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Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC. [ABSTRACT FROM AUTHOR]

Implantation is a milestone event during mammalian embryogenesis. Implantation failure is a considerable cause of early pregnancy loss in humans.sup.1. Owing to the difficulty of obtaining human embryos early after implantation in vivo, it remains unclear how the gene regulatory network and epigenetic mechanisms control the implantation process. Here, by combining an in vitro culture system for the development human embryos after implantation and single-cell multi-omics sequencing technologies, more than 8,000 individual cells from 65 human peri-implantation embryos were systematically analysed. Unsupervised dimensionality reduction and clustering algorithms of the transcriptome data show stepwise implantation routes for the epiblast, primitive endoderm and trophectoderm lineages, suggesting robust preparation for the proper establishment of a mother-to-offspring connection during implantation. Female embryos showed initiation of random X chromosome inactivation based on analysis of parental allele-specific expression of X-chromosome-linked genes during implantation. Notably, using single-cell triple omics sequencing analysis, the re-methylation of the genome in cells from the primitive endoderm lineage was shown to be much slower than in cells of both epiblast and trophectoderm lineages during the implantation process, which indicates that there are distinct re-establishment features in the DNA methylome of the epiblast and primitive endoderm--even though both lineages are derived from the inner cell mass. Collectively, our work provides insights into the complex molecular mechanisms that regulate the implantation of human embryos, and helps to advance future efforts to understanding early embryonic development and reproductive medicine. Transcriptomics and DNA methylomics are used to study the implantation process of human embryos at single-cell resolution., Author(s): Fan Zhou [sup.1] [sup.2] , Rui Wang [sup.1] [sup.2] , Peng Yuan [sup.1] [sup.3] , Yixin Ren [sup.1] [sup.3] , Yunuo Mao [sup.1] [sup.2] , Rong Li [sup.1] [sup.3] [...]

Tumor organoids have emerged as a crucial preclinical model for multiple cancer research. Their high establishment rates, stability, and ability to replicate key biological features of original tumor cells in vivo render them invaluable for exploring tumor molecular mechanisms, discovering potential anti-tumor drugs, and predicting clinical drug efficacy. Here, we review the establishment of tumor organoid models and provide an extensive overview of organoid culturing strategies. We also emphasize the significance of integrating cellular components of the tumor microenvironment and physicochemical factors in the organoid culturing system, highlighting the importance of artificial intelligence technology in advancing organoid construction. Moreover, we summarize recent advancements in utilizing organoid systems for novel anti-cancer drug screening and discuss promising trends for enhancing advanced organoids in next-generation disease modeling., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier B.V.)