Collective cancer cell invasion requires RNA accumulation at the invasive front

Menée in vitro et à l'aide d'une xénogreffe de tumeur de la langue sur un modèle murin, cette étude démontre que l'invasion collective de cellules cancéreuses nécessite l'accumulation, à l'avant des groupes de cellules, d'ARNs codant pour des facteurs impliqués dans la progression tumorale

Résumé en anglais

Specific RNAs are enriched at protrusive regions of migrating cells. This localization is important for cell migration on 2D surfaces. However, in vivo, tumor cells navigate complex 3D environments often in collective groups. Here, we investigated protrusion-enriched RNAs during collective 3D invasion. We show that specific RNAs exhibit a striking accumulation at the front of invasive leader cells. We provide insights into the mechanism underlying RNA accumulation at the invasive front, and we further demonstrate that it is required for efficient 3D invasion of tumor cells. We additionally observe RNA enrichment at invasive sites of in vivo tumors, supporting the physiological relevance of this mechanism and suggesting a targeting opportunity for perturbing cancer cell invasion.Localization of RNAs at protrusive regions of cells is important for single-cell migration on two-dimensional surfaces. Protrusion-enriched RNAs encode factors linked to cancer progression, such as the RAB13 GTPase and the NET1 guanine nucleotide exchange factor, and are regulated by the tumor-suppressor protein APC. However, tumor cells in vivo often do not move as single cells but rather utilize collective modes of invasion and dissemination. Here, we developed an inducible system of three-dimensional (3D) collective invasion to study the behavior and importance of protrusion-enriched RNAs. We find that, strikingly, both the RAB13 and NET1 RNAs are enriched specifically at the invasive front of leader cells in invasive cell strands. This localization requires microtubules and coincides with sites of high laminin concentration. Indeed, laminin association and integrin engagement are required for RNA accumulation at the invasive front. Importantly, perturbing RNA accumulation reduces collective 3D invasion. Examination of in vivo tumors reveals a similar localization of the RAB13 and NET1 RNAs at potential invasive sites, suggesting that this mechanism could provide a targeting opportunity for interfering with collective cancer cell invasion.All study data are included in the article and SI Appendix.