as a key source of failure of current therapies, sufficient drugs to target these cells are not yet introduced. Considering the similarities of polyploid cells in regeneration and cancer, we hypothesized that zoledronic acid (ZA), an osteoclast-targeting agent, might be used to eliminate PGCCs. The 5637-bladder cancer cell line was treated with various doses of cisplatin to enrich polyploid cells and the efficacy of different concentrations of ZA in reducing this population was assessed. The metabolic profile of PGCCs was investigated with gas chromatography-mass spectrometry. Lipid profiles, mitochondrial density, and ROS content were also measured to assess the response of the cells to ZA. Cancer cells surviving after three days of exposure with 6 μM cisplatin were mainly polyploid. These cells demonstrated special morphological features such as fusion with diploid or other polyploid cells and originated in daughter cells through budding. ZA could substantially eradicate PGCCs with the maximal effect observed with 50 μM which resulted in the drop of PGCC fraction from 60±7.5% to 19±1.7%. PGCCs enriched after cisplatin demonstrated a drastic metabolic shift compared to untreated cancer cells with an augmentation of lipids. Further assays confirmed the high content of lipid droplets and cholesterol in these cells which were reduced after ZA administration. Additionally, the mitochondrial density and ROS increased in PGCCs both of which declined in response to ZA. Taken together, we propose that ZA is a potent inhibitor of PGCCs which modulates the significant metabolic alteration of PGCCs. Although this drug has been successfully exploited as adjuvant therapy for some malignancies, the current evidence on its effects on PGCCs justifies further trials to assess its potency for improving the success of current therapies. For tackling tumor resistance and relapse.

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Section: Discussionmentioning

confidence: 94%

Bisphosphonates Fight Against Cancer Roots: Zoledronic Acid Targets Chemo-Resistant Polyploid Giant Cancer Cells

Adibi

Moein

Gheisari

2022

Preprint

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“…Cancer cells, which are constantly faced with various stressors, such as hypoxia of the tumor microenvironment, nutrient fluctuations or anticancer treatment, accumulate LDs. An increase in LDs can affect major cancer features, including cell growth, proliferation, metabolism, migration, inflammation, immunity, aggressiveness and chemotherapy resistance [ 57 ]. Interestingly, polyploid cancer cells have greater accumulation of LDs than nonpolyploid cancer cells [ 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…An increase in LDs can affect major cancer features, including cell growth, proliferation, metabolism, migration, inflammation, immunity, aggressiveness and chemotherapy resistance [ 57 ]. Interestingly, polyploid cancer cells have greater accumulation of LDs than nonpolyploid cancer cells [ 57 , 58 ]. In this study, we visualized the accumulation of LDs in senescent/polyploid cancer cells and showed the increased expression of genes involved in responses to lipids (D3).…”

Section: Discussionmentioning

confidence: 99%

Therapy-Induced Senescent/Polyploid Cancer Cells Undergo Atypical Divisions Associated with Altered Expression of Meiosis, Spermatogenesis and EMT Genes

Czarnecka‐Herok

Śliwińska

Herok

et al. 2022

IJMS

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Upon anticancer treatment, cancer cells can undergo cellular senescence, i.e., the temporal arrest of cell division, accompanied by polyploidization and subsequent amitotic divisions, giving rise to mitotically dividing progeny. In this study, we sought to further characterize the cells undergoing senescence/polyploidization and their propensity for atypical divisions. We used p53-wild type MCF-7 cells treated with irinotecan (IRI), which we have previously shown undergo senescence/polyploidization. The propensity of cells to divide was measured by a BrdU incorporation assay, Ki67 protein level (cell cycle marker) and a time-lapse technique. Advanced electron microscopy-based cell visualization and bioinformatics for gene transcription analysis were also used. We found that after IRI-treatment of MCF-7 cells, the DNA replication and Ki67 level decreased temporally. Eventually, polyploid cells divided by budding. With the use of transmission electron microscopy, we showed the presence of mononuclear small cells inside senescent/polyploid ones. A comparison of the transcriptome of senescent cells at day three with day eight (when cells just start to escape senescence) revealed an altered expression of gene sets related to meiotic cell cycles, spermatogenesis and epithelial–mesenchymal transition. Although chemotherapy (DNA damage)-induced senescence is indispensable for temporary proliferation arrest of cancer cells, this response can be followed by their polyploidization and reprogramming, leading to more fit offspring.

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“…The final way we will consider to target PACCs is by directly killing cells that are in the PACC state. Recent evidence has shown that this may be possible by directed modulation of cellular metabolism by targeting lipid droplets 60 . To incorporate metabolism modulation into Eq.…”

Section: Pacc-targeted Therapiesmentioning

confidence: 99%

A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells

Bukkuri

Pienta²,

Austin

et al. 2022

Sci Rep

Self Cite

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Therapeutic resistance is one of the main reasons for treatment failure in cancer patients. The polyaneuploid cancer cell (PACC) state has been shown to promote resistance by providing a refuge for cancer cells from the effects of therapy and by helping them adapt to a variety of environmental stressors. This state is the result of aneuploid cancer cells undergoing whole genome doubling and skipping mitosis, cytokinesis, or both. In this paper, we create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to (1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and (2) aid in adaptation to environmental stressors by increasing the cancer cell’s ability to generate heritable variation (evolvability) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to allow cancer cells to persist under therapy and evolve therapeutic resistance. By eliminating cells in the PACC state through appropriately-timed PACC-targeted therapies, we show how we can prevent the emergence of resistance and promote cancer eradication.

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Lipid droplet evolution gives insight into polyaneuploid cancer cell lipid droplet functions

Cited by 16 publications

References 80 publications

Bisphosphonates Fight Against Cancer Roots: Zoledronic Acid Targets Chemo-Resistant Polyploid Giant Cancer Cells

Bisphosphonates Fight Against Cancer Roots: Zoledronic Acid Targets Chemo-Resistant Polyploid Giant Cancer Cells

Therapy-Induced Senescent/Polyploid Cancer Cells Undergo Atypical Divisions Associated with Altered Expression of Meiosis, Spermatogenesis and EMT Genes

A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells

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