An overarching theme of my laboratory’s work is the experimental investigation of the network behavior of biological systems relevant to human disease using a variety of biochemical, biophysical, molecular biological, and systems modeling approaches. A primary focus is the biology of gastrointestinal solid tumors such as colorectal and pancreatic cancers.
Proteomic Biomarker Discovery
We use a variety of biochemical tools including high-resolution mass spectrometry for the characterization of proteome-level alterations in primary human tissue samples. Using this approach, we have discovered a variety of novel proteins and pathways in both colorectal cancers and lung adenocarcinomas.
We are refining these approaches to investigate posttranslational modification events directly in primary samples (e.g., phosphorylation or glycosylation events) using novel chemical affinity enrichment techniques as well as metabolic labeling strategies.
Using similar experimental approaches, we have expanded our work to serum samples with the goal of defining the totality of antibody specificities in a patient’s serum - what we term the “autoantigen-ome”. We are now examining the temporal proteomic evolution of the autoantigen-ome in patients with cancers and autoimmune diseases such as lupus. We expect that this will lead to the discovery of novel antigenic epitopes that can be used for both diagnostic and (immuno-)therapeutic purposes.
The Impact of Genomic Aberrations on the Proteome
With near-complete genome sequencing of cancer samples it becomes feasible to use this information (together with transcriptome-wide expression data) to try to answer some fundamental questions about proteome-level effects. For example, we would like to answer the question of how many of the dozens of somatic coding sequence changes at cancer genome level actually make it into detectable aberrant proteins as opposed to leading to unstable mRNA, abortive translation events, or unstable proteins with accelerated turnover. This is an important question because all current targeted therapies are directed against proteins (enzymes or structural proteins), and therapeutic effects will only be experienced when the modified protein is actually made.
To this end, we are sequencing a variety of cancer tissue samples for which we also have high-quality fresh-frozen samples from the very same patient and tumor location. This allows us to inform mass spectrometric investigation with prior knowledge about sequence-predicted, patient-specific alterations and to focus on the direct detection of mutated proteins and peptides.