"I have no special talent. I am only passionately curious." - Albert Einstein

Research Summary

Cancer is a heterogeneous disease driven by various genomic, epigenomic, and proteomic abnormalities. Though conceptually straightforward, targeting cancer-specific abnormalities proves practically challenging due to the complexity of the cellular functions of many potential cancer targets. Our lab is interested in unravelling the biology of cancer-relevant cellular proteins with poorly understood mechanisms. We strongly believe that this could lead to the development of novel therapies and the improvement of existing therapies. Currently we are focusing on two research areas in the context of breast cancer.

Profilin-1: an old protein with new functional twists

Profilin-1 (Pfn1) is a well-characterized actin-binding protein essential for cell proliferation, survival and migration, yet showing paradoxical antitumor and anti-metastatic effects in several types of cancer including breast. Our recent work has suggested a “spatial confinement” model to reconcile its opposing functions (Diamond et al., 2015). Our data suggest that Pfn1 has important yet poorly understood functions in the nucleus in addition to its well-characterized role as an actin-binding and regulatory factor in the cytoplasm. We propose that it is this “moonlighting” activity of Pfn1 in the nucleus that gives rise to its antitumor effects (model below). We are currently utilizing multi-disciplinary approaches (biochemistry, cell biology, imaging, epigenetics, mouse tumor models) to investigate the molecular mechanisms by which nuclear Pfn1 functions as a tumor inhibitor and its mode of deregulation in cancer, and explore opportunities to therapeutically target its activity.

 

 

p97/VCP: a polyubiquitin-specific protein "segregase" orchestrating DNA damage response

Valosin-containing protein (VCP) is an evolutionarily conserved AAA+ ATPase involved in diverse cellular processes. Functioning as a “segregase”, VCP facilitates protein homeostasis by extracting polyubiquitinated proteins from various cellular locations or complexes for subsequent turnover. Recent studies have linked VCP to chromatin-associated protein degradation and genome stability maintenance particularly in the context of DNA damage response (DDR). For instance, in response to DNA double strand breaks, VCP is rapidly recruited to the damage sites and facilitates the proper assembly of DNA repair proteins (e.g. BRCA1 and 53BP1). In addition, it is functionally required for DNA replication and could possibly play a role in cell cycle checkpoint activation. Nevertheless, detailed understanding of its mechanism of action (e.g. identity of its chromatin-associated client proteins), its mode of (de)regulation in cancer, and its relevance to cancer treatments (e.g. radiotherapy and chemotherapy) is lacking, and we are currently studying all these questions.