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Context-Dependent Impact of RAS Oncogene Expression on Cellular Reprogramming to Pluripotency

ras oncogenes cell reprograming ipsc cell plasticity

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#1 Engadin

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Posted 16 May 2019 - 02:45 PM



  •  - Oncogenic Ras enhances cell reprogramming in a wild-type context
  •  - Ras induces gene expression changes that favor reprogramming
  •  - Ras expression in immortal cells impairs cell reprogramming
  •  - Oncogenic transformation and cellular reprogramming are incompatible cell fates


Induction of pluripotency in somatic cells with defined genetic factors has been successfully used to investigate the mechanisms of disease initiation and progression. Cellular reprogramming and oncogenic transformation share common features; both involve undergoing a dramatic change in cell identity, and immortalization is a key step for cancer progression that enhances reprogramming. However, there are very few examples of complete successful reprogramming of tumor cells. Here we address the effect of expressing an active oncogene, RAS, on the process of reprogramming and found that, while combined expression with reprogramming factors enhanced dedifferentiation, expression within the context of neoplastic transformation impaired reprogramming. RAS induces expression changes that promote loss of cell identity and acquisition of stemness in a paracrine manner and these changes result in reprogramming when combined with reprogramming factors. When cells carry cooperating oncogenic defects, RAS drives cells into an incompatible cellular fate of malignancy.


The development of an in vitro cellular system allowing the reprogramming of differentiated somatic cells into induced pluripotent stem cells (iPSCs) by expression of defined genetic elements, represents an opportunity to advance in many different areas of biomedical research. Apart from providing pluripotent cells to develop cell therapies, reverting the differentiated state of the cell offers an opportunity to create faithful disease models and to develop powerful cellular platforms in which to efficiently screen pharmacological interventions.


The application of cellular reprogramming to the study of cancer is just beginning to be explored. One particularly interesting aspect of the application of cellular reprogramming to the study of cancer is the similarity between reprogramming and neoplastic transformation. During reprogramming, cells need to overcome barriers that oppose the drastic change in cell identity characterizing this process and gain the capacity to proliferate indefinitely. Tumor cells, on the other hand, are generally immortal and typically display the features of an undifferentiated state, especially in more advanced cancers. For example, poorly differentiated tumors present an embryonic stem-like gene signature that is considered a hallmark of aggressiveness, and cancer cell dedifferentiation has been proposed as a means to become more malignant. Elucidating the common mechanisms and barriers shared by reprogramming and transformation could illuminate the molecular bases underlying the pathogenesis of cancer.


Illustrating that common barriers prevent cell transformation and cell reprogramming is the observation that cells deficient in tumor suppressor genes which regulate immortality, renders cells susceptible to the transforming activity of activated oncogenes and enhances reprogramming. Actually, the expression of a single oncogene on a normal differentiated cell does not lead to neoplastic transformation. Immortality is required to overcome the barriers that block the transformation into a cancer cell. Since immortalization is a pre-requisite for transformation, one would expect cancer cells to be more susceptible to reprogramming. However, there are strikingly few examples of successful complete reprogramming to pluripotency in cancer cells.


Using the system of cellular reprogramming has already proved extremely useful to identify previously unrecognized activities of tumor suppressors, such as the transcriptional control over pluripotency gene Sox2 exerted by cell-cycle inhibitors p27Kip1 and the retinoblastoma family of pocket proteins. Similarly, it could also represent an opportunity to gain insight into the molecular mechanisms of cellular transformation driven by oncogenes.


In this work, we decided to address the effect of expressing oncogenic RAS on the process of cellular reprogramming. RAS was the first human oncogene isolated from a tumor and it is one of the most frequently mutated genes in human cancer. First, we evaluated the consequences of introducing RAS as part of the reprogramming cocktail together with Oct4Sox2Klf4, and c-Myc (OSKM). Introduction of activated RAS alone on normal differentiated somatic cells does not lead to neoplastic transformation and requires the presence of cooperating oncogenes to allow progression into malignancy. Interestingly, in our case the combined expression of RAS and the reprogramming factors resulted in enhanced reprogramming. This effect of RAS is non-cell autonomous and seems to be a reflection of an endogenous activity played by the oncogene during early stages of a normal reprogramming process. In contrast, expression of oncogenic RAS in the context of full transformation blocks reprogramming. Using in vivo systems, we conclude that oncogene activation generates a tissue microenvironment that renders cells in the vicinity susceptible to dedifferentiation, while transformation and reprogramming seem to be alternative non-compatible cell fates.






F U L L   T E X T : Cell - Stem Cell Reports


Also tagged with one or more of these keywords: ras, oncogenes, cell reprograming, ipsc, cell plasticity

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