Issues

Summary: This Editorial introduces DMM’s new Special Issue on the RAS pathway. The Guest Editors reflect on the impact of the featured articles on the landscape of the RAS field.

Summary: RASopathy is a term used to unify a phenotypically similar group of medical genetic syndromes, yet its definition is challenging and should consider the perspectives of clinicians, scientists and the patients.

Summary: Neurofibromatosis type 1 has provided unprecedented opportunities to define the importance of RAS regulation in health and disease. Emerging research has also unveiled the role of non-canonical RAS and RAS-independent signaling in this RASopathy.

Summary: This Review describes the molecular regulation of the RAS pathway, presents the clinical consequences of its pathological activation in human cancer, and highlights recent advances towards its therapeutic inhibition, using melanoma as an example.

Summary: RASopathies are developmental disorders caused by germline pathogenic variants in RAS/MAPK pathway genes. Here, we review the preclinical studies that provide the basis for future interventional clinical trials for RASopathy patients.

Summary: The acquisition of oncogenic RAS simultaneously causes cellular stress and activates stress-adaptive pathways. Many of these are implicated in resistance mechanisms to RAS-targeting therapies, posing as therapeutic targets to block stress-activated mechanisms of resistance.

Summary: Single-molecule microscopy analysis of factors altering the in vivo dynamics of H-Ras proteins in epidermal cells in living zebrafish embryos revealed that cell architecture and protein activation state determine protein mobility.

Summary: RREB1, a known transcriptional factor that acts downstream of Ras signaling, is expressed in the medial edge epithelium (MEE) region and required for the dissociation of MEE during palatal fusion.

Summary: Characterisation of mouse lung adenoma/adenocarcinoma models treated with atorvastatin revealed that statins remodel the tumour microenvironment in lung adenocarcinoma development to create pro- and anti-tumourigenic effects dependent on disease stage.

Summary: A Costello syndrome (CS) mouse model carrying a heterozygous Hras p.G12V mutation was utilized to investigate Ras pathway dysregulation, revealing that increased MAPK signaling is the main cause of the muscle phenotype in CS.

Summary: Hypoxia pathway inhibition, either genetically or pharmacologically, rescues RAS-induced oncogenesis in a Drosophila acute myeloid leukemia model, mouse xenograft model and human leukemia cells.

Summary: This study investigates how a BRAF-mutant lineage becomes cancerized by escaping cell competition from non-mutant cells in a mouse model of sporadic thyroid cancer.

Summary: Altered proportions, distribution, timing and modes of division for trigeminal ganglion progenitors prefigure divergent trigeminal sensory neuron differentiation and oropharyngeal dysfunction in the LgDel mouse model of 22q11.2 deletion syndrome.

Editors' choice: We developed a new conditional genetically engineered mouse model of rhabdomyosarcoma (RMS) with homologous molecular signature to human RMS that provides valuable pre-clinical models for evaluating novel therapies.