Patient-derived induced pluripotent stem cells in cancer research and precision oncology

Abstract

Together with recent advances in the processing and culture of human tissue, bioengineering, xenotransplantation and genome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for the study of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and how the method intersects with other patient-derived models of cancer, such as organoids, organs-on-chips and patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can provide beyond those offered by existing systems and animal models and present current challenges and crucial areas for future improvements toward wider adoption of this technology.

Figures

Figure 1

An overview of iPSCs and cancer modeling. Tumor cells are isolated and gene transfer of the four TFs OCT4, SOX2, KLF4 and c-MYC (also known as Yamanaka factors) or of alternative factor cocktails is performed using various methods, such as retroviral, lentiviral, episomal or Sendai viruses. After a period of 2–4 weeks, colonies with the characteristic morphology of pluripotent cells appear and are manually re-plated and expanded to create lines. These are then differentiated into the cell type of origin of the initial tumor. Tumor-derived iPSCs intersect with other model systems of cancer in a variety of ways. iPSC-derived differentiated cells can be used to derive organoids, immortalized cell lines, xenografts, co-cultures and organs-on-chips. Co-cultures and organs-on-chips may also incorporate other cell types that can be derived from iPSCs. ‘Secondary’ iPSC-derived cell lines could theoretically be derived from cancer iPSCs, and in turn, used to generate organoid cultures. Either of these could then be transplanted into xenograft models.

Figure 2

Potential uses of iPSCs in basic cancer research. (a) Cancer-derived iPSCs treated with a cancer drug over prolonged periods of time can be used to study resistance mechanisms. (b) Cancer-derived iPSCs and isogenic normal iPSCs, derived either from matched normal tissue of the same patient or through genome-editing alteration of the cancer genes, can be used for mechanistic studies and genome-wide molecular analyses. (c) iPSCs capturing distinct clones (major and minor), representing different stages of cancer, of a single tumor can be used to model cancer progression and to study the principles underlying cooperation among coexisting genetic lesions. (d) Premalignant iPSCs can be used to interrogate recurrent genetic events required for progression. (e) iPSCs differentiated into adult (or tissue-specific) stem and progenitor cells can be used to interrogate the cell of origin of a given cancer (from adult stem, progenitor or more differentiated cells). Tumor-derived iPSCs can also aid investigations of the cancer stem cell concept (positing that at least some cancers are organized hierarchically and sustained by a subpopulation of self-renewing cells that exist at a distinct epigenetic state within a genetically homogeneous cancer cell population).

Figure 3

Applications of iPSCs in translational cancer research. (a) Large collections of iPSCs capturing cancer diversity can be used for drug discovery and precision oncology. (b) Applications in personalized cancer treatment toxicology studies and regenerative medicine.