After passage of wildtype and tumour organoids, the fragments were mixed at approximately 3:1 wildtype organoid to tumoroids ratio. 2source data 3: Source data related to Physique 2C. elife-76541-fig2-data3.xlsx (8.3K) GUID:?B4C39F22-D358-49FE-ACAD-C4E701308E39 Physique 2source data 4: Source data related to Physique 2I. elife-76541-fig2-data4.xlsx (8.0K) GUID:?305C7D97-0B96-4504-B489-CE0188B8296F Physique 2figure product 1source data 1: Initial image of the complete gel for the Western blot presented in Physique 2figure product 1F. elife-76541-fig2-figsupp1-data1.pdf (49K) GUID:?B9327F77-95AB-4035-81B4-F1F91556108A Physique 2figure supplement 1source data 2: Initial image of the complete gel for the Western blot presented in Physique 2figure supplement 1F. elife-76541-fig2-figsupp1-data2.zip (260K) GUID:?30CADDA7-782D-4043-B374-C11FBCA5FE5E Physique 3source data 1: Source data related to Physique 3G. elife-76541-fig3-data1.xlsx (8.0K) GUID:?0ACFAEF8-07D6-470C-9CBE-28DC86E56263 Figure 3source data 2: Source data related to Figure 3H. elife-76541-fig3-data2.xlsx (8.0K) GUID:?C6FA5011-7B29-4DF7-90D2-C94C710F092F Physique 3source data 3: Source data related to Physique 3I. elife-76541-fig3-data3.xlsx (8.1K) GUID:?59BA9A15-EFFA-49AB-8B51-F24E7406647D Physique 3source data 4: Source data related to Physique 3J. elife-76541-fig3-data4.xlsx (8.1K) GUID:?3969F3B9-0E95-4514-ABE4-A438AF061EA7 Figure 3source data 5: Source data related to Figure 3O. elife-76541-fig3-data5.xlsx (8.1K) GUID:?84D359D7-84D6-445F-9FA2-B59EEC63ED0C Physique 3source data 6: Source data related to Physique 3P. elife-76541-fig3-data6.xlsx (8.6K) GUID:?35EAD880-607B-457D-83F2-5BF6F386B691 Physique 3figure product 1source data 1: Source data related to Physique 3figure product 1E. elife-76541-fig3-figsupp1-data1.xlsx (8.3K) GUID:?A12CB269-1F09-4F46-BA4E-D0E47577EB31 Physique 4source data 1: Source data related to Physique 4H. elife-76541-fig4-data1.xlsx (8.1K) GUID:?5DCDA5B5-A41D-41B2-95A3-5F3A3D9E50E2 Physique 4source data 2: Source data related to Physique 4O. elife-76541-fig4-data2.xlsx (9.4K) GUID:?6B633BF4-2CE5-4E1B-B431-8ED971DBAE8B Physique 4source data 3: Source data related to Physique 4P. elife-76541-fig4-data3.xlsx (8.2K) GUID:?D36F413D-9A0D-4E62-8393-20EC4DC3047D Physique 4figure supplement 1source data 1: Source data related to Physique 4figure supplement 1I. elife-76541-fig4-figsupp1-data1.xlsx (8.1K) GUID:?FDD47644-D88F-4DF5-8D25-99B63645D54A Physique 4figure supplement 1source data 2: Source FAI (5S rRNA modificator) data related to Physique 4figure supplement 1J. elife-76541-fig4-figsupp1-data2.xlsx (8.2K) GUID:?B64464D7-BE01-4C11-A1B5-A20CCF356BF7 Figure 5source data 1: Source data related to Figure 5B. elife-76541-fig5-data1.xlsx (8.8K) GUID:?73439766-1394-4964-9617-A3634E1E10A2 Physique 5source data 2: Source data related to Physique 5D. elife-76541-fig5-data2.xlsx (9.6K) GUID:?370383C5-A954-4360-A8A7-36417F1DCFEB Physique 5source data 3: Source data related to Physique 5E. elife-76541-fig5-data3.xlsx (8.2K) GUID:?4563D2BA-B3BE-4997-94DD-FAED71CC1415 Figure 5figure supplement 1source data 1: Source data related to Figure 5figure supplement 1E. elife-76541-fig5-figsupp1-data1.xlsx (8.2K) GUID:?3EF5B80C-508E-4D8C-B85D-BC55413CAF51 Physique 5figure supplement 1source data 2: Source data related to Physique 5figure supplement 1J. elife-76541-fig5-figsupp1-data2.xlsx (8.3K) GUID:?0BBF87B6-6FBE-4ADA-86BE-99BBCE0DD9A0 Figure 5figure product 1source data 3: Source data related to Figure 5figure product 1M. elife-76541-fig5-figsupp1-data3.xlsx (8.9K) GUID:?A4A871BD-E9DC-4A4F-AE26-635634248E4C Transparent reporting form. elife-76541-transrepform1.pdf (206K) GUID:?DEF5EB22-6417-4064-AAE0-D080A0CD97D7 Data Availability StatementSequencing data have been deposited in the Gene Expression Omnibus (GEO) repository under accession code “type”:”entrez-geo”,”attrs”:”text”:”GSE153160″,”term_id”:”153160″GSE153160: Whole-genome transcriptomic analysis of intestinal organoids and tumoroids. Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD020002. All data generated or analysed during this study are included in the manuscript and supporting files; a Source Data file has been provided for all those Figures, including Physique supplements. The following datasets were generated: Jacquemin G. 2020. Whole-genome transcriptomic analysis of intestinal organoids and tumoroids. GEO. GSE153160 Jacquemin G. 2020. Paracrine interactions between epithelial cells promote colon cancer growth. ProteomeXchange. PXD020002 Abstract Tumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the crucial role of stromal cells in affecting tumour growth is usually well established, the impact of mutant malignancy cells on healthy surrounding tissues remains poorly defined. Here, using mouse intestinal organoids, we uncover a paracrine mechanism by which intestinal malignancy cells reactivate foetal and regenerative YAP-associated transcriptional programmes in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identify the glycoprotein thrombospondin-1 (THBS1) as the essential factor that mediates non-cell-autonomous morphological and transcriptional responses. Importantly, Thbs1 is usually associated with bad prognosis in several human cancers. FAI (5S rRNA modificator) This study reveals the THBS1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells in intestinal tumours. mutant intestinal tumours generally NUDT15 grow as hyperproliferative and non-polarised hollow spheres or cysts (Drost et al., 2015; Sato et al., 2011; Jard et al., 2013; Schwank et al., 2013; Germann et al., 2014; Onuma et al., 2013). To study epithelial communications in a FAI (5S rRNA modificator) stroma-free environment, we analysed the influence of mutant organoids derived from main mouse tumours (hereafter defined as tumoroids) on WT small intestinal organoids. We discovered that the co-culture of tumoroids and budding organoids quickly induced a hyperproliferative cystic morphology (referred to as cysts hereafter) in a portion of WT organoids. This conversation did not require cell contact as the effect was recapitulated by the conditioned medium (cM) from tumoroids. We found that the secreted glycoprotein thrombospondin-1 (THBS1) was responsible for mediating these paracrine communications through Yap pathway activation..