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Integrative Analysis to Identify Genes Associated with Stemness and Immune Infiltration in Glioblastoma
Integrative Analysis to Identify Genes Associated with Stemness and Immune Infiltration in Glioblastoma
Abstract
A stem cell population at the anorectal junction maintains homeostasis and participates in tissue regeneration
doi: 10.1038/s41467-021-23034-x.
A stem cell population at the anorectal junction maintains homeostasis and participates in tissue regeneration
Abstract
At numerous locations of the body, transition zones are localized at the crossroad between two types of epithelium and are frequently associated with neoplasia involving both type of tissues. These transition zones contain cells expressing markers of adult stem cells that can be the target of early transformation. The mere fact that transition zone cells can merge different architecture with separate functions implies for a unique plasticity that these cells must display in steady state. However, their roles during tissue regeneration in normal and injured state remain unknown. Here, by using in vivo lineage tracing, single-cell transcriptomics, computational modeling and a three-dimensional organoid culture system of transition zone cells, we identify a population of Krt17+ basal cells with multipotent properties at the squamo-columnar anorectal junction that maintain a squamous epithelium during normal homeostasis and can participate in the repair of a glandular epithelium following tissue injury.
The Diverse Applications of Pancreatic Ductal Adenocarcinoma Organoids
The Diverse Applications of Pancreatic Ductal Adenocarcinoma Organoids
Ronnie Ren Jie Low, Wei Wen Lim , Paul M. Nguyen , Belinda Lee , Michael Christie, Antony W. Burgess ,Peter Gibbs ,Sean M. Grimmond ,Frédéric Hollande andTracy L. Putoczki
Simple Summary
Abstract
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.
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
Dependence receptors: new targets for cancer therapy
Dependence receptors: new targets for cancer therapy
Morgan Brisset 1 2, Mélodie Grandin 1 2, Agnès Bernet 3, Patrick Mehlen 3, Frédéric Hollande 1 2
1 Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne, Vic., Australia.
2 University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Vic., Australia.
3 Apoptosis, Cancer and Development Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France.
Abstract
Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects of tumorigenesis such as proliferation, angiogenesis, invasiveness, and chemoresistance. This involvement in multiple cancer hallmarks has raised interest in dependence receptors as targets for cancer therapy. Although additional studies remain necessary to fully understand the complexity of signaling pathways activated by these receptors and to target them efficiently, it is now clear that dependence receptors represent very exciting targets for future cancer treatment. This manuscript reviews current knowledge on the contribution of dependence receptors to cancer and highlights the potential for therapies that activate pro-apoptotic functions of these proteins.
Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas
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.
FTO-Mediated Cytoplasmic m6Am Demethylation Adjusts Stem-Like Properties in Colorectal Cancer Cell
Sébastien Relier 1, Julie Ripoll 2, Hélène Guillorit 1 3, Amandine Amalric 1, Cyrinne Achour 4 5, Florence Boissière 6, Jérôme Vialaret 7 8, Aurore Attina 7 8, Françoise Debart 9, Armelle Choquet 1, Françoise Macari 1, Virginie Marchand 10, Yuri Motorin 10, Emmanuelle Samalin 1 6, Jean-Jacques Vasseur 9, Julie Pannequin 1, Francesca Aguilo 4 5, Evelyne Lopez-Crapez 6, Christophe Hirtz 7 8, Eric Rivals 11, Amandine Bastide 12, Alexandre David 13 14
- 1IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
- 2LIRMM, Univ. Montpellier, CNRS, Montpellier, France.
- 3Stellate Therapeutics, Paris, France.
- 4Wallenberg Centre for Molecular Medicine (WCMM), Umea University, Umea, Sweden.
- 5Department of Medical Biosciences, Umea University, Umea, Sweden.
- 6ICM, Montpellier, France.
- 7IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France.
- 8INM, Univ. Montpellier, INSERM, Montpellier, France.
- 9IBMM, CNRS, Univ. Montpellier, ENSCM, Montpellier, France.
- 10Université de Lorraine, IMoPA UMR7365 CNRS-UL and UMS2008/US40 IBSLor, UL-CNRS-INSERM, BioPole, Vandoeuvre-les-Nancy, France.
- 11LIRMM, Univ. Montpellier, CNRS, Montpellier, France. rivals@lirmm.fr.
- 12IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France. amandine.bastide@igf.cnrs.fr.
- 13IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France. alexandre.david@igf.cnrs.fr.
- 14IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France. alexandre.david@igf.cnrs.fr.
Abstract
Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N6,2′-O-dimethyladenosine (m6Am) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.
GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer
GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer
Sonia Brun 1, Jean-Marc Pascussi 2, Elena Patricia Gifu 3, Eloïne Bestion 1 4, Zuzana Macek-Jilkova 5 6 7, Guanxiong Wang 3, Firas Bassissi 1, Soraya Mezouar 1, Jérôme Courcambeck 1, Philippe Merle 3 8, Thomas Decaens 5 6 7, Julie Pannequin 2, Philippe Halfon 1, Claude Caron de Fromentel 3
1 Genoscience Pharma, Marseille, France.
2 IGF, University of Montpellier, CNRS, INSERM, Montpellier, France.
3 CRCL, INSERM U1052, CNRS 5286, Université Lyon 1 – Centre Léon Bérard, Lyon, France.
4 Aix-Marseille Univ, MEPHI, APHM, IRD, IHU Méditerranée Infection, Marseille, France.
5 Institute for Advanced Biosciences, Research Center UGA, Inserm U 1209, CNRS 5309, La Tronche, France.
6 University of Grenoble Alpes, Faculté de Médecine, France.
7 Clinique Universitaire d’Hépato-gastroentérologie, Pôle Digidune, CHU Grenoble, France.
8 Hepatology and Gastroenterology Unit, Croix-Rousse Hospital, Hospices Civils de Lyon, France.
Abstract
Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and can regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed in vivo in HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90+CD45–). Thus, GNS561 offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population. Accordingly, a global phase 1b clinical trial in liver cancers was recently completed.
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
Meera Augustus , Donovan Pineau , Franck Aimond , Safa Azar , Davide Lecca , Frédérique Scamps 2, Sophie Muxel 1, Amélie Darlix 1 4, William Ritchie 5, Catherine Gozé 1 6, Valérie Rigau 1 7, Hugues Duffau 1 8, Jean-Philippe Hugnot
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
Elodie Terrié 1 Nadine Déliot 1 Yassine Benzidane 1 Thomas Harnois 1 Laëtitia Cousin 1 Patrick Bois 1 Lisa Oliver 2 Patricia Arnault 1 François Vallette 2, 3 Bruno Constantin 1, 3 Valérie Coronas
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
2 Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
3 Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
4 Department of Medical Oncology, Western Health, Melbourne, VIC 3052, Australia
5 Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia
Simple Summary
Abstract
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
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
Maria M. Haykal, Clara Nahmias, Christine Varon and Océane C. B. Martin
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