January 20, 2021

The Niche

Trusted stem cell blog & resources

Lessons from New IPS Cell Study Showing Tumors

Okano lab, IPS cellA cool new paper is out in Stem Cell Reports describing long-term tumorigenicity of human induced pluripotent stem cells (IPSC or IPS cells). See graphical abstract.

The potential tumorigenicity of IPSC is a major concern when teams around the world are translating IPSC technology to the bedside. Past studies including one from my own lab have shown that there are some parallels between cellular reprogramming to make IPSC and tumorigenicity. MYC has often been viewed as the likely culprit but this paper expands the potentially risky factors to include OCT4. Given that the line that was the focus of this study from the Okano lab was made without MYC, the prediction was that differentiated cells (neurospheres) made from it wouldn’t be tumorigenic, but tumors were evident after long-term follow up of the transplant recipients.

Key factors that influence tumorigenicity include the method of reprogramming, the selection of clonal lines, and how the IPSC are treated thereafter.

Perhaps in part the tumorigenicity reported in this paper could stem from the use of viral transduction-based reprogramming, but an important take home message I think is that one can never be sure about the tumorigenic potential of IPCS unless you test them in a clinically relevant transplantation model system and do long-term follow up. It would also be prudent to carefully examine the transcriptome of your IPSC and the epigenome as well and consult with experts as one plans potential clinical translation. Starting with non-integrating reprogramming methods is crucial.

The tumors that developed in this studies had some characteristics of primitive neuroectodermal tumors and had Nestin+ cells. One open question is whether these tumors are high-grade, lethal tumors (seems likely). Activation of the OCT4 transgene was a proposed mechanism of tumorigenicity. The authors also speculated that “Tumor progression may have been caused by mesenchymal transition of grafted cells”.

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