Biology subjects

Kafka, F.

Publications and source records attributed to Kafka, F..

3 recordsLinked to original sources

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↗

bioRxiv2024

Unveiling the guardians: IL-26-expressing MAIT cells protect epithelial barrier function and are dysregulated in Crohn's disease

BACKGROUND & AIMSInflammatory bowel disease (IBD) is characterized by a dysregulated immune response against the hosts microbiome. Mucosal-associated invariant T (MAIT) cells recognize microbiota-derived riboflavin metabolites and play a crucial role in mucosal homeostasis. However, their specific role in IBD remains enigmatic. MAIT cells express IL-26, a novel IL-10 family cytokine with a controversial role in IBD. We investigated the functions of MAIT cells and IL-26 in IBD using a unique combination of state-of-the-art 3D human intestinal tissue models and clinical samples. METHODSWe analyzed MAIT cells from the peripheral blood and intestinal tissue of Crohns disease (CD) patients, using immunofluorescence staining and flow cytometry to describe the phenotype and IL-26 expression of MAIT cells. We used 3D iPSC-derived intestinal organoids as a complex in vitro model of human tissue and RNA sequencing and functional assays such as wound healing assay to study the role of IL-26 in mucosal homeostasis and inflammation. RESULTSWe observed a reduction of MAIT cells in the peripheral blood of CD patients compared to healthy donors (1.5 {+/-} 0.4%; 4.1 {+/-} 1.1%; p < .0065) and a significant decrease of MAIT cells in inflamed compared to non-inflamed ileum of CD patients (0.1 {+/-} 0.03%; 0.17 {+/-} 0.05%; p < .042). MAIT cells were found pathologically activated in inflamed tissue, exhibiting differences in CD8 and CD4 expression and dysregulation of IL-26 expression. Furthermore, we demonstrated a protective role of IL-26 in mucosal homeostasis and inflammation in the iPSC-derived organoid model. CONCLUSIONOur results show a crucial role for IL-26 and MAIT cells in the homeostasis of intestinal tissue and in the pathogenesis of IBD. These cells may therefore represent new therapeutic targets for CD patients.

immunology↗

bioRxiv2024

Serotonin attenuates tumor-necrosis-factor-alpha-induced intestinal inflammation by interacting with human mucosal tissue

The intestine houses the largest reservoir of immune cells and is serviced by the largest and most complex peripheral nervous system in the human body. The gut-brain axis orchestrates bidirectional communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Using a human 3D in vitro model, we investigated the effect of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Our findings revealed that serotonin attenuates the tumor-necrosis-factor-alpha-induced pro-inflammatory response, mostly by affecting the expression of chemokines. Serotonin was found to impact tissue-migrating monocytes phenotype and distribution, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, using fully human 3D model of intestine, our results show for the first time that serotonin has a crucial role in communication among gut-brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of intestinal inflammation. In vivo studies focused on role of neuromodulators in gut homeostasis and inflammation have shown controversial results, highlighting importance of development of human experimental models. Moreover, our results emphasize importance of human health research in human-cell-based models and suggests serotonin signaling pathway as new potential therapeutic target for inflammatory bowel disease patients.

immunology↗