IL1R1 protein, human; Receptors, Interleukin-1 Type I; Humans; Fibroblasts/pathology; Immune Tolerance; Immunosuppression Therapy; Tumor Microenvironment; Cell Proliferation; Receptors, Interleukin-1 Type I/genetics; Cancer-Associated Fibroblasts/pathology; Colorectal Neoplasms/drug therapy; Colorectal Neoplasms/genetics; Cancer-Associated Fibroblasts; Colorectal Neoplasms; Fibroblasts; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
Résumé :
[en] Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.
Disciplines :
Biochimie, biophysique & biologie moléculaire
Auteur, co-auteur :
KONCINA, Eric ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
NURMIK, Martin ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Serge HAAN
POZDEEV, Vitaly ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
GILSON, Cédric ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
TSENKOVA, Mina ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
BEGAJ, Rubens ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
Stang, S; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
GAIGNEAUX, Anthoula ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Weindorfer, C; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
RODRIGUEZ, Fabien ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
SCHMOETTEN, Maryse ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
KLEIN, Eliane ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
KARTA, Jessica ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
Atanasova, V S; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
ULLMANN, Pit ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine
HALDER, Rashi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Sequencing Platform
Hengstschläger, M; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
Graas, J; Clinical and Epidemiological Investigation Center, Department of Population Health, Luxembourg Institute of Health, Luxembourg, Luxembourg
Augendre, V; National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg
Karapetyan, Y E; Integrated BioBank of Luxembourg, Dudelange, Luxembourg
KERGER, Lucien ; University of Luxembourg ; Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
Zuegel, N; Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
SKUPIN, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Integrative Cell Signalling
HAAN, Serge ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
MEISER, Johannes ; University of Luxembourg ; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Dolznig, H ; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. helmut.dolznig@meduniwien.ac.at
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
We thank the patients who kindly donated their samples and made this study possible. We thank all the contributing surgeons and nurses from the Centre Hospitalier Emile Mayrisch, the Laboratoire National de Santé and the Clinical and Epidemiological Investigation Centre of the LIH for their work with the patients. We would like to thank the Fondation Cancer for its support during the setup of the Luxembourgish CRC patient cohort. We also thank Prof. Dr. Michel Mittelbronn and the pathologists and macroscopy team from NCP/LNS. The authors would also like to thank their collaborators at the IBBL, Dr. Fay Betsou, Dr. Nikolai Goncharenko, Dr. Christelle Bahlawane and Amélie Gaignaux for the overall setup of the patient sample collection and the management of the cohort. We would also like to thank Dr. Lynn Bonetti for providing us with the Th17 gene signature. We would also like to thank the whole team of the animal facility at the University of Luxembourg, especially our veterinarian Jennifer Behm and our facility manager Djalil Coowar. Finally we would like to thank Professor Olivier de Wever for the kind gift of the Ct5.3 fibroblasts. Parts of the data processing presented in this manuscript were carried out using the HPC facility of the University of Luxembourg ( https://hpc.uni.lu ). Figures a, and Supplementary Fig. were created with BioRender.com ( https://biorender.com ). The diagrams shown in Figs. b, and Supplementary Fig. were generated using Inkscape ( https://inkscape.org/ ) and the mouse clipart used in Figs. b and are adapted from “Mouse” from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License ( https://smart.servier.com )’. This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (L.E.), CORE/C20/BM/14591557 (L.E.), PoC/18/12554295 (L.E.), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit—CANBIO (PRIDE15/10675146/CANBIO) to N.M. and B.R. and MICROH PRIDE17/11823097 to T.M., as well as by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (E-AGR-0023-10-Z; T.M.), the Fondation Schumacher (B.R.), and the Fondation Gustave et Simone Prévot (L.E.). The project was further supported by CCC research grant (Initiative Krebsforschung) of the MedUni Vienna (D.H.), European Commission, SECRET ITN 859962 (D.H.) and Gesellschaft für Forschungsförderung Niederösterreich m.b.H.; LSC18-017 (D.H.)]. The collection of colorectal cancer samples is supported by the Fondation Cancer (L.E.) and the Doctoral School in Science and Engineering (T.M.) and the Department of Life Sciences and Medicine at the University of Luxembourg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.We thank the patients who kindly donated their samples and made this study possible. We thank all the contributing surgeons and nurses from the Centre Hospitalier Emile Mayrisch, the Laboratoire National de Santé and the Clinical and Epidemiological Investigation Centre of the LIH for their work with the patients. We would like to thank the Fondation Cancer for its support during the setup of the Luxembourgish CRC patient cohort. We also thank Prof. Dr. Michel Mittelbronn and the pathologists and macroscopy team from NCP/LNS. The authors would also like to thank their collaborators at the IBBL, Dr. Fay Betsou, Dr. Nikolai Goncharenko, Dr. Christelle Bahlawane and Amélie Gaignaux for the overall setup of the patient sample collection and the management of the cohort. We would also like to thank Dr. Lynn Bonetti for providing us with the Th17 gene signature. We would also like to thank the whole team of the animal facility at the University of Luxembourg, especially our veterinarian Jennifer Behm and our facility manager Djalil Coowar. Finally we would like to thank Professor Olivier de Wever for the kind gift of the Ct5.3 fibroblasts. Parts of the data processing presented in this manuscript were carried out using the HPC facility of the University of Luxembourg61(https://hpc.uni.lu). Figures 4 a, 7 and Supplementary Fig. 4a were created with BioRender.com (https://biorender.com). The diagrams shown in Figs. 5 b, 6a and Supplementary Fig. 1b were generated using Inkscape (https://inkscape.org/) and the mouse clipart used in Figs. 5 b and 6a are adapted from “Mouse” from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com)’. This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (L.E.), CORE/C20/BM/14591557 (L.E.), PoC/18/12554295 (L.E.), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit—CANBIO (PRIDE15/10675146/CANBIO) to N.M. and B.R. and MICROH PRIDE17/11823097 to T.M., as well as by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (E-AGR-0023-10-Z; T.M.), the Fondation Schumacher (B.R.), and the Fondation Gustave et Simone Prévot (L.E.). The project was further supported by CCC research grant (Initiative Krebsforschung) of the MedUni Vienna (D.H.), European Commission, SECRET ITN 859962 (D.H.) and Gesellschaft für Forschungsförderung Niederösterreich m.b.H.; LSC18-017 (D.H.)]. The collection of colorectal cancer samples is supported by the Fondation Cancer (L.E.) and the Doctoral School in Science and Engineering (T.M.) and the Department of Life Sciences and Medicine at the University of Luxembourg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Jin, M.-Z. & Jin, W.-L. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct. Target. Ther. 5, 166 (2020). DOI: 10.1038/s41392-020-00280-x
Yoshida, G. J., Azuma, A., Miura, Y. & Orimo, A. Activated fibroblast program orchestrates tumor initiation and progression; molecular mechanisms and the associated therapeutic strategies. Int. J. Mol. Sci. 20, 2256 (2019). DOI: 10.3390/ijms20092256
Berdiel-Acer, M. et al. Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information. Mol. Oncol. 8, 1290–1305 (2014). DOI: 10.1016/j.molonc.2014.04.006
Nurmik, M., Ullmann, P., Rodriguez, F., Haan, S. & Letellier, E. In search of definitions: cancer‐associated fibroblasts and their markers. Int. J. Cancer 146, 895–905 (2020). DOI: 10.1002/ijc.32193
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016). DOI: 10.1038/nrc.2016.73
Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med 214, 579–596 (2017). DOI: 10.1084/jem.20162024
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018). DOI: 10.1016/j.ccell.2018.01.011
Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017). DOI: 10.1038/ng.3818
Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020). DOI: 10.1038/s43018-020-0082-y
Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov 10, 1330–1351 (2020). DOI: 10.1158/2159-8290.CD-19-1384
Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148–154 (2022). DOI: 10.1038/s41586-022-05272-1
Biffi, G. et al. IL1-Induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov 9, 282–301 (2019). DOI: 10.1158/2159-8290.CD-18-0710
Díaz-Maroto, N. G. et al. The blockade of tumoral IL1β-mediated signaling in normal colonic fibroblasts sensitizes tumor cells to chemotherapy and prevents inflammatory CAF activation. Int. J. Mol. Sci. 22, 4960 (2021). DOI: 10.3390/ijms22094960
Nicolas, A. M. et al. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell 40, 168–184.e13 (2022). DOI: 10.1016/j.ccell.2022.01.004
Fleischmann, M. et al. ACO/ARO/AIO-21—Capecitabine-based chemoradiotherapy in combination with the IL-1 receptor antagonist anakinra for rectal cancer patients: a phase I trial of the German rectal cancer study group. Clin. Transl. Radiat. Oncol. 34, 99–106 (2022). DOI: 10.1016/j.ctro.2022.04.003
Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459.e29 (2020). DOI: 10.1016/j.cell.2020.03.048
Lee, H.-O. et al. Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat. Genet. 52, 594–603 (2020). DOI: 10.1038/s41588-020-0636-z
Qian, J. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res 30, 745–762 (2020). DOI: 10.1038/s41422-020-0355-0
Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012). DOI: 10.1016/j.ccr.2012.08.013
Nishida, N. et al. Microarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clusters. Clin. Cancer Res 18, 3054–3070 (2012). DOI: 10.1158/1078-0432.CCR-11-1078
Kramer, N. et al. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene 36, 5460–5472 (2017). DOI: 10.1038/onc.2017.144
Unger, C. et al. Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms. Oncogene 36, 5341–5355 (2017). DOI: 10.1038/onc.2017.116
Yoshihara, K. et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013). DOI: 10.1038/ncomms3612
Luo, H. et al. Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment. Nat. Commun. 13, 6619 (2022). DOI: 10.1038/s41467-022-34395-2
Chen, Z. et al. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 11, 5077 (2020). DOI: 10.1038/s41467-020-18916-5
Said, A., Raufman, J.-P. & Xie, G. The role of matrix metalloproteinases in colorectal cancer. Cancers 6, 366–375 (2014). DOI: 10.3390/cancers6010366
Akishima-Fukasawa, Y. et al. Prognostic significance of CXCL12 expression in patients with colorectal carcinoma. Am. J. Clin. Pathol 132, 202–210 (2009). DOI: 10.1309/AJCPK35VZJEWCUTL
Sanchez-Lopez, E. et al. Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. Oncogene 35, 2634–2644 (2016). DOI: 10.1038/onc.2015.326
Kobayashi, H. et al. The origin and contribution of cancer-associated fibroblasts in colorectal carcinogenesis. Gastroenterology 162, 890–906 (2022). DOI: 10.1053/j.gastro.2021.11.037
Liao, D., Luo, Y., Markowitz, D., Xiang, R. & Reisfeld, R. A. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4, e7965 (2009). DOI: 10.1371/journal.pone.0007965
Dimitrov, D. et al. Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data. Nat. Commun. 13, 3224 (2022). DOI: 10.1038/s41467-022-30755-0
Cortés, J. R. et al. Maintenance of immune tolerance by Foxp3+ regulatory T cells requires CD69 expression. J. Autoimmun. 55, 51–62 (2014). DOI: 10.1016/j.jaut.2014.05.007
Yu, L. et al. CD69 enhances immunosuppressive function of regulatory T-cells and attenuates colitis by prompting IL-10 production. Cell Death Dis. 9, 1–14 (2018). DOI: 10.1038/s41419-018-0927-9
Stadler, M. et al. Stromal fibroblasts shape the myeloid phenotype in normal colon and colorectal cancer and induce CD163 and CCL2 expression in macrophages. Cancer Lett. 520, 184–200 (2021). DOI: 10.1016/j.canlet.2021.07.006
Prados, A., Kollias, G. & Koliaraki, V. CollagenVI-Cre mice: a new tool to target stromal cells in secondary lymphoid organs. Sci. Rep. 6, 33027 (2016). DOI: 10.1038/srep33027
Armaka, M. et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–337 (2008). DOI: 10.1084/jem.20070906
Koliaraki, V., Pasparakis, M. & Kollias, G. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J. Exp. Med. 212, 2235–2251 (2015). DOI: 10.1084/jem.20150542
Ye, J., Livergood, R. S. & Peng, G. The role and regulation of human Th17 cells in tumor immunity. Am. J. Pathol. 182, 10–20 (2013). DOI: 10.1016/j.ajpath.2012.08.041
Chung, Y. et al. Critical regulation of early Th17 cell differentiation by IL-1 signaling. Immunity 30, 576–587 (2009). DOI: 10.1016/j.immuni.2009.02.007
Ikeda, S. et al. Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-β–induced Foxp3 expression. J. Immunol. 192, 1449–1458 (2014). DOI: 10.4049/jimmunol.1300387
Fischer, M. M. et al. RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations. Sci. Rep. 7, 15270 (2017). DOI: 10.1038/s41598-017-15704-y
Mesci, A. et al. RSPO3 is a prognostic biomarker and mediator of invasiveness in prostate cancer. J. Transl. Med. 17, 125 (2019). DOI: 10.1186/s12967-019-1878-3
Shiratsuchi, I. et al. Expression of IGF-1 and IGF-1R and their relation to clinicopathological factors in colorectal cancer. Anticancer Res. 31, 2541–2545 (2011).
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019). DOI: 10.1158/2159-8290.CD-19-0094
Wang, L. et al. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J. Exp. Med 206, 1457–1464 (2009). DOI: 10.1084/jem.20090207
Tosolini, M. et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 71, 1263–1271 (2011). DOI: 10.1158/0008-5472.CAN-10-2907
Su, X. et al. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J. Immunol. 184, 1630–1641 (2010). DOI: 10.4049/jimmunol.0902813
McAndrews, K. M. et al. αSMA+ fibroblasts suppress Lgr5+ cancer stem cells and restrain colorectal cancer progression. Oncogene 40, 4440–4452 (2021). DOI: 10.1038/s41388-021-01866-7
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA 110, 20212–20217 (2013). DOI: 10.1073/pnas.1320318110
Chen, L., Qiu, X., Wang, X. & He, J. FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression. Biochem. Biophys. Res. Commun. 487, 8–14 (2017). DOI: 10.1016/j.bbrc.2017.03.039
Itoh, G. et al. Cancer‐associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T‐cell suppression. Mol. Oncol. 16, 166–187 (2022). DOI: 10.1002/1878-0261.13077
Kaneko, N., Kurata, M., Yamamoto, T., Morikawa, S. & Masumoto, J. The role of interleukin-1 in general pathology. Inflamm. Regen. 39, 12 (2019). DOI: 10.1186/s41232-019-0101-5
Letellier, E. et al. Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer. Br. J. Cancer 111, 726–735 (2014). DOI: 10.1038/bjc.2014.377
Stadler, S. et al. Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling. Cell. Mol. Life Sci. 74, 1907–1921 (2017). DOI: 10.1007/s00018-016-2441-5
Macosko, E. Z. et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161, 1202–1214 (2015). DOI: 10.1016/j.cell.2015.05.002
Haghverdi, L., Lun, A. T. L., Morgan, M. D. & Marioni, J. C. Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat. Biotechnol. 36, 421–427 (2018). DOI: 10.1038/nbt.4091
Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015). DOI: 10.1038/nm.3967
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830.e14 (2018). DOI: 10.1016/j.immuni.2018.03.023
Szabo, P. A. et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat. Commun. 10, 4706 (2019). DOI: 10.1038/s41467-019-12464-3
Yao, J. et al. Single-cell transcriptomic analysis in a mouse model deciphers cell transition states in the multistep development of esophageal cancer. Nat. Commun. 11, 3715 (2020). DOI: 10.1038/s41467-020-17492-y
Varrette, S., Bouvry, P., Cartiaux, H. & Georgatos, F. Management of an academic HPC cluster: the UL experience. In 2014 International Conference on High Performance Computing Simulation (HPCS) 959–967 (IEEE, 2014).
