Translational control of breast cancer plasticity

Jewer, Michael; Lee, Laura; Leibovitch, Matthew; Zhang, Guihua; Liu, Jiahui; Findlay, Scott D.; Vincent, Krista; Tandoc, Kristofferson; Dieters-Castator, Dylan Z.; Quail, Daniela F.; Dutta, Indrani; Coatham, Mackenzie; Xu, Zhihua; Puri, Aakshi; Guan, Bo‐Jhih; Hatzoglou, Maria; Brumwell, Andrea; Uniacke, James; Patsis, Christos; Koromilas, Antonis E.; Schueler, Julia; Siegers, Gabrielle M.; Topisirović, Ivan; Postovit, Lynne-Marie

doi:10.1038/s41467-020-16352-z

Cited by 88 publications

(68 citation statements)

References 55 publications

(75 reference statements)

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“…Changes in thioredoxin, granzyme A, and EIF2 signaling pathways suggested that cell survival mechanisms were initiated early within 5 to 30 min of Octpep-1 treatment in MM96L cells. EIF2 activation is of interest since it arrests tumor progression by manipulating the metabolism and redox status [ 24 ]. In addition, the granzyme signaling A pathway activation leads to cell death via caspase-independent pathways [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Moral-Sanz

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Mukhopadhyay

et al. 2021

Toxins

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Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the Octopus Kaurna-derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations.

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Section: Discussionmentioning

confidence: 99%

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Moral-Sanz

Potriquet

Mukhopadhyay

et al. 2021

Toxins

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“…Inhibiting mTOR resensitizes cancer cells to carboplatin and is accompanied by a reduced translation of mRNAs supporting cell survival, proliferation, and DNA repair [ 119 , 120 ]. Conversely, in breast cancer cells, chemotherapeutics (e.g., paclitaxel), active-site mTOR inhibitors (e.g., INK128), as well as hypoxia induce translation of NODAL , NANOG , and SNAI1 mRNAs, promoting stem-like phenotypes and drug resistance [ 121 ]. Intriguingly, NODAL , NANOG , and SNAI1 mRNAs have multiple 5′ UTR isoforms, some of which are preferentially translated under conditions of limiting eIF4F and TC levels [ 121 ].…”

Section: Introductionmentioning

confidence: 99%

Cancer Plasticity: The Role of mRNA Translation

et al. 2021

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Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.

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“…Moreover, NODAL expression emerges in breast cancers as they transition from DCIS into IDC [46] , wherein interactions between cancer and stromal cells are critical. NODAL inhibition reduces breast cancer-induced neovascularization and mitigates BCSC frequency, tumor growth, and invasion [ 47 , 48 , 49 ]. NODAL may also play an essential role in remodeling the TME.…”

Section: Introductionmentioning

confidence: 99%

Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes

et al. 2021

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The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.

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Translational control of breast cancer plasticity

Cited by 88 publications

References 55 publications

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Cancer Plasticity: The Role of mRNA Translation

Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes

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