Developing a HTS platform in identifying microbiome-modulated small molecule impacts on multiple glioblastoma signalling pathways
Despite the advances in cancer research, glioblastoma multiforme (GBM) remains poorly understood and largely incurable, mostly, due to its intra- and inter- tumour heterogeneity. Mutations in specific genes are thought to be driving the development of GBM. However, most of these genes are only studied at the genomic level, with no deep investigation on how these mutations dysregulate the cellular signalling pathways. Therefore, a better understanding of the GBM molecular pathways, without disregarding inter-pathway impacts, will help in identifying cancer modulators with the potential to block these pathways to limit the tumorigenic abilities of GBM.
In the last few years, multiple studies have suggested a central role for the microbiome in modulating cancer initiation, progression, and treatment responsiveness. The microbiome consists of an ecosystem of indigenous microorganisms inhabiting on and within the human body surfaces (including the gut, oral cavity, vagina, and skin). Alterations in the habitual compositional structure of microbiome communities have been also associated with different diseases. Importantly, recent works demonstrate possible causal impacts of the microbiome on cancer-related phenotypes. Knowledge regarding the microbiome impacts on intracellular signalling events, and the associated cancer cell behaviour in glioblastoma remains elusive. Such causal understanding of host-microbiome modulatory activity on signalling pathways central to GBM development and clinical behaviour may hold promise in harnessing microbes and their secreted products into new biological therapies preventing and treating GBM.
In this proposed project, we aim to establish a high throughput screening pipeline enabling to massively screen thousands of microbiome-related, food-related and host-related molecules involved in the host-microbiome niche and their simultaneous effects on multiple key signalling pathways in human GBM. Using this innovative system, we aim to shed new light into the mechanisms orchestrating microbiome regulation of GBM formation and development and harness this molecular knowledge towards identification and experimentation in new microbiome-based modulators of GBM signalling and cellular activity. In short, our long-term objectives in this project include uncovering microbes and metabolites participating in the modulation of specific cellular events in tumour cells, impacting tumour development, and progression.