Neoglycosylation Epitopes in Metaplasia and Cancer

PROJECT SUMMARY / ABSTRACT
This application proposes a five-year research career development program focused on determining how
glycosylation epitopes expressed during metaplasia and cancer contribute to these clinically significant cellular
transformations. The applicant, Jeffrey W. Brown, M.D., Ph.D., is an Instructor of Medicine in the Division of
Gastroenterology at Washington University School of Medicine. Since completing gastroenterology fellowship,
Dr. Brown had worked in the laboratory of Jason Mills, where he has discovered a novel cellular process that he
calls cathartocytosis [Greek: cellular cleansing] which is used by cells to efficiently dedifferentiate in the
processes of metaplasia and cancer. He has subsequently determined that cathartocytosis is annotated by the
glycan 3’-Sulfo-LeA/C and mice null for galectins that preferentially bind this epitope either fail to perform
cathartocytosis or fail to package sulfomucins into mature granules. As glycobiology is a new field for Dr. Brown,
Stuart Kornfeld will serve as his primary mentor with continued support from Jason Mills (Co-Mentor). Together,
the candidate will be uniquely positioned to acquire the knowledge and skill set necessary to develop an
independent research program investigating how specific glycosylation epitopes modulate tissue transformation
and differentiation states in metaplasia and cancer.
The expression and secretion of sulfomucins is uniformly present in Barrett’s esophagus and esophageal
cancer, is the defining feature of type III [high-risk] gastric intestinal metaplasia, and is currently the best
biomarker for detecting high-grade dysplasia and cancer in pancreatic cystic lesions. Using a comprehensive
approach involving cell lines, organoid culture, and murine models, the experiments proposed herein will
determine the proteome carrying 3’-Sulfo-LeA/C, the cellular signaling and transcriptional profile regulating its
synthesis and secretion, as well as the molecular mechanism by which specific galectins modulate cellular
differentiation. Ultimately, with the mentorship provided by Stuart Kornfeld, Jason Mills, and the research
advisory committee, the knowledge and technical skills derived from the proposed experiments, and completion
of the outlined career development plan, Dr. Brown will be well-prepared to establish an independent research
program and is expected to be highly-competitive for R01 funding.

Grant Number: 5K08DK132496-05
NIH Institute/Center: NIH
Principal Investigator: Jeffrey Brown