Modeling Familial Cancer with Induced Pluripotent Stem Cells

Abstract

SUMMARY In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni Syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.

Current challenges in the therapeutic use of induced pluripotent stem cells (iPSCs) in cancer therapy

“…Interestingly, it was observed that the parental cell line was strictly dependent on the BCR-ABL signaling, however, reprogrammed cells lost this dependency and became resistant to the BCR-ABL inhibitor imatinib. This finding thus indicated that the therapeutic agent imatinib targets cells in a specific epigenetic differentiated cell state and this may contribute to its inability to fully eradicate disease in chronic myeloid leukemia patients [26]. In another study published by Choi et.al 2011 have used EBV-immortalized B lymphocyte cell lines which represent an important source of genetic information from patients of various diseases including cancer.…”

Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation

“…In contrast to the latter, a recent study showed an oncogenic GOF effect of the G245S p53 mutation in osteosarcomas that were developed following reprogramming of fibroblasts obtained from LFS patients into induced pluripotent stem cells (iPSCs) that were further differentiated into osteoblasts. The mechanism of this GOF was manifested by suppressing the expression of the imprinted gene H19 during osteogenesis (Lee et al 2015). Another interesting example of the variation in the p53 GOF effect resulting from different substitutions of a single amino acid at the same location of the p53 gene is represented in humanized p53 knockin (HUPKI) mouse models.…”

“…Another facet associated with the understanding of mut-p53 GOF is related to microRNAs (miRs) , in which mut-p53 was found to affect Dicer, a pivotal regulator and processer of miRs ) and noncoding RNAs, such as H19 (Lee et al 2015). Furthermore, mut-p53 can bind to non-B DNA structure and supercoiled DNA with high affinity (Gohler et al 2005;Brazdova et al 2013) and thus might affect transcription by binding to DNA motifs.…”

Targeting the Hedgehog Signaling Pathway by Glasdegib Limits the Self- Renewal of MDS-Derived Induced Potent Stem Cells (iPSC)

“…Although massive parallel sequencing studies have revealed a number of genomic alterations associated with MDS, functional consequence of these alterations remain poorly understood, mainly due to a difficulty in the ex vivo culture of primary MDS cells and lack of appropriate animal model [4]. The discovery of key transcription factors enabling reprograming a somatic cell into a pluripotent stem cell, called induced pluripotent stem cell (iPSC) open new avenues in medicine [5][6][7]. Since iPSC can be maintained indefinitely in vitro, they represent an unlimited source of cells, which could overcome the difficulty of obtaining sufficient amounts of MDS cells [8].…”