Author:
Chitrangi Swati,Vaity Pooja,Jamdar Aishwarya,Bhatt Shweta
Abstract
Abstract
Background
Despite recent advances in research, there are still critical lacunae in our basic understanding of the cause, pathogenesis, and natural history of many cancers, especially heterogeneity in patient response to drugs and mediators in the transition from malignant to invasive phenotypes. The explication of the pathogenesis of cancer has been constrained by limited access to patient samples, tumor heterogeneity and lack of reliable biological models. Amelioration in cancer treatment depends on further understanding of the etiologic, genetic, biological, and clinical heterogeneity of tumor microenvironment. Patient-derived organoids recapitulate the basic features of primary tumors, including histological complexity and genetic heterogeneity, which is instrumental in predicting patient response to drugs.
Methods
Human iPSCs from healthy donors, breast and ovarian cancer patients were successfully differentiated towards isogenic hepatic, cardiac, neural and endothelial lineages. Multicellular organoids were established using Primary cells isolated from tumor tissues, histologically normal tissues adjacent to the tumors (NATs) and adipose tissues (source of Mesenchymal Stem Cells) from ovarian and breast cancer patients. Further these organoids were propagated and used for drug resistance/sensitivity studies.
Results
Ovarian and breast cancer patients’ organoids showed heterogeneity in drug resistance and sensitivity. iPSCs-derived cardiomyocytes, hepatocytes and neurons showed donor–to-donor variability of chemotherapeutic drug sensitivity in ovarian cancer patients, breast cancer patients and healthy donors.
Conclusion
We report development of a novel integrated platform to facilitate clinical decision-making using the patient's primary cells, iPSCs and derivatives, to clinically relevant models for oncology research.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Reference68 articles.
1. Mangione W, Falls Z, Samudrala R. Effective holistic characterization of small molecule effects using heterogeneous biological networks. Front Pharmacol. 2023;26(14):1113007. https://doi.org/10.3389/fphar.2023.1113007.PMID:37180722;PMCID:PMC10169664.
2. Chung TDY, Terry DB, Smith LH. In Vitro and In vivo Assessment of ADME and PK Properties During Lead Selection and Lead Optimization – Guidelines, Benchmarks and Rules of Thumb. 2015. In: Markossian S, Grossman A, Brimacombe K, et al., editors. Assay Guidance Manual. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-.
3. Ncube KN, Jurgens T, Steenkamp V, Cromarty AD, van den Bout I, Cordier W. Comparative Evaluation of the Cytotoxicity of Doxorubicin in BT-20 Triple-Negative Breast Carcinoma Monolayer and Spheroid Cultures. Biomedicines. 2023;11(5):1484. https://doi.org/10.3390/biomedicines11051484.PMID:37239157;PMCID:PMC10216410.
4. Csöbönyeiová M, Polák Š, Danišovic L. Toxicity testing and drug screening using iPSC-derived hepatocytes, cardiomyocytes, and neural cells. Can J Physiol Pharmacol. 2016;94(7):687–94. https://doi.org/10.1139/cjpp-2015-0459. (Epub 2016 Feb 1 PMID: 27128322).
5. Kramer JA, Sagartz JE, Morris DL. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat Rev Drug Discov. 2007;6(8):636–49. https://doi.org/10.1038/nrd2378. (PMID: 17643090).
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献