Project description:Understanding the phenotypic alterations that play a role in differential response to drugs will be pivotal in identifying predictive biomarkers and developing efficacious therapies for advanced CRC. The bulk of research to date has focused on the value of organoids as a predictive tool; some have characterized the transcriptomic profile in relation to drug sensitivity in an effort to identify predictive biomarkers, but only a limited number of studies have used quantitative proteomic analysis to characterize PDOs. Extensive literature indicates that transcriptomic and proteomic expression profiles lack correlation due to significant post-transcriptional regulation, which could explain why RNA signatures are rarely useful as drug response predictors in the clinic. In this study we generated PDO models from advanced CRC patients including heavily pre-treated patients and a model of microsatellite instable- (MSI) high CRC, for which pre- and post chemotherapy liver disease PDOs were established and characterized to ensure biological fidelity with the original tumors. Our main objective was to integrate functional drug assays on PDOs with proteotranscriptomic study to explore the mechanisms underlying drug response. To this end, we used SWATH-MS (sequential window acquisition of all theoretical mass spectrometry), a highly accurate proteomic quantification technique and a bulk RNA-seq analysis. This strategy could represent a useful tool to discover new therapeutic targets in advanced CRC and to guide personalized therapies.

2025-02-03 | PXD038149 | Pride

Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Project description: Not available

| S-EPMC10733660 | biostudies-literature

Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids.

Project description: Not available

| S-EPMC11579375 | biostudies-literature

Exploring high-throughput drug sensitivity testing in neuroblastoma cell lines and patient-derived tumor organoids in the era of precision medicine.

Project description: Not available

| S-EPMC11884408 | biostudies-literature

In vitro drug testing using patient-derived ovarian cancer organoids.

Project description: Not available

| S-EPMC11445862 | biostudies-literature

Patient-derived response estimates from zero-passage organoids of luminal breast cancer

Project description:Background: Primary luminal breast cancers lose hormone receptors rapidly in standard tissue culture. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Methods: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates to increase throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these “zero–passage” organoids by withdrawing β-estradiol and adding tamoxifen. We tested sulforaphane as an electrophilic stress and commercial neutraceutical. Genetic perturbations were introduced by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing; organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of cellular doubling times. Results: We achieved >50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Few clinical parameters reliably impacted success. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases. Combining sulforaphane with knockout of NQO1 (a phase II enzyme) also yielded a breadth of growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material.

2024-03-22 | GSE262110 | GEO

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