Tumour progression and metastasis formation relies on the ability of cancer cells to modify proximal and distal microenvironments in order to spread to other areas of the body. It is well established that extracellular vesicles (EVs) are pivotal in intercellular communication responsible for premetastatic niche formation. However, it is less characterized how tumour cells reprogram EV contents to favour their growth and dissemination.
This project takes the cue from recent evidence that autophagy, in addition to act as a survival process, is also involved in the regulation of EV loading and secretion.
This project aims to shed light on how autophagy impacts on the EV cargo sorting in tumour cells, and, in turn, on cell-to-cell communication in the context of cancer metastasis. In particular, we will focus our study on the role of autophagy in regulating the ability of EV released from colorectal cancer cells to promote the epithelial-to-mesenchymal transition (EMT) in hepatocytes.
The specific aims of this project will be:
1. To identify the molecular signatures underlying the autophagy-dependent compartmentalization of regulatory RNAs and RNA binding proteins in EVs produced by colorectal cancer cells.
2. To functionally characterize the role of autophagy-regulated EV RNAs released by colorectal cancer cells in promoting EMT of hepatocytes.
The characterization of the crosstalk between autophagy and EV sorting machinery here proposed will i) contribute to elucidate the molecular signalling responsible for premetastatic niche formation by tumour cells, and ii) disclose the therapeutic potential of inhibiting autophagy in tumour cells to interfere with cell-to-cell communication and prevent metastasis formation.
The recent evidence that autophagy plays a key role in the formation and loading of EVs has opened up new perspectives regarding the regulation of cell-to-cell communication.
The main innovative aspect of this project is to apply this new knowledge on exosome biogenesis to the cancer field by investigating which could be the contribution of autophagy-regulated EVs to the multifaceted role played by autophagy in the regulation of tumour metastasis.
Tumour metastasis usually indicates a poor prognosis and is the leading cause of cancer-related death. Thus, preventing formation of tumour metastasis is an important task to cure cancer patients. In recent years, the concept of a pre-metastatic niche has provided new ideas to prevent tumour metastasis. The pre-metastatic niche refers to the microenvironment, which is favourable for tumour cells to colonize in.
Many evidence point at EVs as a tool by which tumour cells can induce directly or indirectly a pre-metastatic niche.
Acquiring cancer-specific knowledge about the relationship between autophagy and the mechanisms involved in non-coding RNAs compartmentalization within EVs as well as the identification of specific miRNAs whose extracellular release impacts on tumour progression will both expand our understanding of the molecular mechanisms responsible for the reprogramming of exosome repertoire and to envisage novel therapeutic approaches to halt metastasis. For example, these information will allow to select chemical modulators of autophagy that selectively interfere with the generation of EVs enriched in pathogenic non-coding RNAs. Moreover, it will contribute to identify specific non-coding RNA and associated RNA-binding proteins to be proposed as candidate diagnostic markers of tumour stage and potential therapeutic targets for gene therapy approaches.