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ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a “Toggle Switch” of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells
Fabien Almairac , Laurent Turchi , Nathalie Sakakini , David Nicolas Debruyne , Sarah Elkeurti , Elisabet Gjernes , Beatrice Polo , Laurence Bianchini , Denys Fontaine , Philippe Paquis , Herve Chneiweiss , Marie-Pierre Junier , Patrick Verrando , Fanny Burel-Vandenbos , Thierry Virolle.
There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated “toggle switch” that promotes pluripotency marker expression and stem-like features in GBM cells. SIGNIFICANCE: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency
doi: 10.1158/0008-5472.CAN-19-0855. Epub 2020 May 4.
CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies
Dongrui Wang, Briana C Prager, Ryan C Gimple, Brenda Aguilar, Darya Alizadeh, Hongzhen Tang, Deguan Lv, Renate Starr, Alfonso Brito, Qiulian Wu, Leo J.Y Kim, Zhixin Qiu, Peng Lin, Michael H. Lorenzini, Behnam Badie, Stephen J Forman, Qi Xie, Christine E Brown and Jeremy N. Rich
Cancer Discov; Published OnlineFirst December 16, 2020; doi:10.1158/2159-8290.CD-20-1243
Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas
Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis.
Organotypic Modeling of the Tumor Landscape
Maria Haykal, Clara Nahmias, Christine Varon, Océane Martin
Cancer is a complex disease and it is now clear that not only epithelial tumor cells play a role in carcinogenesis. The tumor microenvironment is composed of non-stromal cells, including endothelial cells, adipocytes, immune and nerve cells, and a stromal compartment composed of extracellular matrix, cancer-associated fibroblasts and mesenchymal cells. Tumorigenesis is a dynamic process with constant interactions occurring between the tumor cells and their surroundings. Even though all connections have not yet been discovered, it is now known that crosstalk between actors of the microenvironment drives cancer progression. Taking into account this complexity, it is important to develop relevant models to study carcinogenesis. Conventional 2D culture models fail to represent the entire tumor microenvironment properly and the use of animal models should be decreased with respect to the 3Rs rule. To this aim, in vitro organotypic models have been significantly developed these past few years. These models have different levels of complexity and allow the study of tumor cells alone or in interaction with the microenvironment actors during the multiple stages of carcinogenesis. This review depicts recent insights into organotypic modeling of the tumor and its microenvironment all throughout cancer progression. It offers an overview of the crosstalk between epithelial cancer cells and their microenvironment during the different phases of carcinogenesis, from the early cell autonomous events to the late metastatic stages. The advantages of 3D over classical 2D or in vivo models are presented as well as the most promising organotypic models. A particular focus is made on organotypic models used for studying cancer progression, from the less complex spheroids to the more sophisticated body-on-a-chip. Last but not least, we address the potential benefits of these models in personalized medicine which is undoubtedly a domain paving the path to new hopes in terms of cancer care and cure.
Frontiers in Cell and Developmental Biology, Frontiers media, 2020, 8,
Online ahead of print. ff10.3389/fcell.2020.606039f
Autophagy in Osteosarcoma Cancer Stem Cells Is Critical Process which Can Be Targeted by the Antipsychotic Drug Thioridazine
Olivier Camuzard , Marie-Charlotte Trojani , Sabine Santucci-Darmanin , Sophie Pagnotta , Véronique Breuil, Georges F Carle , Valérie Pierrefite-Carle
Cancer stem cells (CSCs) represent a minor population of cancer cells with stem cell-like properties which are able to fuel tumor growth and resist conventional treatments. Autophagy has been described to be upregulated in some CSCs and to play a crucial role by maintaining stem features and promoting resistance to both hostile microenvironments and treatments. Osteosarcoma (OS) is an aggressive bone cancer which mainly affects children and adolescents and autophagy in OS CSCs has been poorly studied. However, this is a very interesting case because autophagy is often deregulated in this cancer. In the present work, we used two OS cell lines showing different autophagy capacities to isolate CSC-enriched populations and to analyze the autophagy in basal and nutrient-deprived conditions. Our results indicate that autophagy is more efficient in CSCs populations compared to the parental cell lines, suggesting that autophagy is a critical process in OS CSCs. We also showed that the antipsychotic drug thioridazine is able to stimulate, and then impair autophagy in both CSC-enriched populations, leading to autosis, a cell death mediated by the Na+/K+ ATPase pump and triggered by dysregulated accumulation of autophagosomes. Taken together, our results indicate that autophagy is very active in OS CSCs and that targeting this pathway to switch their fate from survival to death could provide a novel strategy to eradicate these cells in osteosarcoma.
Cancers, 2020 Dec 7;12(12):3675
doi: 10.3390/cancers12123675.
Organotypic Modeling of the Tumor Landscape
Maria M. Haykal, Clara Nahmias, Christine Varon and Océane C. B. Martin
CD44 regulates epigenetic plasticity by mediating iron endocytosis
Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth
Leventoux N1, Augustus M, Azar S, Riquier S, Villemin JP, Guelfi S, Falha L, Bauchet L, Gozé C, Ritchie W, Commes T, Duffau H, Rigau V, Hugnot JP
Sci Rep. 2020 Mar 26;10(1):5504. doi: 10.1038/s41598-020-62145-1.
PMID: 32218467
Heterotypic cell–cell communication regulates glandular stem cell multipotency
Alessia Centonze, Shuheng Lin, Elisavet Tika, Alejandro Sifrim, Marco Fioramonti, Milan Malfait, Yura Song, Aline Wuidart, Jens Van Herck, Anne Dannau, Gaelle Bouvencourt, Christine Dubois, Nina Dedoncker, Amar Sahay, Viviane de Maertelaer, Christian W. Siebel, Alexandra Van Keymeulen, Thierry Voet & Cédric Blanpain
Nature volume 584, pages608–613(2020)
A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells
Arfaoui A, Rioualen C, Azzoni V, Pinna G, Finetti P, Wicinski J, Josselin E, Macario M, Castellano R, Léonard-Stumpf C, Bal A, Gros A, Lossy S, Kharrat M, Collette Y, Bertucci F, Birnbaum D, Douik H, Bidaut G, Charafe-Jauffret E, Ginestier C.
EMBO Mol Med. 2019 Oct;11(10):e9930. doi: 10.15252/emmm.201809930. Epub 2019 Sep 2.
PMID: 31476112
Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia
Torres Á, Erices JI, Sanchez F, Ehrenfeld P, Turchi L, Virolle T, Uribe D, Niechi I, Spichiger C, Rocha JD, Ramirez M, Salazar-Onfray F, San Martín R, Quezada C.
Cancer Lett. 2019 Apr 1;446:112-122. doi: 10.1016/j.canlet.2019.01.004. Epub 2019 Jan 18.
PMID: 30660649
Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner
Soubéran A, Cappaï J, Chocry M, Nuccio C, Raujol J, Colin C, Lafitte D, Kovacic H, Quillien V, Baeza-Kallee N, Rougon G, Figarella-Branger D, Tchoghandjian A.
Stem Cells. 2019 Jun;37(6):731-742. doi: 10.1002/stem.2997. Epub 2019 Mar 28.
PMID:30920104
The SCRIB Paralog LANO/LRRC1 Regulates Breast Cancer Stem Cell Fate through WNT/?-Catenin Signaling
Lopez Almeida L, Sebbagh M, Bertucci F, Finetti P, Wicinski J, Marchetto S, Castellano R, Josselin E, Charafe-Jauffret E, Ginestier C, Borg JP, Santoni MJ.
Stem Cell Reports. 2018 Nov 13;11(5):1040-1050. doi: 10.1016/j.stemcr.2018.09.008. Epub 2018 Oct 18.
PMID:30344009
The ribosome, (slow) beating heart of cancer (stem) cell
Bastide A, David A. Oncogenesis. 2018 Apr 20;7(4):34. doi: 10.1038/s41389-018-0044-8. Review. PMID:29674660
Dek overexpression in murine epithelia increases overt esophageal squamous cell carcinoma incidence
Matrka MC, Cimperman KA, Haas SR, Guasch G, Ehrman LA, Waclaw RR, Komurov K, Lane A, Wikenheiser-Brokamp KA, Wells SI.
PLoS Genet. 2018 Mar 14;14(3):e1007227. doi: 10.1371/journal.pgen.1007227. eCollection 2018 Mar.
PMID:29538372
Impact of STAT3 phosphorylation in glioblastoma stem cells radiosensitization and patient outcome
Masliantsev K, Pinel B, Balbous A, Guichet PO, Tachon G, Milin S, Godet J, Duchesne M, Berger A, Petropoulos C, Wager M, Karayan-Tapon L.
Oncotarget. 2017 Dec 16;9(3):3968-3979. doi: 10.18632/oncotarget.23374. eCollection 2018 Jan 9.
PMID:29423098
Cellular Pliancy and the Multistep Process of Tumorigenesis
Puisieux A, Pommier RM, Morel AP, Lavial F.
Cancer Cell. 2018 Feb 12;33(2):164-172. doi: 10.1016/j.ccell.2018.01.007. Review.
PMID:29438693
Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells
Paquet-Fifield S, Koh SL, Cheng L, Beyit LM, Shembrey C, Mølck C, Behrenbruch C, Papin M, Gironella M, Guelfi S, Nasr R, Grillet F, Prudhomme M, Bourgaux JF, Castells A, Pascussi JM, Heriot AG, Puisieux A, Davis MJ, Pannequin J, Hill AF, Sloan EK, Hollande F.
Cancer Res. 2018 Jun 1;78(11):2925-2938. doi: 10.1158/0008-5472.CAN-17-1869. Epub 2018 Mar 6.
PMID:29510994
DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression
Debruyne DN, Turchi L, Burel-Vandenbos F, Fareh M, Almairac F, Virolle V, Figarella-Branger D, Baeza-Kallee N, Lagadec P, Kubiniek V, Paquis P, Fontaine D, Junier MP, Chneiweiss H, Virolle T.
Oncogene. 2018 Jan 11;37(2):241-254. doi: 10.1038/onc.2017.323. Epub 2017 Sep 18.
PMID:28925399
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Solid tumor cancer stem cell network