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RAS oncogenes: weaving a tumorigenic web

Key Points

  • RAS is a GTPase that is frequently mutated in cancer and that affects a variety of cancer-driving processes. Unique properties of RAS isoforms, and of particular activating mutations, may distinctly affect the process of neoplastic conversion in different tissues.

  • RAS drives cellular proliferation by providing both cell-autonomous and non-cell-autonomous cues, which ultimately converge in the transformed cells to promote pro-growth and to inhibit anti-growth signals. RAS-mediated proliferative overdrive may induce replicative stress and activation of DNA damage responses.

  • The suppression of a cell death response by oncogenic RAS is a consequence of a perturbation of homeostatic balance between pro-apoptotic and anti-apoptotic signals. To keep up with the high energy needs of growing cells, the survival of RAS-transformed cells is further aided by metabolic reprogramming towards glycolysis that is mediated by MAPK- and PI3K-dependent regulation of hypoxia-inducible factor 1α (HIF1α).

  • Oncogenic RAS modulates the tumour microenvironment by promoting pro-angiogenic mechanisms and by altering host-mediated immune responses. Transformation by RAS can also promote changes in motility and cellular adhesion, leading to the acquisition of invasive and metastatic properties of cancer cells.

  • Breakthroughs in real-time imaging, computational approaches, high-throughput screening and genetically engineered mouse modelling promise to advance our capacity to integrate the complexity of RAS signalling pathways with the context specificity of their oncogenic activities, undoubtedly aiding the implementation of successful remedial strategies in the clinic.

Abstract

RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis.

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Figure 1: Frequency of mutations at G12, G13 and Q61 in RAS isoforms.
Figure 2: RAS effects on proliferation.
Figure 3: RAS effects on apoptosis.
Figure 4: Effect of RAS on energy metabolism in cancer cells: generating macromolecular precursors.
Figure 5: RAS and angiogenesis.

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Acknowledgements

The authors' work was supported by the US National Institutes of Health Grants CA055360 and GM078266 (D.B.-S.), the Ruth L. Kirschstein National Service Award 1F32CA13922 (E.G.) and the Irvington Institute Fellowship Program of the Cancer Research Institute (Y.P.-G). The authors would like to apologize to all their colleagues whose work was not included owing to space constraints.

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Correspondence to Dafna Bar-Sagi.

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Guanine nucleotide exchange factors

(GEFs). Proteins that promote the exchange of GDP for GTP on a GTPase, thus facilitating its activation.

GTPase-activating proteins

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Costello syndrome

This is a rare genetic disorder associated with developmental delay, mental retardation, and heart and facial defects. Patients with Costello syndrome are predisposed to rhabdomyosarcoma.

G0 phase

A specialized, non-dividing (or resting) state of cellular quiescence.

DNA damage response

(DDR). Cellular responses to DNA damage, involving a cascade of signalling pathways that coordinate cell cycle arrest and DNA repair.

Apoptosis

The process of programmed cell death that can be initiated by either extracellular or intracellular mediators in response to a predefined developmental programme or in response to cellular stress.

Extracellular matrix

(ECM). A collection of proteins, such as collagen and laminin, and carbohydrates, that provides vital structural and signalling support to cells.

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Pylayeva-Gupta, Y., Grabocka, E. & Bar-Sagi, D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11, 761–774 (2011). https://doi.org/10.1038/nrc3106

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