Alex Wenzel, a graduate student in Jill Mesirov's lab (UC San Diego). Gene Set Enrichment Analysis (GSEA) is a valuable tool for understanding the behavior of molecular pathways in cancer. This approach and similar methods are heavily dependent on resources like the Molecular Signatures Database (MSigDB), a collection of gene sets corresponding to biological processes and pathways. This project seeks to develop algorithmic, data-driven approach to refine the gene sets in MSigDB so to provide more coherent and context-specific gene sets thereby enabling more powerful enrichment analyses.
Dana Steffen, a graduate student in Silvio Gutkind's lab (UC San Diego). G protein coupled receptors (GPCRs) are currently the largest class of drug targets, with a long history of success for treating cardiovascular and airway diseases. In cancer however, GPCR-targeting drugs are underexploited. We have found that approximately 5% of all sequenced cancer genomes contain GNAS mutants, resulting in a constitutively active Gαs. Gαs activation leads to the intracellular accumulation of cyclic adenosine monophosphate (cAMP) which then activates protein kinase A (PKA). This project seeks to further elucidate the Gαs- PKA signaling network as this may reveal novel mechanisms by which PKA promotes cancer progression.
Daniel Schwarz, a graduate student in Jason Gestwicki's lab (UCSF). Protein phosphorylation is a fundamental and essential cellular signaling mechanism. We have developed a novel inhibitor to the peptidyl-prolyl isomerase Pin1, the only peptidyl-prolyl isomerase for prolines adjacent to a phosphorylated serine or threonine. We recently screened a library of kinase inhibitors that identified inhibitors of the PI3K / AKT / mTOR pathway as synergistic with our PIN1 inhibitor. Next we will perform a genome-wide CRISPRi chemogenetic screen to identify sensitizing and protective genes in the presence of a Pin1-inhibitor.
Kirti Chahal, a graduate student in Irina Kufareva's lab (UC San Diego). Aberrant Hedgehog (Hh) signaling pathway activation is found in several types of cancers, including basal cell carcinoma (BCC) and medulloblastoma (MB). Hh pathway activation involves the intracellular trafficking of several signaling components between the plasma membrane, intracellular membranes, primary cilia (PC) and the nucleus; however, our understanding of the molecular mechanisms behind these trafficking events is limited. The goal of this project is to use APEX proximity biotinylation to map signaling dynamics in aberrant Hh signaling activation.
Lucas Stolerman, postdoctoral fellow in Padmini Rangamani's lab (UC San Diego). Small monomeric GTPases such as Ras and Rho family members play key roles in various cancers. Previous efforts in the lab have explored how GTPases impact cAMP levels, an important second messenger. Using a new computation model that described a monomeric GTPase connected with a trimeric GTPase by feedforward and feedback loops, we will test the hypothesis that cancer initiation is correlated with enhanced organellar cooperativity driven by GTPase circuits.
Mayaan Baron, a postdoctoral fellow in Trey Ideker's lab (UC San Diego). Acquired resistance to cancer treatments is largely mediated by ‘persister’ cells, super-resistant cancer cells that can survive high drug concentrations. Identifying the pathways leading to resistance is likely to have a substantial impact on how to overcome resistance and optimize therapy. To study these pathways, I will pursue an epigenetic-phenotypic measurement approach combining single-cell high throughput technologies with gene networks and artificial intelligence to develop an interpretable model predicting drug resistance based on the epigenetic state of a cell.
Michelle Moritz, a Research Biochemist in Nevan Krogan's and David Agard's lab (UCSF). The goal of this project is to use the state-of-the-art mass spectrometry and cryo-EM facilities in the Krogan and Agard labs to take an innovative and integrative approach to understanding protein complexes important in cancer at a level of atomic detail rarely possible previously. This objective of this project is to gain an atomic-level understanding of the interaction of the regulatory casein kinase-1δ and the microtubule-nucleating γ-Tubulin Ring Complex (γTuRC) using cross-linking mass spectrometry (XL-MS) and cryo-electron microscopy (cryoEM). This work will serve as a test case for solving structures of other cancer-related protein complexes that were identified through affinity-purification mass spectrometry (AP-MS).
