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  1. Article ; Online: Role of dual specificity phosphatases (DUSPs) in melanoma cellular plasticity and drug resistance.

    Singh, Mithalesh K / Altameemi, Sarah / Lares, Marcos / Newton, Michael A / Setaluri, Vijayasaradhi

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 14395

    Abstract: Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often associated with drug resistance. The mechanisms that ... ...

    Abstract Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often associated with drug resistance. The mechanisms that control melanoma phenotype plasticity and its role in drug resistance are not fully understood. We previously demonstrated that emergence of MAPK inhibitor (MAPKi)-resistance phenotype is associated with decreased expression of stem cell proliferation genes and increased expression of MAPK inactivation genes, including dual specificity phosphatases (DUSPs). Several members of the DUSP family genes, specifically DUSP1, -3, -8 and -9, are expressed in primary and metastatic melanoma cell lines and pre-and post BRAFi treated melanoma cells. Here, we show that knockdown of DUSP1 or DUSP8 or treatment with BCI, a pharmacological inhibitor of DUSP1/6 decrease the survival of MAPKi-resistant cells and sensitizes them to BRAFi and MEKi. Pharmacological inhibition of DUSP1/6 upregulated nestin, a neural crest stem cell marker, in both MAPKi-sensitive cells and cells with acquired MAPKi-resistance. In contrast, treatment with BCI resulted in upregulation of MAP2, a neuronal differentiation marker, only in MAPKi-sensitive cells but caused downregulation of both MAP2 and GFAP, a glial marker, in all MAPKi-resistant cell lines. These data suggest that DUSP proteins are involved in the regulation of cellular plasticity cells and melanoma drug resistance and are potential targets for treatment of MAPKi-resistant melanoma.
    MeSH term(s) Cell Line, Tumor ; Cell Plasticity/genetics ; Drug Resistance, Neoplasm/genetics ; Dual-Specificity Phosphatases/genetics ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Protein Kinase Inhibitors/pharmacology
    Chemical Substances Protein Kinase Inhibitors ; Dual-Specificity Phosphatases (EC 3.1.3.48)
    Language English
    Publishing date 2022-08-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-18578-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes.

    Sadangi, Shreyans / Milosavljevic, Katarina / Castro-Perez, Edgardo / Lares, Marcos / Singh, Mithalesh / Altameemi, Sarah / Beebe, David J / Ayuso, Jose M / Setaluri, Vijayasaradhi

    Cancers

    2022  Volume 14, Issue 5

    Abstract: ... ...

    Abstract BRAF
    Language English
    Publishing date 2022-02-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14051233
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The role of satellite cell-derived TRIM28 in mechanical load- and injury-induced myogenesis.

    Lin, Kuan-Hung / Hibbert, Jamie E / Lemens, Jake L / Torbey, Melissa M / Steinert, Nathaniel D / Flejsierowicz, Philip M / Melka, Kiley M / Lares, Marcos / Setaluri, Vijayasaradhi / Hornberger, Troy A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discovered that this myogenic potential of satellite cells requires a ... ...

    Abstract Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discovered that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Unexpectedly, multiple lines of both
    Language English
    Publishing date 2023-12-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.20.572566
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Microfluidic model with air-walls reveals fibroblasts and keratinocytes modulate melanoma cell phenotype, migration, and metabolism.

    Ayuso, Jose M / Sadangi, Shreyans / Lares, Marcos / Rehman, Shujah / Humayun, Mouhita / Denecke, Kathryn M / Skala, Melissa C / Beebe, David J / Setaluri, Vijayasaradhi

    Lab on a chip

    2021  Volume 21, Issue 6, Page(s) 1139–1149

    Abstract: Melanoma evolution is a complex process. The role epidermal keratinocytes and dermal fibroblasts play in this process and the mechanisms involved in tumor-stroma interactions remain poorly understood. Here, we used a microfluidic platform to evaluate the ...

    Abstract Melanoma evolution is a complex process. The role epidermal keratinocytes and dermal fibroblasts play in this process and the mechanisms involved in tumor-stroma interactions remain poorly understood. Here, we used a microfluidic platform to evaluate the cross-talk between human primary melanoma cells, keratinocytes and dermal fibroblasts. The microfluidic device included multiple circular chambers separated by a series of narrow connection channels. The microdevice design allowed us to develop a new cell patterning method based on air-walls, removing the need for hydrogel barriers, porous membranes, or external equipment. Using this method, we co-cultured melanoma cells in the presence of keratinocytes and/or dermal fibroblasts. The results demonstrated that the presence of dermal fibroblasts and keratinocytes led to changes in melanoma cell morphology and growth pattern. Molecular analysis revealed changes in the chemokine secretion pattern, identifying multiple secreted factors involved in tumor progression. Finally, optical metabolic imaging showed that melanoma cells, fibroblasts, and keratinocytes exhibited different metabolic features. Additionally, the presence of stromal cells led to a metabolic shift in melanoma cells, highlighting the role the skin microenvironment on melanoma evolution.
    MeSH term(s) Cells, Cultured ; Fibroblasts ; Humans ; Keratinocytes ; Melanoma ; Microfluidics ; Phenotype ; Tumor Microenvironment
    Language English
    Publishing date 2021-02-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2056646-3
    ISSN 1473-0189 ; 1473-0197
    ISSN (online) 1473-0189
    ISSN 1473-0197
    DOI 10.1039/d0lc00988a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression.

    Krishnan, Aishwarya / Bhasker, Aishwarya I / Singh, Mithalesh K / Rodriguez, Carlos I / Pérez, Edgardo Castro / Altameemi, Sarah / Lares, Marcos / Khan, Hamidullah / Ndiaye, Mary / Ahmad, Nihal / Schieke, Stefan M / Setaluri, Vijayasaradhi

    Molecular cancer research : MCR

    2022  Volume 20, Issue 10, Page(s) 1548–1560

    Abstract: Exchange proteins directly activated by cAMP (EPAC) belong to a family of RAP guanine nucleotide exchange factors (RAPGEF). EPAC1/2 (RAPGEF3/4) activates RAP1 and the alternative cAMP signaling pathway. We previously showed that the differential growth ... ...

    Abstract Exchange proteins directly activated by cAMP (EPAC) belong to a family of RAP guanine nucleotide exchange factors (RAPGEF). EPAC1/2 (RAPGEF3/4) activates RAP1 and the alternative cAMP signaling pathway. We previously showed that the differential growth response of primary and metastatic melanoma cells to cAMP is mediated by EPAC. However, the mechanisms responsible for this differential response to EPAC signaling are not understood. In this study, we show that pharmacologic inhibition or siRNA-mediated knockdown of EPAC selectively inhibits the growth and survival of primary melanoma cells by downregulation of cell-cycle proteins and inhibiting the cell-cycle progression independent of ERK1/2 phosphorylation. EPAC inhibition results in upregulation of AKT phosphorylation but a downregulation of mTORC1 activity and its downstream effectors. We also show that EPAC regulates both glycolysis and oxidative phosphorylation, and production of mitochondrial reactive oxygen species, preferentially in primary melanoma cells. Employing a series of genetically matched primary and lymph node metastatic (LNM) melanoma cells, and distant organ metastatic melanoma cells, we show that the LNM and metastatic melanoma cells become progressively less responsive and refractory to EPAC inhibition suggesting loss of dependency on EPAC signaling correlates with melanoma progression. Analysis of The Cancer Genome Atlas dataset showed that lower RAPGEF3, RAPGEF4 mRNA expression in primary tumor is a predictor of better disease-free survival of patients diagnosed with primary melanoma suggesting that EPAC signaling facilitates tumor progression and EPAC is a useful prognostic marker. These data highlight EPAC signaling as a potential target for prevention of melanoma progression.
    Implications: This study establishes loss of dependency on EPAC-mTORC1 signaling as hallmark of primary melanoma evolution and targeting this escape mechanism is a promising strategy for metastatic melanoma.
    MeSH term(s) Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Melanoma/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics ; RNA, Small Interfering ; Reactive Oxygen Species ; Signal Transduction
    Chemical Substances Guanine Nucleotide Exchange Factors ; RAPGEF4 protein, human ; RNA, Messenger ; RNA, Small Interfering ; Reactive Oxygen Species ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2022-07-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2098788-2
    ISSN 1557-3125 ; 1541-7786
    ISSN (online) 1557-3125
    ISSN 1541-7786
    DOI 10.1158/1541-7786.MCR-22-0026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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