PUBLICATIONS

Cutting-edge research on CSCs

Found 80 Results
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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

Despite the development of new therapeutic strategies, cancer remains one of the leading causes of mortality worldwide. One of the current major challenges is the resistance of cancers to chemotherapy treatments inducing metastases and relapse of the tumor. The Hedgehog receptor Patched (Ptch1) is overexpressed in many types of cancers. We showed that Ptch1 contributes to the efflux of doxorubicin and plays an important role in the resistance to chemotherapy in adrenocortical carcinoma (ACC), a rare cancer which presents strong resistance to the standard of care chemotherapy treatment. In the present study, we isolated and characterized a subpopulation of the ACC cell line H295R in which Ptch1 is overexpressed and more present at the cell surface. This cell subpopulation is more resistant to doxorubicin, grows as spheroids, and has a greater capability of clonogenicity, migration, and invasion than the parental cells. Xenograft experiments performed in mice and in ovo showed that this cell subpopulation is more tumorigenic and metastatic than the parental cells. These results suggest that this cell subpopulation has cancer stem-like or persistent cell properties which were strengthened by RNA-seq. If present in tumors from ACC patients, these cells could be responsible for therapy resistance, relapse, and metastases

Date Publication: 2022 Type: Sunrise member publications

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.

Date Publication: 2022 Type: Sunrise member publications

BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells

Abstract

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

Date Publication: 2022 Type: Sunrise member publications

Circulating Tumor Cell Lines: an Innovative Tool for Fundamental and Translational Research.

ABSTRAT

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.

Date Publication: 2021 Type: Sunrise member publications

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.

Date Publication: 2022 Type: Sunrise member publications

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

Sophie Guelfi^1 2, Béatrice Orsetti³, Virginie Deleuze⁴, Valérie Rigau^5 6, Luc Bauchet^6 7, Hugues Duffau^6 7, Bernard Rothhut², Jean-Philippe Hugnot^6 8

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

Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-?1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.

Date Publication: 2021 Type: Sunrise member publications

Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance

Abstract

Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5?-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.

Date Publication: 2022 Type: Sunrise member publications

CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM

Simple Summary

In the present work, we describe (for the first time) the use of the transmembrane protein, CD44v6, to detect CTCs from blood samples of several patients with colorectal or breast cancer. We used CD44v6 antibodies to demonstrate that live CTCs can be specifically purified from CRC patient blood samples via magnetic bead- or FACS-based isolation techniques. Finally, we demonstrated that CD44v6-positive CTCs rarely expressed EpCam, which is currently the gold standard to enumerate CTCs, suggesting the need to use a combination of markers for a more comprehensive view of CTC heterogeneity.

Abstract

Circulating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity.

Date Publication: 2021 Type: Sunrise member publications

Integrative Analysis to Identify Genes Associated with Stemness and Immune Infiltration in Glioblastoma

Neerada Meenakshi Warrier,Prasoon Agarwal and Praveen Kumar

Abstract

It is imperative to identify the mechanisms that confer stemness to the cancer cells for more effective targeting. Moreover, there are not many studies on the link between stemness characteristics and the immune response in tumours. Therefore, in the current study involving GBM, we started with the study of BIRC5 (one of the rare genes differentially expressed in normal and cancer cells) and CXCR4 (gene involved in the survival and proliferation of CSCs). Together, these genes have not been systematically explored. We used a set of 27 promoter methylated regions in GBM. Our analysis showed that four genes corresponding to these regions, namely EOMES, BDNF, HLA-A, and PECAM1, were involved with BIRC5 and CXCR4. Interestingly, we found EOMES to be very significantly involved in stemness and immunology and it was positively correlated to CXCR4. Additionally, BDNF, which was significant in methylation, was negatively correlated to BIRC5

Date Publication: 2021 Type: Sunrise member publications

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

Affiliations

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.

Date Publication: 2021 Type: Sunrise member publications

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

Cancers 2021, 13(19), 4979

Simple Summary

Patients diagnosed with pancreatic cancer have very few treatment options. In order to identify new treatment opportunities, and develop new drugs for clinical use, appropriate model systems that take into account the complexities of a tumor are required. In this review, we summarize the current and emerging opportunities to accurately model pancreatic cancer using organoid technologies. We highlight the need for continued development of these complex model systems in order to inform personalized treatment.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. While immortalized cancer cell lines and genetically engineered murine models have increased our understanding of PDAC tumorigenesis, they do not recapitulate inter- and intra-patient heterogeneity. PDAC patient derived organoid (PDO) biobanks have overcome this hurdle, and provide an opportunity for the high throughput screening of potential new therapies. This review provides a summary of the PDAC PDO biobanks established to date, and discusses how they have advanced our understanding of PDAC biology. Looking forward, the development of coculturing techniques for specific immune or stromal cell populations will enable a better understanding of the crosstalk that occurs within the tumor microenvironment, and the impact of this crosstalk on treatment response.

Date Publication: 2021 Type: Sunrise member publications

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.

Date Publication: 2020 Type: Sunrise member publications

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

Date Publication: 2020 Type: Seminal publications

Dependence receptors: new targets for cancer therapy

Direct and Indirect Regulators of Epithelial-Mesenchymal Transition (EMT)-mediated Immunosuppression in Breast Carcinomas

Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Prathapan Thiru, Maria Zagorulya, Sunita Nepal, Tuba Banaz, Anna Martner, Stefani Spranger and Robert A. Weinberg

Cancer Discov; Published OnlineFirst December 16, 2020; doi:10.1158/2159-8290.CD-20-0603

Date Publication: 2020 Type: Seminal publications

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.

Date Publication: 2020 Type: Sunrise member publications

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

Sébastien Relier¹, Julie Ripoll², Hélène Guillorit^1 3, Amandine Amalric¹, Cyrinne Achour^4 5, Florence Boissière⁶, Jérôme Vialaret^7 8, Aurore Attina^7 8, Françoise Debart⁹, Armelle Choquet¹, Françoise Macari¹, Virginie Marchand¹⁰, Yuri Motorin¹⁰, Emmanuelle Samalin^1 6, Jean-Jacques Vasseur⁹, Julie Pannequin¹, Francesca Aguilo^4 5, Evelyne Lopez-Crapez⁶, Christophe Hirtz^7 8, Eric Rivals¹¹, Amandine Bastide¹², 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.

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 (m⁶A_m) demethylase activity. While m⁶A_m 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 m⁶A_m level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m⁶A_m methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m⁶A_m modification in stem-like properties acquisition. FTO-mediated regulation of m⁶A_m marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m⁶A_m modification and its potential adverse consequences for colorectal cancer management.

Date Publication: 2021 Type: Sunrise member publications

GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer

Date Publication: 2021 Type: Sunrise member publications

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 Scamps², Sophie Muxel¹, Amélie Darlix^1 4, William Ritchie⁵, 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.

Date Publication: 2021 Type: Sunrise member publications

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

Date Publication: 2020 Type: Sunrise member publications

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