Fortea, M. | bioRxiv Science

bioRxiv2024

ERK3/MAPK6 promotes triple-negative breast cancer progression through collective migration and EMT plasticity

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and is associated with high cell plasticity, recurrence, and metastatic rate. During epithelial-to-mesenchymal transition (EMT), cancer cells display EMT plasticity, or partial-EMT features, which are required for breast cancer metastasis, such as collective migration. ERK3 has been implicated in promoting migration and invasion of breast cancer, but the mechanisms remain elusive. Here, we investigated ERK3 expression across patient-derived datasets of breast cancer and established its association with aggressive breast cancer phenotypes and poor clinical outcomes. Leveraging the hypothesis that ERK3 contributes to TNBC progression by supporting a partial-EMT state, we showed that ERK3 is essential in different steps of the metastatic process, especially by enabling collective migration but also by modulating cell-extracellular matrix adhesion, anchorage-independent growth, extravasation and colonization. In conclusion, our results demonstrate that ERK3 contributes to TNBC progression and potentially metastasis by promoting EMT plasticity and collective migration.

cancer biology↗

bioRxiv2023

D-Serine agonism of GluN1-GluN3 NMDA receptors regulates the activity of enteric neurons and coordinates gut motility

The enteric nervous system (ENS) is a complex network of diverse molecularly defined classes of neurons embedded in the gastrointestinal wall and responsible for controlling the major functions of the gut. As in the central nervous system, the vast array of ENS neurons is interconnected by chemical synapses. Despite several studies reporting the expression of ionotropic glutamate receptors in the ENS, their roles in the gut remain elusive. Here, by using an array of immunohistochemistry, molecular profiling and functional assays, we uncover a new role for D-serine (D-Ser) and non-conventional GluN1-GluN3 N-methyl D-aspartate receptors (NMDARs) in regulating ENS functions. We demonstrate that D-Ser is produced by serine racemase (SR) expressed in enteric neurons. By using both in situ patch clamp recording and calcium imaging, we show that D-Ser alone acts as an excitatory neurotransmitter in the ENS independently of the conventional GluN1-GluN2 NMDARs. Instead, D-Ser directly gates the non-conventional GluN1-GluN3 NMDARs in enteric neurons from both mouse and guinea-pig. Pharmacological inhibition or potentiation of GluN1-GluN3 NMDARs had opposite effects on mouse colonic motor activities, while genetically driven loss of SR impairs gut transit and fluid content of pellet output. Our results demonstrate the existence of native GluN1-GluN3 NMDARs in enteric neurons and open new perspectives on the exploration of excitatory D-Ser receptors in gut function and diseases.

neuroscience↗