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.

The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials

Céline Hervieu,  Niki Christou, Serge Battu, Muriel Mathonnet

• EA 3842 CAPTuR “Control of Cell Activation in Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, Genomics, Environment, Immunity, Health and Therapeutics (GEIST) Institute, University of Limoges, 87025 Limoges CEDEX, France.
• Department of General, Endocrine and Digestive Surgery, University Hospital of Limoges, 87025 Limoges CEDEX, France.

Abstract

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.

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.

doi: 10.3390/cancers12123675.

FTO-Mediated Cytoplasmic m6Am Demethylation Adjusts Stem-Like Properties in Colorectal Cancer Cell

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

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)

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

CD44 regulates epigenetic plasticity by mediating iron endocytosis

Organotypic Modeling of the Tumor Landscape

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