Room 201, School of Arts and Sciences
Central Campus
Lower survival rates for many cancer types correlate with changes in nuclear size/scaling in a tumor-type/tissue-specific manner. Hypothesizing that such changes might confer an advantage to tumor cells, we screened for approved compounds that reverse the direction of characteristic tumor nuclear size changes in PC3, HCT116, and H1299 cell lines reflecting respectively prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous lung cancer. Consistent with the tumor-type/tissue differences in the size changes, we found distinct, largely non-overlapping sets of compounds that rectify nuclear size changes for each tumor cell line. Several classes of compounds including e.g. serotonin uptake inhibitors, cyclo-oxygenase inhibitors, beta-adrenergic receptor agonists, and Na+/K+ ATPase inhibitors displayed coherent nuclear size phenotypes focused on a particular cell line or across cell lines and treatment conditions. Several compounds from classes far afield from current chemotherapy regimens were also identified. Seven nuclear size-rectifying compounds selected for further investigation all inhibited cell migration and/or invasion. Thus, we propose that combining chemotherapy regimens with minimally toxic drugs yielding nuclear size rectification should reduce metastatic spread and increase survival.
Eric Schirmer (PhD, University of Chicago; post-doc, The Scripps Research Institute) is a Professor at the University of Edinburgh’s Institute of Cell Biology. During his post-doc he worked on lamin heterotypic interactions and identified many novel nuclear envelope transmembrane proteins (NETs). His lab in Edinburgh postulated that many NETs would be tissue-specific and they identified hundreds more NETs by sampling several different tissues. This tissue-specific nuclear envelope proteome even undergoes significant changes with cell state changes such as lymphocyte activation. His lab currently focuses on tissue-specific NET functions in developmental genome organization and its disruption in inherited disease, fusing DamID, Hi-C and expression data. A core finding is that these NETs tend to be part of tethering complexes at the nuclear envelope which recruit genes from alternative differentiation pathways to be more strongly repressed, yet also influence the release and activation of genes specific to functioning of a particular tissue. Hypotheses being investigated for how a tethering complex can also influence gene release/activation are focused on partner proteins in the complexes, their post-translational modification, and the idea of "constrained diffusion" where constitutive distal nuclear envelope tethers can restrict the area genes and enhancers can sample so as to facilitate their interaction. The lab also investigates nuclear size changes in cancer and virus interactions with the nuclear envelope.
