Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity

Abstract

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer

“…Our previous work had already shown that neoplastic transformation and pluripotency are two incompatible cellular fates 25 . Cells expressing OSKM trigger a molecular trajectory that, although initially intersecting with that originated by the transforming activity of Ras/c-Myc, diverges towards an independent cellular state 26 . Identifying the key regulatory elements of cancer cell identity is instrumental for the discovery of novel vulnerabilities that would allow us to design new and more effective therapeutic strategies 4,38,39 .…”

“…However, when oncogenic RAS is switched off the capacity of reprogramming is fully restored, suggesting that cancer and reprogramming are incompatible cellular fates. Supporting this concept others have also recently found that the molecular trajectories of reprogramming and oncogenic transformation, although initially shared, diverge into two separate and defined cell entities 26 .…”

Modulating the epigenetic state promotes the reprogramming of transformed cells to pluripotency in a line-specific manner

“…There is an intimate but unclear link between reprogramming and transformation (Iglesias et al ., 2017; Kim & Zaret, 2015). This link was recently explored in a novel system with multiple inducible genes that could be manipulated to either transform MEFs or perform reprogramming to iPSCs (Huyghe et al ., 2022). This elegant exploration showed that reprogramming and transformation followed similar initial paths, but then later diverged.…”

“…This elegant exploration showed that reprogramming and transformation followed similar initial paths, but then later diverged. The system they used for transformation was K-ras G12D and Myc overexpression (Huyghe et al ., 2022), which is similar to the Hras.Myc ( Hras G12V / Myc ) line described in this manuscript. Intriguingly, we show that Hras.Myc is not compatible with reprogramming, and those cells fail very early in the reprogramming process.…”

“…Curiously, despite being an artificial process, the reprogramming of somatic cells to iPSCs passes through distinct phases, reminiscent of a developmental program (Hussein et al , 2014; Polo et al , 2012; Xu et al , 2016). Tumorigenic transformation also passes through a series of distinct phases in a process that has similarities to somatic cell reprogramming (Huyghe et al , 2022; Iglesias et al ., 2017). Some studies suggest direct links between reprogramming and cancer.…”