Deciphering OSM cytokine’s role in the breast tumor microenvironment / Dysregulated fatty acid metabolism as a non-cell autonomous mechanism in ALS

Deciphering OSM cytokine’s role in the breast tumor microenvironment

Advanced breast cancer, particularly triple-negative (TN) breast cancer, presents a critical challenge due to its poor prognosis and the lack of effective targeted therapies. Addressing this urgent clinical need, our research focuses on the pro-inflammatory cytokine Oncostatin M (OSM) and its signalling pathways. OSM is significantly overexpressed in TN breast cancer, where it not only enhances tumour invasiveness but also alters the tumour microenvironment (TME) by acting on both tumour cells and fibroblasts. This study explores the hypothesis that OSM contributes to a harmful metabolic state within the TME, potentially leading to immune evasion. Prior investigations into OSM’s role revealed a shift towards glycolysis, a characteristic of cancer cells’ metabolic adaptation. Here, we aim to corroborate these findings through mass spectrometry and assess OSM’s immunosuppressive effects. Our findings clarify OSM’s contribution to breast cancer progression, hinting at the malignancy-promoting metabolism and immune suppression it induces. Thus, targeting the OSM signalling pathway emerges as a potential strategy for developing novel treatments for breast cancer.

Dysregulated fatty acid metabolism as a non-cell autonomous mechanism in ALS

The talk will address the crucial role of lipids in the central nervous system (CNS), focusing on their significance in neuronal and astrocytic function. Lipids, essential macromolecules, serve as structural components of membranes, signaling molecules, and contributors to electric signaling conductivity in neurons. Notably, while neurons avoid utilizing lipids as metabolic substrates, astrocytes play a pivotal role in maintaining lipid homeostasis through oxidative phosphorylation (OxPhos). Glial dysfunctions and perturbations in lipid homeostasis are deeply implicated in the pathogenesis of motor neuron diseases, particularly amyotrophic lateral sclerosis (ALS). The latter is evidenced by gene ontology and pathway enrichment analyses. Our work aims at exploring how astrocytes’ metabolic capacity, influenced by ALS pathogenic factors, such as TDP-43 loss-of-function, could impact lipid detoxification and neuronal health. The findings, indicate impaired energy production pathways in TDP-43 knockdown astrocytes, potentially linked to disrupted fatty acid oxidation (FAO) and lipid accumulation. Future directions include elucidating the mechanisms underlying FAO alterations and validating findings in human pluripotent stem cell-derived astrocytes and ALS patient tissues.