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Persistent Properties of a Subpopulation of Cancer Cells Overexpressing the Hedgehog Receptor Patched
Feliz Morel, Á.J.; Hasanovic, A.; Morin, A.; Prunier, C.; Magnone, V.; Lebrigand, K.; Aouad, A.; Cogoluegnes, S.; Favier, J.; Pasquier, C.; Mus-Veteau, I.
Pharmaceutics 2022, 14, 988.
Abstract
Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy.
Bansard L, Bouvet O, Moutin E, Le Gall G, Giammona A, Pothin E, Bacou M, Hassen-Khodja C, Bordignon B, Bourgaux JF, Prudhomme M, Hollande F, Pannequin J, Pascussi JM, Planque C.
2022 Feb 22;S2213-6711(22)00094-7
Abstract
Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer.
BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells
Abstract
Circulating Tumor Cell Lines: an Innovative Tool for Fundamental and Translational Research.
Metastasis is a leading cause of cancer death. Despite improvements in treatment strategies, metastatic cancer has a poor prognosis. We thus face an urgent need to understand the mechanisms behind metastasis development, and thus to propose efficient treatments for advanced cancer. Metastatic cancers are hard to treat, as biopsies are invasive and inaccessible. Recently, there has been considerable interest in liquid biopsies including both cell-free circulating deoxyribonucleic acid (DNA) and circulating tumor cells from peripheral blood and we have established several circulating tumor cell lines from metastatic colorectal cancer patients to participate in their characterization. Indeed, to functionally characterize these rare and poorly described cells, the crucial step is to expand them. Once established, circulating tumor cell (CTC) lines can then be cultured in suspension or adherent conditions. At the molecular level, CTC lines can be further used to assess the expression of specific markers of interest (such as differentiation, epithelial or cancer stem cells) by immunofluorescence or cytometry analysis. In addition, CTC lines can be used to assess drug sensitivity to gold-standard chemotherapies as well as to targeted therapies. The ability of CTC lines to initiate tumors can also be tested by subcutaneous injection of CTCs in immunodeficient mice.
Finally, it is possible to test the role of specific genes of interest that might be involved in cancer dissemination by editing CTC genes, by short hairpin ribonucleic acid (shRNA) or Crispr/Cas9. Modified CTCs can thus be injected into immunodeficient mouse spleens, to experimentally mimic part of the metastatic development process in vivo.
In conclusion, CTC lines are a precious tool for future research and for personalized medicine, where they will allow prediction of treatment efficiency using the very cells that are originally responsible for metastasis.
HDAC8 suppresses the epithelial phenotype and promotes EMT in chemotherapy-treated basal-like breast cancer
Abstract:
Background
Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy.
Results
Using whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4, 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3, Elf5, Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses.
Conclusion
The current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics.
SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme
Affiliations
- 1VIB-KU Leuven Center for Cancer Biology, 3000 Leuven, Belgium.
- 2Institut des Neurosciences de Montpellier, University of Montpellier (UM), Institut National de la Santé et la Recherche Médicale (INSERM), 34091 Montpellier, France.
- 3Institut de Recherche en Cancérologie de Montpellier, University of Montpellier (UM), INSERM, 34298 Montpellier, France.
- 4Institut de Génétique Moléculaire de Montpellier, University of Montpellier (UM), Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France.
- 5Department of Pathology and Oncobiology, Hôpital Gui de Chauliac, 34295 Montpellier, France.
- 6Institut de Génomique Fonctionelle, University of Montpellier (UM), CNRS, INSERM, 34094 Montpellier, France.
- 7Neurosurgery Department, Hôpital Gui de Chauliac, 34295 Montpellier, France.
- 8Department of Biology, University of Montpellier (UM), CEDEX 5, 34095 Montpellier, France.
Abstract
Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance
Abstract
CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM
Simple Summary
Abstract
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
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