Progenitor cells derived from gene‐engineered human induced pluripotent stem cells as synthetic cancer cell alternatives for in vitro pharmacology

• Published in: Biotechnology journal 2022-06, Vol.17 (6), p.e2100693-n/a
• Main Authors: Uhlmann, Constanze, Nickel, Ann‐Christin, Picard, Daniel, Rossi, Andrea, Li, Guanzhang, Hildebrandt, Barbara, Brockerhoff, Gabriele, Bendt, Farina, Hübenthal, Ulrike, Hewera, Michael, Steiger, Hans‐Jakob, Wieczorek, Dagmar, Perrakis, Aristoteles, Zhang, Wei, Remke, Marc, Koch, Katharina, Tigges, Julia, Croner, Roland S., Fritsche, Ellen, Kahlert, Ulf D.
• Format: Article
• Language: English
• Subjects: cancer stem cells; Cell Differentiation - genetics; Cells, Cultured; c‐MYC; EGFR; GLI1; Humans; in vitro pharmacology; Induced Pluripotent Stem Cells; Neoplasms - genetics; Neoplasms - therapy; progenitor cells; TP53
• ISSN: 1860-6768; 1860-7314
• DOI: 10.1002/biot.202100693

Limitations in genetic stability and recapitulating accurate physiological disease properties challenge the utility of patient‐derived (PD) cancer models for reproducible and translational research. A portfolio of isogenic human induced pluripotent stem cells (hiPSCs) with different pan‐cancer relevant oncoprotein signatures followed by differentiation into lineage‐committed progenitor cells was genetically engineered. Characterization on molecular and biological level validated successful stable genetic alterations in pluripotency state as well as upon differentiation to prove the functionality of our approach. Meanwhile proposing core molecular networks possibly involved in early dysregulation of stem cell homeostasis, the application of our cell systems in comparative substance testing indicates the potential for cancer research such as identification of augmented therapy resistance of stem cells in response to activation of distinct oncogenic signatures. Graphical and Lay Summary Traditional cancer research relies on cell lines or primary cell cultures derived from tumor specimens. Based on the scientific concept that cancer arises from cells with stem cell properties, this work presents the development of an alternative human cancer cell platform using genetically customized human induced pluripotent stem cells from a healthy donor featuring stable oncogene activation. Furthermore, the suitability of this platform to generate oncogene activated tissue‐specific progenitor cells to support the development of targeted chemotherapies was shown.