Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis
Menée à l'aide de lignées cellulaires, de sphéroïdes et de modèles murins de cancer du poumon à petites cellules, cette étude met en évidence un mécanisme par lequel des interactions entre les cellules cancéreuses et les astrocytes favorisent la formation de métastases cérébrales en induisant des programmes d'expression génétique similaires à ceux impliqués dans le développement du cerveau
Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression programmes that are similar to those found during early brain development in neurons and astrocytes. Mechanistically, the brain development factor Reelin, secreted by SCLC cells, recruits astrocytes to brain metastases. These astrocytes in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron–astrocyte interactions during brain development. Targeting such developmental programmes activated in this cancer ecosystem may help prevent and treat brain metastases.
Nature Cell Biology 2023