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      Epigenetics and metabolism at the crossroads of stress-induced plasticity, stemness and therapeutic resistance in cancer

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          Abstract

          Despite the recent advances in the treatment of cancers, acquired drug resistance remains a major challenge in cancer management. While earlier studies suggest Darwinian factors driving acquired drug resistance, recent studies point to a more dynamic process involving phenotypic plasticity and tumor heterogeneity in the evolution of acquired drug resistance. Chronic stress after drug treatment induces intrinsic cellular reprogramming and cancer stemness through a slow-cycling persister state, which subsequently drives cancer progression. Both epigenetic and metabolic mechanisms play an important role in this dynamic process. In this review, we discuss how epigenetic and metabolic reprogramming leads to stress-induced phenotypic plasticity and acquired drug resistance, and how the two reprogramming mechanisms crosstalk with each other.

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          Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

          Vasanthi S Viswanathan, Matthew J. Ryan, Harshil D Dhruv … (2017)
          Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial–mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
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            Extension of life-span by introduction of telomerase into normal human cells.

            A. G. Bodnar, M. Ouellette, M Frolkis … (1998)
            Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.
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              Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

              M. Serrano, A. Lin, M. McCurrach … (1997)
              Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Theranostics
                Journal ID (iso-abbrev): Theranostics
                Journal ID (publisher-id): thno
                Title: Theranostics
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1838-7640
                Publication date Collection: 2020
                Publication date (Electronic): 15 May 2020
                Volume: 10
                Issue: 14
                Pages: 6261-6277
                Affiliations
                [1 ]Department of Dermatology, University of Colorado School of Medicine, Aurora, CO, USA
                [2 ]The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, OLD, Australia
                [3 ]Eastern Colorado VA Health Care System, Aurora CO, USA
                [4 ]Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
                Author notes
                ✉ Corresponding authors: Mayumi Fujita, University of Colorado School of Medicine, 12801 E.17th Ave, MS 8127, RC-1S, Rm L18-4124, Aurora, CO 80045. Phone: 303-724-4045; Fax: 303-724-4048; E-mail: mayumi.fujita@ 123456cuanschutz.edu . Helmut Schaider, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba QLD 4102, Australia. T 61 7 3443 7395; F 61 7 3443 7799; E-mail: h.schaider@ 123456uq.edu.au

                *These authors contributed equally to the study

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: thnov10p6261
                DOI: 10.7150/thno.42523
                PMC ID: 7255038
                SO-VID: aacc5e2a-8c51-47ab-a4ea-d5cec78cb9f3
                Copyright © © The author(s)
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 27 December 2019
                Date accepted : 13 February 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: epigenetics,metabolism,stress-induced plasticity,stemness
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: epigenetics, metabolism, stress-induced plasticity, stemness

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