On Saturday, 28.10.2023, we teamed up with local, national and international initiatives for the Walk of Hope to provide the public first-hand insights into early detection, treatment and research of breast cancer.
It was exciting to interact with so many interested people at our interactive booths. All the questions we were asked and especially the conversations with affected people and their relatives were moving and encouraging to pursue our efforts for the development of better treatments for patients with breast cancer.
We are very much looking forward to the next Walk of Hope!
Congratulations to Joana, Milica, Charly and the co-authors of our latest publication in EMBO Journal!!!
In this study, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the metabolic enzyme nicotinamide N-methyltransferase (NNMT). NNMT expression is associated with poor clinical outcome in breast cancer patients and accordingly, its genetic ablation dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix related genes, whose expression is key for establishing the foreign metastatic niche. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.
PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer
The protein tyrosine phosphatase SHP2 activates oncogenic pathways downstream of most receptor tyrosine kinases (RTK) and has been implicated in various cancer types. Although allosteric inhibitors of SHP2 have been developed and are currently being evaluated in clinical trials, neither the mechanisms of the resistance to these agents, nor the means to circumvent such resistance have been clearly defined. The PI3K signalling pathway is also hyperactivated via activation of RTKs in breast cancer and contributes to resistance to anticancer therapies. We therefore assessed the effect of targeting PI3K and SHP2 alone or in combination in preclinical models of metastatic TNBC. In addition to the beneficial inhibitory effects of SHP2 alone, dual PI3K/SHP2 treatment decreased primary tumor growth synergistically, blocked the formation of lung metastases, and increased survival in preclinical models. Mechanistically, transcriptome and phospho-proteome analyses revealed that resistance to SHP2 inhibition is mediated by PDGFR?-evoked activation of PI3K signalling. Altogether, our data provide a rationale for co-targeting of SHP2 and PI3K in metastatic TNBC.
Ioanna obtained her MSc in Biomedical Sciences from the University of Patras where she also received her BSc in Biology. Her research was focused on unraveling molecular links between the lipoprotein system and metabolic diseases. After completing her studies, she worked at the University of Bern where she examined the therapeutic potential of the modulation of tumor microenvironment in pancreatic cancer by targeting the fibroblastic stroma and immune-mediated resistance. Ioanna joined our lab to characterize the crosstalk between the microbiome and tumor microenvironment in breast cancer aiming to identify novel targets for clinical use.
After graduating for Pharmaceutical Biotechnologies at University of Padua, Livio had the opportunity to do cancer immunology research working in Guido Kroemer Lab in Gustave Roussy Cancer Center (Paris) on dendritic cell cross-presentation and migration in the tumour context. Thereafter, he joined our group in January 2023. His project aims to identify the mechanisms responsible for the immunotherapy resistance in breast cancers in a translational approach that lays the groundwork for the discovery and development of novel therapeutic targets.