Modeling cancer progression using human pluripotent stem cell-derived cells and organoids

Abstract

Conventional cancer cell lines and animal models have been mainstays of cancer research. More recently, human pluripotent stem cells (hPSCs) and hPSC-derived organoid technologies, together with genome engineering approaches, have provided a complementary platform to model cancer progression. Here, we review the application of these technologies in cancer modeling with respect to the cell-of-origin, cancer propagation, and metastasis. We further discuss the benefits and challenges accompanying the use of hPSC models for cancer research and discuss their broad applicability in drug discovery, biomarker identification, decoding molecular mechanisms, and the deconstruction of clonal and intra-tumoral heterogeneity. In summary, hPSC-derived organoids provide powerful models to recapitulate the pathogenic states in cancer and to perform drug discovery.

Keywords: Cancer propagation; Cell-of-origin; Drug discovery; Human pluripotent stem cells; Metastasis; Organoids.

Fig. 1.

Cancer disease modeling using hPSC-derived organoids. Adult stem cells that undergo mutagenesis might give rise to the cancer cell-of-origin. Multistep accumulation of mutations then occurs to give rise to mutant subpopulations which escape cell senescence and acquire invasive properties to undergo metastasis. To model this progression, the somatic cells of cancer patients or healthy volunteers or the tumor cells of patients can be reprogrammed to form iPSCs. Additionally, ESCs can be obtained from the inner cell mass of the blastocyst. Some important tools for genetic engineering include CRISPR/Cas9 editing and TALEN. On the other hand, epigenetic programming can make use of methods that incorporate histone modifications or vary DNA methylation states including differential miRNA expression or expression of relevant transcription factors and genes. iPSCs and ESCs with self-renewal and proliferative capacity can be differentiated into three lineages to form committed progenitors, differentiated cells and subsequently organoids to mimic the process of cancer propagation.

Fig. 2.

The applications of hPSC-based cancer modeling. iPSCs derived from patient cells or tumor samples, together with genetically engineered hPSCs with cancer-associated alterations undergo directed differentiation into cells of interest that represent the likely cancer cell-of-origin. These cells can be used to generate 3D tumor organoids under appropriate conditions. The hPSC-derived cancer models can be used in a variety of cancer studies including chemical screening for drug discovery, genetic screening to identify biomarkers and molecular mechanisms, as well as for the investigation of intra-tumoral heterogeneity by single cell sequencing and multi-omics profiling. The lower left image of biomarker identification was adapted from (Kim et al., 2013).