RESUMEN
BACKGROUND: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor. METHODS: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action. RESULTS: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype. CONCLUSION: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.
RESUMEN
Studying repeated adaptation can provide insights into the mechanisms allowing species to adapt to novel environments. Here, we investigate repeated evolution driven by habitat specialization in the common bottlenose dolphin. Parapatric pelagic and coastal ecotypes of common bottlenose dolphins have repeatedly formed across the oceans. Analyzing whole genomes of 57 individuals, we find that ecotype evolution involved a complex reticulated evolutionary history. We find parallel linked selection acted upon ancient alleles in geographically distant coastal populations, which were present as standing genetic variation in the pelagic populations. Candidate loci evolving under parallel linked selection were found in ancient tracts, suggesting recurrent bouts of selection through time. Therefore, despite the constraints of small effective population size and long generation time on the efficacy of selection, repeated adaptation in long-lived social species can be driven by a combination of ecological opportunities and selection acting on ancestral standing genetic variation.
