3 year fixed-term contract (with possible extension to four years), full time, start date: immediately.
Invadopodia are actin-rich membrane protrusions that facilitate tumor cell invasion through dense extracellular matrix (ECM) by recruiting transmembrane and secreted metalloproteinases (MMPs) able to catalyze ECM component degradation, and creating pores through which mesenchymal tumor cells can migrate. We recently identified CRP2 (cysteine- and glycine-rich protein 2) as a critical cytoskeletal component of invadopodia. From a mechanistic standpoint, we found that CRP2 promotes invadopodia formation and elongation by stabilizing their actin core, which serves as a backbone of the structure. In addition, CRP2 shuttles to the nucleus where it drives expression of pro-metastatic genes, including several members of the matrix metalloproteinase (MMP) family involved in ECM remodeling and which are associated with cancer cell invasion and metastasis (article in preparation).
We previously reported that breast cancer (BC) patients with higher CRP2 expression show significantly increased risks of metastases and reduced survival. Moreover, partial knockdown of CRP2 in highly invasive and metastatic BC cells is sufficient to significantly inhibit metastasis in two mouse models of metastatic BC, supporting that CRP2 holds great potential as a therapeutic target to prevent/treat metastatic BC. However, CRP2 is a small (193 amino acid-long), non-enzymatic and non-receptor, protein, complicating direct pharmacological inhibition of its activities. Like many other LIM domain-containing and cytoskeletal proteins, CRP2 biological functions critically rely on ability to mediate protein-protein interactions.
In the view of transferring our discoveries to clinical applications that benefit patients, we aim at identifying CRP2 protein interactome, identify interactions that are most critical to BC invasion, establish a high-throughput screening assay to select inhibitors of these interactions and evaluate the anti-invasion and anti-metastatic potential of such inhibitors in vitro and in pre-clinical models of BC.
The Cytoskeleton and Cancer Progression (CCP) group belongs to the Department of Oncology, whose activities focus on the cellular and molecular mechanisms of tumor progression using a wide range of cutting edge technologies, including genomic, transcriptomic and proteomic analyses, and in vitro and in vivo imaging modalities as well as state of-the art animal models for cancer research. The CCP group focuses on actin regulatory proteins and related signaling pathways driving tumor cell invasion and immune evasion, with the goal to identify new prognostic markers and therapeutic targets (see our webiste). We combine biochemistry, cell biology, reversegenetics and advanced live-cell imaging approaches as well as mouse models of breast cancer metastasis.
Related publications of the group
- Hoffmann et al. (2014) Human Muscle LIM Protein Dimerizes along the Actin Cytoskeleton and Cross-Links Actin Filaments. Molecular and cellular biology 34 (16):3053-3065.
- Hoffmann et al. (2016) CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis. Oncotarget 7 (12):13688-13705.
- Hoffmann et al. (2018) Hypoxia promotes breast cancer cell invasion through HIF-1alpha-mediated up-regulation of the invadopodial actin bundling protein CSRP2. Sci Rep 8 (1):10191.
Researchers are supported by easy access to scientific expertise, well-equipped facilities, an active seminar program as well as opportunities for conference attendance and collaborations with other research organisations.
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