Project Details
Projekt
Characterization and exploitation of novel ferroptosis regulators to target MYCN amplified cancers
Applicant
Professor Andreas Trumpp, Ph.D.
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461837449
Ferroptosis is a specific metabolic form of iron-mediated cell death that has recently been linked to a variety of diseases and patho-mechanisms. Recent studies have shown that cancer cells that develop resistance to conventional chemotherapy are particularly sensitive to modulation of the ferroptosis network. This opens up the possibility of developing ferroptosis modulators for specific applications in cancer therapy. Our own current data show that the oncogene MYCN sensitizes neuroblastoma cells to ferroptosis. MYC and MYCN are both central regulators of the cell metabolism, which drive proliferation, metastasis and resistance to therapy. Both are deregulated or amplified in many cancers and their overexpression is associated with poor prognosis. Specific approaches that would exploit MYC overexpression to sensitize such cancer cells to certain drugs are not available. Despite intensive research activities since the discovery of ferroptosis in 2012, only few of the components and regulators of the network have been identified. A comprehensive picture of the molecular and metabolic processes involved in the regulation of ferroptosis in different cell types and cancers is still missing. To address both (a) the identification of new members of the ferroptosis network and (b) the elucidation of their role in MYCN-amplified tumors, our application for SPP 2306 aims to elucidate the anti-ferroptotic role of new gene candidates that we have recently identified by CRISPR activation screens (CRISPRa). In addition to known ferroptosis proteins such as SLC7A11, AIFM2 (FSP1) and GCH1, our screens have identified a number of novel candidate genes. If overexpressed, they make MYCN-amplified neuroblastomas resistant to treatment with Erastin or RSL3 or both. We now plan to identify for 36 hits the associated mechanisms responsible for ferroptosis resistance using a coupled single-cell CRISPRa secondary screening approach (Aim 1). We will then use different molecular and metabolic assays to accurately characterize the biological role of five of these novel ferroptosis regulators in MYCN amplified neuroblastoma and breast cancer cells (Aim 2). These data will then be further developed in preclinical PDX mouse models to evaluate their role in ferroptosis induction/repression in vivo. In addition, we plan to develop combinatorial strategies to treat MYCN-amplified breast cancer by induction of ferroptosis in cultured cancer cells and in PDX mouse models. The overall goal of our SPP2306 proposal is the molecular and functional characterization of novel ferroptosis network components and the development of novel innovative strategies to combat MYCN-amplified cancers. We expect our data to be of significant importance for the members of SPP 2306. Conversely, the data and findings of the SPP teams will be crucial for the joint development of an effective preclinical strategy to target aggressive and previously incurable cancers by inducing ferroptosis.
DFG Programme
Priority Programmes
Co-Investigator
Hamed Alborzinia, Ph.D.
