Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation

Abstract

Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns. The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation. These findings suggest that epigenetic regulation associated with iPSC derivation may drive development of particular types of cancer.

Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior

“…In this study, we used a doxycycline (Dox)-inducible system to transduce reprogramming factors [octamerbinding transcription factor (Oct3/4), sex determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and avian myelocytomatosis viral oncogene homolog (c-Myc)]. Apc Min/+ mice were crossed with in vivo reprogrammable mice (9). The macroscopic colon tumors in the DSS-treated compound mice were carefully resected, and tumor cells were cultured in Dox-containing ES cell (ESC) medium.…”

“…Generation of chimeric mice, histological analysis, qRT-PCR, and microarray analysis were performed as described previously (9). The accession number for microarray data reported in this paper is GSE77202.…”

Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape

“…genetic changes are considered irreversible and thus, thought to drive a somatic evolution process that follows the Darwinian principle of selection of the fitter (most adapted) inheritable random variants (16). However, this scheme of explanation faces the challenge of the increasing realization that nongenetic dynamics play a role in creating the variety of tumor phenotypes (i.e., tumor cells can acquire new selectable phenotype without genomic alterations but as part of their nongenetic phenotype dynamics) (11,17,18). As a first step, as singlecell resolution static snapshots of the tumor cell population become increasingly routine (14), it is paramount to examine quantitatively, in an experimental model of noncancerous and cancerous cells, the attractor dynamics that underlie the cell population diversity, resilience to noise, and readiness to convert to another phenotype.…”

Present and future challenges of induced pluripotent stem cells

“…That the reprogramming process, in some respects, resembles the cancer initiation process [104][105][106][107][108][109][110] implies the involvement of common molecular mechanisms. The incomplete reprogramming by overexpression of OSKM factors drove the development of Wilms-like tumours in mouse kidney without any genomic alterations [111]. Further OSKM expression can reprogram these tumour cells into complete iPSCs in vitro, suggesting that an epigenetic change, but not genomic mutation, could be sufficient for the occurrence of some tumorigenesis.…”