Bugs, Fungi and Cells in Cells – the weird side of colorectal cancer and tumour progression
Speaker: Prof. Jochen Prehn
Institution: Centre for Systems Medicine Dublin, Ireland
Place: CIPF conference room
My talk will focus on two new aspects of cancer biology and tumour progression in the setting of colorectal cancer: the role of the microbiome and the role of cell dynamics and formation of cell-in-cell structures.
Entosis is a form of non-phagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumours show evidence of entosis, however factors controlling entosis remain to be elucidated. I will present data showing that death receptor activation is a potent induces of entosis in colon cancer cells. Induction of entosis and apoptosis by an activation of death receptors by ligands such as TRAIL occurred simultaneously and required the presence of caspase-8. Analysis of colorectal cancer tumours showed a significant association between expression levels of TRAIL and CICs. Notably, the presence of CICs in the invasive front regions of colorectal tumors was significantly correlated with adverse patient prognosis.
Dysbiosis of the microbiome has also been implicated in colorectal cancer (CRC) development, progression and response to therapy. Fusobacterium nucleatum (Fn), a commensal Gram-negative anaerobe from the Fusobacteriales order, is an onco-bacterium in CRC as a causal relationship between Fn prevalence and CRC pathogenesis, progression and treatment response has been reported in vivo. We showed that Fn/Fusobacteriales prevalence is associated with immune involvement (decrease in macrophages M1 and increase in macrophages M2) and activation of specific signalling programs (inflammation, DNA damage, WNT, metastasis, proliferation, cell cycle) in the host tumours, and is prognostic in particular in mesenchymal CRC tumors. We also systematically investigated alterations in the bacteriome and mycobiome of CRC patients in tumours and matched adjacent mucosa resulting in the identification of microbiome-based subtypes associated with host clinico-pathological and molecular characteristics. Tumours and adjacent mucosa samples were classified into 4 microbial subtypes, termed C1 to C4, based on the bacteriome and mycobiome composition. Microbial subtypes were associated with distinct tumour and patient phenotypes including T stage, tumour location, history of colon polyps and other malignancies, age, lymphovascular invasion and p53 status and disease-free survival.