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1. Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ

Author

Giulia Della Chiara, Andrea Cassingena, Valeria Ranzani, Andrea Pisani Ceretti, Francesca Zanconato, Paola Gruarin, Grazisa Rossetti, Michaela Fakiola, Luca Gianotti, Luca Azzolin, Giulia Moreni, Ivan Ferrari, Oriana Romano, N. Mariani, Tanya Fabbris, Alberto Bardelli, Claudio Tripodo, Claudia D'Oria, Lorenzo Drufuca, Chiara Godano, Salvatore Siena, Massimiliano Pagani, Ramona Bason, Maria Lucia Sarnicola, Andrea Sartore-Bianchi, Enrico Opocher, Michelangelo Cordenonsi, Jimmy Caroli, Francesco Panariello, Federica Pisati, Marco De Simone, Stefano Piccolo, Silvio Bicciato, Nicola Zucchini, Giuseppe Testa, Mattia Forcato, Raoul J. P. Bonnal, Giuseppe Macino, Federica Gervasoni, Graduate School, Medical Microbiology and Infection Prevention, Della Chiara, G, Gervasoni, F, Fakiola, M, Godano, C, D'Oria, C, Azzolin, L, Bonnal, R, Moreni, G, Drufuca, L, Rossetti, G, Ranzani, V, Bason, R, De Simone, M, Panariello, F, Ferrari, I, Fabbris, T, Zanconato, F, Forcato, M, Romano, O, Caroli, J, Gruarin, P, Sarnicola, M, Cordenonsi, M, Bardelli, A, Zucchini, N, Ceretti, A, Mariani, N, Cassingena, A, Sartore-Bianchi, A, Testa, G, Gianotti, L, Opocher, E, Pisati, F, Tripodo, C, Macino, G, Siena, S, Bicciato, S, Piccolo, S, Pagani, M, Della Chiara G., Gervasoni F., Fakiola M., Godano C., D'Oria C., Azzolin L., Bonnal R.J.P., Moreni G., Drufuca L., Rossetti G., Ranzani V., Bason R., De Simone M., Panariello F., Ferrari I., Fabbris T., Zanconato F., Forcato M., Romano O., Caroli J., Gruarin P., Sarnicola M.L., Cordenonsi M., Bardelli A., Zucchini N., Ceretti A.P., Mariani N.M., Cassingena A., Sartore-Bianchi A., Testa G., Gianotti L., Opocher E., Pisati F., Tripodo C., Macino G., Siena S., Bicciato S., Piccolo S., and Pagani M.

Subjects
0301 basic medicine, Organoid, Epigenomics, Transcription Factor, General Physics and Astronomy, Colorectal Neoplasm, Adaptor Proteins, Signal Transducing, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Histone Code, Humans, Models, Genetic, Organoids, RNA-Seq, Single-Cell Analysis, Trans-Activators, Transcription Factors, Tumor Cells, Cultured, Enhancer Elements, Genetic, Epigenesis, Genetic, 0302 clinical medicine, Models, Adaptor Proteins, Signal Transducing, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic,Histone Code, Humans, Models, Genetic, Organoids, RNA-Seq, Single-Cell Analysis, Trans-Activators, Transcription Factors, Tumor Cells, Cultured, Enhancer Elements, Genetic, Epigenesis, Genetic, Cancer genomics, Histone code, Transcriptional Coactivator with PDZ-Binding Motif Proteins, YAP-Signaling Proteins, Multidisciplinary, Cultured, Adaptor Proteins, 3. Good health, Chromatin, Tumor Cells, Single-Cell Analysi, Trans-Activator, 030220 oncology & carcinogenesis, Human, Enhancer Elements, Science, Tumour heterogeneity, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetic, medicine, Epigenetics, Enhancer, Transcription factor, Neoplastic, Signal Transducing, Cancer, General Chemistry, medicine.disease, Colorectal cancer, digestive system diseases, 030104 developmental biology, Gene Expression Regulation, Cancer cell, Cancer research, Epigenesis
Abstract

Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues., The role of epigenetic deregulation in colorectal cancer (CRC) is not fully understood yet. Here the authors use patient-derived organoids, epigenomics and single-cell RNA-seq to reveal that YAP/TAZ are key regulators that bind to active enhancers in CRC and promote tumour survival.

Published
2021

2. Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression

Author

Salvatore Siena, Emilia Maria Cristina Mazza, Giulia Della Chiara, Chiara Godano, Nicola Zucchini, Valeria Ranzani, Stefania Oliveto, Paola Gruarin, Jens Geginat, Roberto Bosotti, Claudia D'Oria, Elena Carelli, Pierluigi Novellis, Saveria Mazzara, Ylenia Silvestri, Marco Passaro, Alessio Amatu, Marco Alloisio, Antonio Lanzavecchia, Stefano Biffo, Giorgia Alvisi, Federica Gervasoni, Maria Lucia Sarnicola, N. Mariani, Alberto Bardelli, Ramona Bason, Jolanda Brummelman, Mariangela Lorenzo, Giulia Veronesi, Emanuela Bonoldi, Massimiliano Pagani, Daniele Prati, Enrico Opocher, Lorenzo Drufuca, Martina Martinovic, Andrea Sartore-Bianchi, Sergio Abrignani, Alessandro Giani, Marco De Simone, Enrico Lugli, Chiara Cordiglieri, Serena Curti, Grazisa Rossetti, Valeria Bevilacqua, Andrea Pisani Ceretti, Raoul J. P. Bonnal, Bonnal, R. J. P., Rossetti, G., Lugli, E., De Simone, M., Gruarin, P., Brummelman, J., Drufuca, L., Passaro, M., Bason, R., Gervasoni, F., Della Chiara, G., D'Oria, C., Martinovic, M., Curti, S., Ranzani, V., Cordiglieri, C., Alvisi, G., Mazza, E. M. C., Oliveto, S., Silvestri, Y., Carelli, E., Mazzara, S., Bosotti, R., Sarnicola, M. L., Godano, C., Bevilacqua, V., Lorenzo, M., Siena, S., Bonoldi, E., Sartore-Bianchi, A., Amatu, A., Veronesi, G., Novellis, P., Alloisio, M., Giani, A., Zucchini, N., Opocher, E., Ceretti, A. P., Mariani, N., Biffo, S., Prati, D., Bardelli, A., Geginat, J., Lanzavecchia, A., Abrignani, S., and Pagani, M.

Subjects
Male, 0301 basic medicine, Lung Neoplasms, T-Lymphocytes, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Drug Resistance, Datasets as Topic, Kaplan-Meier Estimate, Granzymes, 0302 clinical medicine, Cancer immunotherapy, Single-cell analysis, 80 and over, Immunology and Allergy, RNA-Seq, Non-Small-Cell Lung, Immune Checkpoint Inhibitors, Adjuvant, Colectomy, Chitinases, Cell Differentiation, Forkhead Transcription Factors, Middle Aged, Flow Cytometry, Regulatory, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Chemotherapy, Adjuvant, Clonal Hematopoiesis, Colon, Colorectal Neoplasms, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Primary Cell Culture, Single-Cell Analysis, T-Box Domain Proteins, T-Lymphocytes, Regulatory, Immunology, Biology, 03 medical and health sciences, Immune system, medicine, Chemotherapy, Neoplastic, Carcinoma, Immunotherapy, 030104 developmental biology, Gene Expression Regulation, Cell culture, Cancer research, Neoplasm, Granzyme K, Eomesodermin Homolog, Checkpoint Blockade Immunotherapy, 030215 immunology
Abstract

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4+ Treg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 Treg-like CD4+ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

Published
2021
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