Phenotypic tumour cell plasticity as a resistance mechanism and therapeutic target in melanoma

Roesch, Alexander; Paschen, Annette; Landsberg, Jenny; Helfrich, Iris; Becker, Jürgen C.; Schadendorf, Dirk

doi:10.1016/j.ejca.2016.02.023

Cited by 48 publications

(44 citation statements)

References 31 publications

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“…Further studies revealed an important role of increased expression of Pdx1 and Nkx6.1 in this acquired sensitivity (Nielsen et al 2004). The potential link between dedifferentiation and adaptation/resistance to stress seems to be a conserved biological mechanism that has also been described in other cell types and models including cancer cells (Del Vecchio et al 2014, Roesch et al 2016 and even plant cells (Grafi & Barak 2015). Future work is needed to validate this hypothesis in β-cells and to fully characterize the response of dedifferentiated β-cells to different types of stress.…”

Section: Dedifferentiation As a Potential Adaptive Mechanismmentioning

confidence: 85%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

202

171

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Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: (1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes; (2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells, the β-cell forbidden genes; and (3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of Foxo1, Myc and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions.

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Section: Dedifferentiation As a Potential Adaptive Mechanismmentioning

confidence: 85%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

202

171

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“…Thus, tumors that show initial response can rapidly become therapy-tolerant and progress. Unfortunately, drug resistance has turned out to be a multifactorial phenomenon, which is especially based on the property of tumor cells to present high phenotypic cell plasticity and heterogeneity [90,91]. In order to investigate how interactions between cancer cells and the tumor microenvironment affect the response to cancer therapy, some light has been shed on the role of the β1-subunit mechano-transduction and signalling [92,93].…”

Section: Changing the Tension In Cancermentioning

confidence: 99%

“…Furthermore, they identified the β1-subunit, and its downstream effector, JNK, as mediators of tissue stiffening-induced drug resistance, indicating that changes in the rigidity of the underlying substrate can alter integrin-mediated intracellular signalling, which ultimately may change the efficacy of drug treatments [93]. Also, the β1-subunit has been implicated as a driver of drug resistance in erlotinib resistant lung cancer cells [94] as well as in lapatinib and trastuzumab resistance in breast cancer [91,95]. Along the same line, the group of Erik Sahai has discovered a complex and dynamic cross-talk between tumor cells, tumor associated host cells and proteins of the tumor matrix in the context of therapy-resistant BRAF-mutant melanoma cells [92].…”

Section: Changing the Tension In Cancermentioning

confidence: 99%

Tension in Cancer

Löffek

Franzke

Helfrich

2016

IJMS

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Integrins represent a large family of cell receptors that mediate adhesion to the extracellular matrix (ECM), thereby modulating a variety of cellular functions that are required for proliferation, migration, malignant conversion and invasiveness. During tumorigenesis the conversion of a tumor cell from sessile, stationary phenotype to an invasive phenotype requires the ability of tumor cells to interact with their environment in order to transduce signals from the ECM into the cells. Hence, there is increasing evidence that changes in the composition, topography and tension of tumor matrix can be sensed by integrin receptors, leading to the regulation of intracellular signalling events which subsequently help to fuel cancer progression. The fact that intracellular signals perceived from integrin ligand binding impact on almost all steps of tumor progression, including tumor cell proliferation, survival, metastatic dissemination and colonization of a metastatic niche, renders integrins as ideal candidates for the development of therapeutic agents. In this review we summarize the role of integrins in cancer with the special focus on cancer therapies and the recent progress that has been made in the understanding of “integrin-induced tension in cancer”. Finally, we conclude with clinical evidence for the role of integrin-mediated mechanotransduction in the development of therapy-resistant tumors.

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“…Next to genetic tumor evolution, particularly temporal phenotypic cell plasticity is an emerging problem in cancer [34][35][36] . In melanoma, various cell phenotypes intrinsically co-exist that have been identified to drive tumor progression 5 .…”

Section: Discussionmentioning

confidence: 99%

Persister state-directed transitioning and vulnerability in melanoma

Chauvistré

Shannan

Daignault

et al. 2020

Preprint

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Phenotypic intratumoral heterogeneity and temporal transitions between cell differentiation states represent major drivers of tumor fitness in melanoma. Expression of the histone H3K4 demethylase KDM5B/JARID1B follows a highly dynamic equilibrium across melanoma cells.When challenged for example with targeted or cytotoxic drugs, the intrinsically slow-cycling KDM5B high cell state becomes initially enriched, whereas under persistent drug-exposure melanomas decrease KDM5B expression again to re-enter cell proliferation for long-term tumor repopulation. However, the exact role of KDM5B for tumor cell differentiation and fate remained elusive so far. Here, we show that melanoma fitness can be overcome by molecular enforcement of high KDM5B expression levels. KDM5B-up-scaled melanoma cells are transcriptionally reprogramed towards a differentiated melanocytic profile including a slowcycling state. This effect can be phenocopied by a newly identified chemical compound also leading to decelerated tumor growth. Mechanistically, KDM5B represents a checkpoint for coordinating the differentiation phenotype of melanoma cells via transcriptional reprograming, cell cycle delay, and attenuation of cytokinetic abscission. These findings indicate that tumor plasticity per se, i.e. the necessity of cancer cells to dynamically switch between different cell cycling and differentiation states, represents an important oncologic process that can be chemically overcome.

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Phenotypic tumour cell plasticity as a resistance mechanism and therapeutic target in melanoma

Cited by 48 publications

References 31 publications

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Tension in Cancer

Persister state-directed transitioning and vulnerability in melanoma

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