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Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses

ABSTRACT: Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses

PROVIDER: PRJNA999180 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25436305_1.fastq.gz	Fastqsanger.gz
	SRR25436305_2.fastq.gz	Fastqsanger.gz
	SRR25436306_1.fastq.gz	Fastqsanger.gz
	SRR25436306_2.fastq.gz	Fastqsanger.gz
	SRR25436307_1.fastq.gz	Fastqsanger.gz

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Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses

Project description:Patient-derived organoids (PDOs) can model personalized therapy responses, however current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly-multiplexed mass cytometry platform to measure post translational modification (PTM) signaling, DNA-damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment specific drug responses in thousands of single-cell datasets, we developed Trellis — a highly-scalable, hierarchical tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rare, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate cancer cell plasticity — shifting proliferative stem cells to slow-cycling revival stem cells via YAP to protect cancer cells from chemotherapy.

2023-12-06 | GSE239386 | GEO

Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells

Project description:Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity, and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from ox 1 idative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development. Global gene expression profiles of PDX cells showed high similarity to those of original primary cells. The correlation coefficient of gene expression profiles between PDX cells and the originalprimary cells was 0.814-0.890.

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Tumor evolution and drug response in patient-derived organoid models of bladder cancer

Project description:Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied and relatively lacking in suitable models. Here we describe a biobank of patient-derived organoid lines that recapitulates the spectrum of human bladder cancer at the histopathological and molecular levels. Organoid lines can be established efficiently from patient biopsies, including from patients before and after disease recurrence, and are interconvertible with orthotopic xenografts. Notably, these organoid lines often retain tumor heterogeneity and exhibit changes in their mutational profiles that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Overall, our studies indicate that patient-derived bladder tumor organoids represent a model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

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Project description:The development of high-throughput anticancer drug screening using patient-derived cancer cell lines (PDCs) that maintain their original characteristics in an in vitro three-dimensional (3D) culture system poses a significant challenge for achieving personalized cancer medicine. Because stromal tissue plays a critical role in the composition and maintenance of the cancer microenvironment, in vitro 3D-culture using reconstructed stromal tissues has attracted much attention. Here, a simple and unique in vitro 3D-culture method using heparin and collagen together with fibroblast and endothelial cells to fabricate vascularized 3D-stromal tissues for in vitro culture of PDCs is reported. While co-treatment with bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, and 5-fluorouracil (5-FU) significantly reduced the survival rate of the 3D-cultured PDCs to 30%, separate addition of each drug did not induce such strong cytotoxicity, suggesting the possibility of evaluating the combined effect of anticancer drug and an angiogenesis inhibitor. Surprisingly, drug evaluation using eight PDCs with the 3D-culture method resulted in a drug efficacy concordance rate of 75% with clinical history. The model is expected to be applied to in vitro throughput drug screening for the development of personalized cancer medicine.

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Tumor evolution and drug response in patient-derived organoid models of bladder cancer

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An Organoid Biobank for Childhood Kidney Cancers that Captures Disease and Tissue Heterogeneity

Project description:Kidney tumours are among the most common solid tumours in children, comprising several distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. The malignant rhabdoid tumour organoids represent the first organoid model for tumours of non-epithelial origin. The tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug vulnerabilities. We further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like. Our organoid biobank captures the cellular heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterized models for basic cancer research, drug-screening, and personalized medicine.

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