2009 Scientific Report

Van Andel Research Institute | Scientific Report
We work with clinical collaborators at several institutions to address various clinical needs. One such need is to help doctors
make a more accurate diagnosis of patients with suspected pancreatic cancer. Since pancreatic cancer can be difficult to
distinguish from benign conditions of the gastrointestinal tract, highly accurate biomarkers are needed to match patients to the
appropriate procedures at the earliest possible time. We also are developing biomarkers to screen for clinically undetectable
pancreatic cancer. Among populations at an increased risk for developing pancreatic cancer—including those suffering from
chronic pancreatitis or with a family history of pancreatic cancer—an accurate screening test could detect new cancers early
enough to allow more effective treatment. Further, we are testing our novel biomarkers for use in drug trials. Biomarkers that
give early indications of the effectiveness of a candidate drug could accelerate drug trials and better match patients with the
drugs that benefit them most.
Another novel class of biomarker we are developing is for the diagnosis of patients with pancreatic cysts. Cystic lesions of the
pancreas are increasingly being recognized due to the widespread use of high-resolution abdominal imaging. Since certain
cyst types are precursors of invasive cancer, this situation presents an opportunity to intervene prior to malignant progression.
Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions based on
differences in their malignant potential. In collaboration with Dr. Diane Simeone at the University of Michigan, we have identified
glycan variants of secreted mucins that distinguish benign from pre-cancerous cysts with an 87% accuracy—better than the best
current markers. Ongoing work is aimed at validating and building upon these results. Ultimately, we hope to implement a test
that could be used to determine which pancreatic cysts should be surgically removed in order to prevent progression to cancer.
Origin and function of secreted glycan alterations in pancreatic cancer
Our laboratory also studies the origins and functions of cancer-cell secretions bearing altered glycans. The carbohydrate
alterations observed in pancreatic tumors are strongly associated with accelerated disease progression, but it is not known
whether these alterations functionally contribute to that progression. We have shown that certain glycoprotein alterations
Figure 2
are likely the product of subpopulations of tumor
cells that are more likely to be aggressive. Using
ALSA in a study of cultured pancreatic cancer
cells, we have shown that cells bearing markers
of high tumor-forming capability (termed “cancer
stem cell markers”) display distinct glycan characteristics.
The glycans of such cancer cells
are distinctly altered in response to inflammatory
signaling from the environment, showing the link
between secreted glycan structures and the
cellular state. Additional studies have shown
distinct glycan alterations produced when cells
transition from a stationary to a migratory state.
This transition initiates metastasis and results in
tumors at new sites. This work clearly links the
origin of particular cancer-associated glycans with
aggressive cancer cells.
Figure 2. Distinct changes to glycan levels associated with cell type. Cell lines were treated with various pro-inflammatory signals,
including oxidative stress (H 2
O 2
) and the cytokines IFNg, TNFa, or IL-a1. The cell lines and their treatments are indicated by the column
labels. Six cell lines were treated: two bearing cell-surface markers characteristic of tumorigenicity (labeled in red); two not bearing the
markers (labeled in black); and two partially bearing the markers (labeled in green). Using the ALSA assay, the levels of various glycans
on the mucins MUC1, MUC5AC, and MUC16 in the secretions of the cells were measured before and after treatment. The row labels
indicate the lectin used for detection (which determines the glycan detected) and the capture antibody. The color of each square
represents the fold-change of the signal after treatment divided by the signal before treatment. The cells bearing markers of tumorigenicity
uniquely increased particular glycans, showing a difference from the other cells in their glycan characteristics.
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