Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

Zecena, Helma; Tveit, Daniel Myklatun; Wang, Zi; Farhat, Ahmed; Panchal, Parvita; Liu, Jing; Singh, Simar; Sanghera, Amandeep; Bainiwal, Ajay; Teo, Shuan Y.; Meyskens, Frank L.; Liu‐Smith, Feng; Filipp, Fabian V.

doi:10.1101/231142

Cited by 3 publications

(1 citation statement)

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“…In this context, interacting non-DE genes could not be used as markers, their role is just limited to enhance the functional information conveyed by DE genes. These approaches are very efficient at identifying sub-modules, improving the functional description of biological processes (enrichment analysis) and identifying novel anti-cancer drug targets (Zecena et al, 2018;Tran and Pham, 2021). For example, Barel and Herwig found different gene sets when comparing the effect of structural analogs of anthracyclines, with very little overlap (Barel and Herwig, 2018).…”

Section: Shared Functional Content Within Subnetworkmentioning

confidence: 99%

Tetrabromobisphenol A effects on differentiating mouse embryonic stem cells reveals unexpected impact on immune system

2022

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Tetrabromobisphenol A (TBBPA) is a potent flame retardant used in numerous appliances and a major pollutant in households and ecosystems. In vertebrates, it was shown to affect neurodevelopment, the hypothalamic-pituitary-gonadal axis and thyroid signaling, but its toxicity and modes of actions are still a matter of debate. The molecular phenotype resulting from exposure to TBBPA is only poorly described, especially at the level of transcriptome reprogramming, which further limits our understanding of its molecular toxicity. In this work, we combined functional genomics and system biology to provide a system-wide description of the transcriptomic alterations induced by TBBPA acting on differentiating mESCs, and provide potential new toxicity markers. We found that TBBPA-induced transcriptome reprogramming affect a large collection of genes loosely connected within the network of biological pathways, indicating widespread interferences on biological processes. We also found two hotspots of action: at the level of neuronal differentiation markers, and surprisingly, at the level of immune system functions, which has been largely overlooked until now. This effect is particularly strong, as terminal differentiation markers of both myeloid and lymphoid lineages are strongly reduced: the membrane T cell receptor (Cd79a, Cd79b), interleukin seven receptor (Il7r), macrophages cytokine receptor (Csf1r), monocyte chemokine receptor (Ccr2). Also, the high affinity IgE receptor (Fcer1g), a key mediator of allergic reactions, is strongly induced. Thus, the molecular imbalance induce by TBBPA may be stronger than initially realized.

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Section: Shared Functional Content Within Subnetworkmentioning

confidence: 99%

Tetrabromobisphenol A effects on differentiating mouse embryonic stem cells reveals unexpected impact on immune system

2022

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Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming

Brashears

Rathore

Schultze

et al. 2020

Preprint

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22Arginine auxotrophy due to the silencing of argininosuccinate synthetase 1 (ASS1) occurs in many 23 cancers, especially sarcomas. Arginine deiminase (ADI-PEG20) therapy exploits this metabolic 24 vulnerability by depleting extracellular arginine, causing arginine starvation. ASS1-negative cells 25 develop resistance to ADI-PEG20 through a metabolic adaptation that includes re-expressing 26 ASS1. As arginine-based multiagent therapies are being developed, further characterization of 27 the changes induced by arginine starvation is needed. In order to develop a systems-level 28 understanding of these changes, activity-based proteomic profiling (ABPP) and 29 phosphoproteomic profiling were performed before and after ADI-PEG20 treatment in ADI-30 PEG20-sensitive and resistant sarcoma cells. When integrated with previous metabolomic 31 profiling (Kremer et al, 2017a), this multi-omic analysis reveals that cellular response to arginine 32 starvation is mediated by adaptive ERK signaling, driving a Myc-Max transcriptional network. 33Concomitantly, these data elucidate proteomic changes that facilitate oxaloacetate production by 34 enhancing glutamine and pyruvate anaplerosis, and altering lipid metabolism to recycle citrate for 35 oxidative glutaminolysis. Based on the complexity of metabolic and cellular signaling interactions, 36 these multi-omic approaches could provide valuable tools for evaluating response to metabolically 37 targeted therapies. 65invariably contribute to ABPP as well (Wolfe et al, 2013; Piazza et al, 2018a; Veyel et al, 2018). 66Ultimately, ABPP integrates multiple informative proteomic parameters and provides a broad view 67 of proteomic regulation. For example, ABPP can identify adaptive kinomic changes based on 68 either altered kinase expression or activity (Duncan et al, 2012). 69The mechanisms of developing resistance to arginine starvation in sarcomas have been 70 partially defined, and include stabilization of nuclear cMyc (Prudner et al, 2019b), and increased 71 glutamine anaplerosis in order to produce aspartate (Kremer et al, 2017a). In addition, others 72 have examined mechanisms of ASS1 re-expression (Tsai et al, 2017; Long et al, 2017) and 73Deptor regulation (Ohshima et al, 2017). However, the underlying proteomic changes that initiate 74 these events and coordinate metabolic reprogramming remain unknown. We pursued systems 75 biology profiling to understand resistance to arginine starvation, as these approaches have proven 76 effective in delineating the adaptive changes involved in highly pleiotropic phenotypes such as 77 drug resistance (Zecena et al, 2018; Galluzzi et al, 2014), Myc activation, and various metabolic 78 changes (Tomita & Kami, 2012; Schaub et al, 2018). 79To understand ADI-PEG20-resistance of ASS1-negative sarcomas at a systems level, we 80 performed multi-omic profiling using phosphoproteomics and activity-based proteomics, and 81 coupled these data with existing metabolomic analyses (Kremer et al, 2017a). ADI-PEG20-82 senstive leiomyosarcoma cells (SKLMS1) h...

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Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

et al. 2018

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Background Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. Methods The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Results Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors. Conclusions The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell ...

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Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

Cited by 3 publications

References 51 publications

Tetrabromobisphenol A effects on differentiating mouse embryonic stem cells reveals unexpected impact on immune system

Tetrabromobisphenol A effects on differentiating mouse embryonic stem cells reveals unexpected impact on immune system

Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

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