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GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer
Identification of CRYAB + KCNN3 + SOX9 + Astrocyte-Like and EGFR + PDGFRA + OLIG1 + Oligodendrocyte-Like Tumoral Cells in Diffuse IDH1-Mutant Gliomas and Implication of NOTCH1 Signalling in Their Genesis
Abstract
Diffuse grade II IDH-mutant gliomas are slow-growing brain tumors that progress into high-grade gliomas. They present intratumoral cell heterogeneity, and no reliable markers are available to distinguish the different cell subtypes. The molecular mechanisms underlying the formation of this cell diversity is also ill-defined. Here, we report that SOX9 and OLIG1 transcription factors, which specifically label astrocytes and oligodendrocytes in the normal brain, revealed the presence of two largely nonoverlapping tumoral populations in IDH1-mutant oligodendrogliomas and astrocytomas. Astrocyte-like SOX9+ cells additionally stained for APOE, CRYAB, ID4, KCNN3, while oligodendrocyte-like OLIG1+ cells stained for ASCL1, EGFR, IDH1, PDGFRA, PTPRZ1, SOX4, and SOX8. GPR17, an oligodendrocytic marker, was expressed by both cells. These two subpopulations appear to have distinct BMP, NOTCH1, and MAPK active pathways as stainings for BMP4, HEY1, HEY2, p-SMAD1/5 and p-ERK were higher in SOX9+ cells. We used primary cultures and a new cell line to explore the influence of NOTCH1 activation and BMP treatment on the IDH1-mutant glioma cell phenotype. This revealed that NOTCH1 globally reduced oligodendrocytic markers and IDH1 expression while upregulating APOE, CRYAB, HEY1/2, and an electrophysiologically-active Ca2+-activated apamin-sensitive K+ channel (KCNN3/SK3). This was accompanied by a reduction in proliferation. Similar effects of NOTCH1 activation were observed in nontumoral human oligodendrocytic cells, which additionally induced strong SOX9 expression. BMP treatment reduced OLIG1/2 expression and strongly upregulated CRYAB and NOGGIN, a negative regulator of BMP. The presence of astrocyte-like SOX9+ and oligodendrocyte-like OLIG1+ cells in grade II IDH1-mutant gliomas raises new questions about their role in the pathology.
Keywords: BMP; NOTCH1 pathway; brain tumors; cellular heterogeneity; diffuse IDH1-mutant gliomas; diffuse grade II IDH-mutant glioma.
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
Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis.
Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma
Cancers 2021, 13(14), 3428
2 CRCINA-ÉQUIPE 9 – Apoptosis and Tumor Progression, CRCINA – Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
Glioblastoma is the most frequent and deadly form of primary brain tumors. Despite multimodal treatment, more than 90% of patients experience tumor recurrence. Glioblastoma contains a small population of cells, called glioblastoma stem cells (GSC) that are highly resistant to treatment and endowed with the ability to regenerate the tumor, which accounts for tumor recurrence. Transcriptomic studies disclosed an enrichment of calcium (Ca2+) signaling transcripts in GSC. In non-excitable cells, store-operated channels (SOC) represent a major route of Ca2+ influx. As SOC regulate the self-renewal of adult neural stem cells that are possible cells of origin of GSC, we analyzed the roles of SOC in cultures of GSC previously derived from five different glioblastoma surgical specimens. Immunoblotting and immunocytochemistry experiments showed that GSC express Orai1 and TRPC1, two core SOC proteins, along with their activator STIM1. Ca2+ imaging demonstrated that SOC support Ca2+ entries in GSC. Pharmacological inhibition of SOC-dependent Ca2+ entries decreased proliferation, impaired self-renewal, and reduced expression of the stem cell marker SOX2 in GSC. Our data showing the ability of SOC inhibitors to impede GSC self-renewal paves the way for a strategy to target the cells considered responsible for conveying resistance to treatment and tumor relapse.
The Diverse Applications of Pancreatic Ductal Adenocarcinoma Organoids
The Diverse Applications of Pancreatic Ductal Adenocarcinoma Organoids
The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials
- 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
The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient’s overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity.
USP22 promotes HER2-driven mammary carcinoma aggressiveness by suppressing the unfolded protein response
Prokakis E, Dyas A, Grün R, Fritzsche S, U Bedi, Kazerouni ZB, Kosinsky RL, Johnsen SA, Wegwitz F
Oncogene 2021 May 18.
The Ubiquitin-Specific Protease 22 (USP22) is a deubiquitinating subunit of the mammalian SAGA transcriptional co-activating complex. USP22 was identified as a member of the so-called “death-from-cancer” signature predicting therapy failure in cancer patients. However, the importance and functional role of USP22 in different types and subtypes of cancer remain largely unknown. In the present study, we leveraged human cell lines and genetic mouse models to investigate the role of USP22 in HER2-driven breast cancer (HER2+-BC) and demonstrate for the first time that USP22 is required for the tumorigenic properties in murine and human HER2+-BC models. To get insight into the underlying mechanisms, we performed transcriptome-wide gene expression analyses and identified the Unfolded Protein Response (UPR) as a pathway deregulated upon USP22 loss. The UPR is normally induced upon extrinsic or intrinsic stresses that can promote cell survival and recovery if shortly activated or programmed cell death if activated for an extended period. Strikingly, we found that USP22 actively suppresses UPR induction in HER2+-BC cells by stabilizing the major endoplasmic reticulum (ER) chaperone HSPA5. Consistently, loss of USP22 renders tumor cells more sensitive to apoptosis and significantly increases the efficiency of therapies targeting the ER folding capacity. Together, our data suggest that therapeutic strategies targeting USP22 activity may sensitize tumor cells to UPR induction and could provide a novel, effective approach to treat HER2+-BC.
CD44 regulates epigenetic plasticity by mediating iron endocytosis
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)
Organotypic Modeling of the Tumor Landscape
The Epigenetic Progenitor Origin of Cancer Reassessed: DNA Methylation Brings Balance to the Stem Force
Marco Bruschi
U981-Molecular Predictors and New Targets in Oncology, INSERM, Gustave Roussy, University Paris-Saclay, 114 rue Édouard Vaillant, 94800 Villejuif, France
Département de Cancérologie de l’Enfant et de l’Adolescent, Gustave Roussy, Université Paris-Saclay, 94800 Villejuif, France
Epigenomes 2020, 4(2), 8
https://doi.org/10.3390/epigenomes4020008
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
Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer
Clara Morral , Jelena Stanisavljevic , Xavier Hernando-Momblona , Elisabetta Mereu , Adrián Álvarez-Varela , Carme Cortina , Diana Stork , Felipe Slebe , Gemma Turon , Gavin Whissell , Marta Sevillano , Anna Merlos-Suárez , Àngela Casanova-Martí , Catia Moutinho , Scott W Lowe , Lukas E Dow , Alberto Villanueva , Elena Sancho , Holger Heyn , Eduard Batlle
PMID: 32396863
DOI: 10.1016/j.stem.2020.04.012
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
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