Menu
MapConnectionsTopicsBulgariaThe Night (K-TRIO)Marie Skłodowska-CurieFor studentsFor teachersMethodologySurprise me
H2020Individual fellowship2016–2018

S-OS · Exosomes as microenvironmental cue for engaging mesenchymal stem cells in osteosarcoma progression

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-01-01 → 2018-05-03
EU contribution
€165,599
Participants
2
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

Exosomes as microenvironmental cue for engaging mesenchymal stem cells in osteosarcoma progression

Osteosarcoma (OS) is a very aggressive bone tumor that mainly affects children and adolescents. It is characterized by rapid growth and a strong tendency to recur and to form lung metastasis. In the presence of metastatic disease the prognosis is really poor and survival does not exceed 20%. The rarity, the heterogeneity and the genetic complexity of this type of tumor challenge the identification of therapeutic targets. As a consequence no improvements in OS treatment have been achieved in the last 30 year and novel therapeutic strategies are urgently needed. Tumors are very dynamic structure in which tumor cells constantly communicate with surrounding normal cells and can even instruct them to support tumor growth and metastasis formation. Understanding and blocking these interactions might represent an effective strategy to stop cancer. Because OS occurs during the adolescent growth spurt and at sites of rapid bone growth, the local and systemic environment in which the tumor develops might have a crucial role in cancer development and progression. In this project we explored the communication mediated by small extracellular vesicles (EVs) between tumor and normal stem cells residing in the bone marrow, called mesenchymal stem cells (MSC). We found that EVs secreted by highly malignant osteosarcoma cells alter the behavior of MSCs by inducing the production of proinflammatory factors. By releasing increased amounts of proinflammatory IL6, the educated MSCs promote OS growth and lung metastasis formation. Importantly, blockade of IL6 signaling with a therapeutic antibody abrogated the tumor-promoting effects of educated MSCs. Our findings suggest that tumor EV are critical mediators of intercellular communication driving OS progression and provide the basis for testing immunomodulatory agents as new therapeutic options for osteosarcoma patients.

Data: CORDIS, © European Union

Project objective

Osteosarcoma (OS) is a very aggressive malignant bone tumor that develops primarily during childhood and adolescence. It is characterized by rapid growth, a strong tendency for recurrence and an extremely high metastatic potential. In the last three decades OS survival in the presence of metastasis has stagnated at a dismal 30%, clinical trials proved unsuccessful and no major breakthrough in the treatment of OS has been reported. To stop OS mortality, alternative therapeutical approaches urgently need to be explored. Studies into the molecular and cellular events underlying OS revealed complex and heterogeneous genetic alterations, which challenge the prospect of finding and exploiting an unique molecular driver underlying OS. Because OS onset occurs at sites of rapid bone growth during the adolescent growth spurt, microenvironmental factors and tumor stroma may have a defining role in OS development and progression. Surprisingly, the intercellular cross-talk between OS cells and components of the tumor stroma, in particular mesenchymal stem cells (MSCs), have been poorly investigated.Here I intend to demonstrate that tumor secreted vesicles called “exosomes” function as a key microenvironmental factor in OS progression by controlling tumor-stromal cells interactions. Specifically, we aim to explore whether MSC become pro-tumorigenic and pro-metastatic upon interaction with OS exosomes in bioluminescent mouse xenograft models. To identify the molecular signals (i.e. proteins and regulatory RNAs) in OS exosomes responsible for altering MSC behavior, we will employ state-of-the-art proteomics and deep-sequencing techniques. Finally, by means of functional assays we wish to discover the mechanisms by which OS exosome “educate” MSCs.The identification of and interference with this completely unexplored layer of communication will lay the groundwork for novel therapeutical approaches to stop OS high mortality rate.

Original text from CORDIS.

Participants

Links

Data: CORDIS, © European Union