EngineeringSARCOMAs Building models of fusion-driven sarcomas via cell fate engineering

Summary

One of the unsolved problems in cancer biology is why and how do certain oncogenic driver genes promote cancer in one cellular context but not in another. This project focuses on fusion oncogenes relevant to sarcomas, which are sarcoma type-specific and tumorigenic only in certain cellular states. By combining cell fate engineering of human pluripotent stem cells (hPSCs) with forced expression of sarcoma-linked fusions, I will systematically probe the cellular contexts and molecular mechanisms of fusion-driven sarcomagenesis, with the prospect of building novel disease models that could be used for testing new therapies.
I hypothesize that fusion-driven sarcomas emerge from the combination of an oncogenic fusion protein and a cell-of-origin that is defined by a characteristic state prone to transformation. I will investigate the interplay between a specific cellular context and the activity of a particular fusion and whether a permissive cellular context is sufficient for fusions to execute their tumorigenic programs.
I will pursue a “build it to understand it” approach and construct sarcoma models starting from hPSCs inducible for the expression of five sarcoma-linked fusions respectively. I will validate these models against single-cell and spatial maps of sarcoma tumors available in the host lab. I will exploit two complementary approaches for creating cells permissive to different fusion oncogenes: i. Programmed differentiation of hPSCs with precise molecular intervention in vitro (Objective 1); ii. Genetically engineered teratomas that could allow for full in vivo modeling of sarcomas (Objective 2).
Alignment with the call: Innovative, collaborative, multidisciplinary project expected to qualify the applicant for a principal investigator position and an ERC starting grant. Candidate is promising early career female scientist moving from Italy to Austria. The candidate will bring her knowledge and new possible collaborations to the host lab.

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Web resources:	https://cordis.europa.eu/project/id/101149215
Start date:	01-05-2024
End date:	30-04-2026
Total budget - Public funding:	- 183 600,00 Euro

Cordis data

Original description

One of the unsolved problems in cancer biology is why and how do certain oncogenic driver genes promote cancer in one cellular context but not in another. This project focuses on fusion oncogenes relevant to sarcomas, which are sarcoma type-specific and tumorigenic only in certain cellular states. By combining cell fate engineering of human pluripotent stem cells (hPSCs) with forced expression of sarcoma-linked fusions, I will systematically probe the cellular contexts and molecular mechanisms of fusion-driven sarcomagenesis, with the prospect of building novel disease models that could be used for testing new therapies.
I hypothesize that fusion-driven sarcomas emerge from the combination of an oncogenic fusion protein and a cell-of-origin that is defined by a characteristic state prone to transformation. I will investigate the interplay between a specific cellular context and the activity of a particular fusion and whether a permissive cellular context is sufficient for fusions to execute their tumorigenic programs.
I will pursue a build it to understand it approach and construct sarcoma models starting from hPSCs inducible for the expression of five sarcoma-linked fusions respectively. I will validate these models against single-cell and spatial maps of sarcoma tumors available in the host lab. I will exploit two complementary approaches for creating cells permissive to different fusion oncogenes: i. Programmed differentiation of hPSCs with precise molecular intervention in vitro (Objective 1); ii. Genetically engineered teratomas that could allow for full in vivo modeling of sarcomas (Objective 2).
Alignment with the call: Innovative, collaborative, multidisciplinary project expected to qualify the applicant for a principal investigator position and an ERC starting grant. Candidate is promising early career female scientist moving from Italy to Austria. The candidate will bring her knowledge and new possible collaborations to the host lab.