Understanding the metastasis cascade: still a long way ahead
Metastasis can be considered as the end product of a multistep bio-mechano-chemical process where cancer cells disseminate to distant organs and home in a new tissue microenvironment (Fig.1). Metastases are resistantto multiple therapies and are responsible for the large majority of cancer-related deaths. It is now clear that the invasion-angiogenesis-metastasis cascade is not only dependent on genetic and epigenetic alterations within cancer cells, but also involves non-neoplastic stromal cells that contribute to cancer progression. However, the molecular and cellular mechanisms driving metastasis formation remain to be elucidated and better described in a realistic in vivo context. In this context, tumor cells interact with their surrounding microenvironment and corrupt it to their own benefit. For example, exosomes are small extracellular vesicles, which recently emerged as potent mediators involved in this communication. These vesicles are from an endosomal origin, contain proteins, mRNAs, non-coding RNAs and DNA; they circulate in all our body fluids and can be internalized by specific distant cells and ultimately deliver a functional message. Tumor cells release large amounts of exosomes bearing tumoral markers, which can subsequently disseminate at distance. In addition, tumor exosomes contain pro-metastatic factors that shape pre-metastatic niches (PMN), before the actual arrival of tumor cells, while determining tumor metastatic organo-tropism. These properties have promoted exosomes as new targets for anti-tumoral therapies and major candidates for non-invasive diagnosis in cancer using liquid biopsies (blood and urine), and intense research is currently conducted to identify exosome-carried biomarkers.
While much progress has been made towards understanding the key steps of the metastasis cascade, many gaps remain to be filled. Indeed, the molecular and cellular mechanisms driving metastasis formation remain to be elucidated and better described in a realistic in vivo context. This requires the usage of state-of-the-art imaging technologies that are compatible with relevant animal models for tracking each steps of the metastasis cascade (Axis 1). In addition, biomechanical forces are key drivers of metastatic evolution. For example, tumors sense and respond to stiffening of its surrounding stroma by increasing their invasive potential. High extravascular stress caused by tumor growth and interstitial fluid pressure leads to vascular compression that impairs perfusion and eventually promotes tumor progression, immunosuppression, and treatment resistance. Further work is required to better understand whether and how biomechanical forces shape metastatic growth (Axis 2). Finally, tumor exosomes have been shown to shape premetastatic niches and thereby favor metastastic colonization. However, the exact exosome–carried molecular mechanisms remain to be identified. Our plan is to fully exploit the potential of the intravital CLEM (Correlative Light and Electron Microscopy) technology that we have developped and to tackle key biological events driving tumor invasion and metastasis formation. In addition, we plan to fully exploit the synergy between our expertise in tumor exosomes and the unit expertise in immunology and « omics » approaches to dissect the molecular mechanisms by which tumor exosomes favor tumor progression and metastatic niche formation (Axis 3). Successful funding and consolidation of our group (based today on 4 permanent researchers, see Team structure) make us very confident in addressing the following questions. In addition, my group will integrate the future Center for Biomedical Research of Strasbourg (CRBS).
Thus, in the coming years, we propose to:
1 : Further develop intravital correlative imaging approaches to dissect tumor cell behavior in vivo(zebrafish (ZF) and mouse) at nanoscale (Axis1)
2 : Further dissect the contribution of mechanical forces to tumor invasion and metastasis formation (Axis2)
3 : Decipher the fate and function of tumor exosomes on local and distant microenvironment during the priming of metastatic niches (Axis3)