Anson Lowe, M.D., Associate Professor, Department of Medicine, Gastroenterology Division

Research description: Pancreatic biology and disease have been a long-standing focus of the Lowe laboratory. In classical investigations of the mechanisms of secretory granule biogenesis in the pancreatic exocrine cell, Dr. Lowe studied the mechanisms underlying the formation of secretory granules and how proteins were sorted to these organelles. Specifically, he discovered a set of membrane proteins shared between exocrine, neural, and endocrine secretory granules derived from different tissues. He discovered the presence of VAMP2 in secretory granule, which was later determined to be responsible for secretory vesicle targeting and fusion.

He also made seminal discoveries about the dominant membrane protein of the pancreatic exocrine secretory granule, GP2. Many laboratories had proposed GP2 to function in the sorting and packaging of digestive enzymes into the secretory granule, Dr. Lowe produced GP2 knockout mouse that revealed that GP2 did not function in secretory granule biogenesis or protein sorting. Instead, a role for GP2 in defense against bacteria infection was established. From a translational perspective, he established that GP2 serves as a useful clinical marker for acute and chronic pancreatitis.

Gene expression profiling led to a current focus on the gene Anterior Gradient 2 (AGR2), which is expressed in all pancreatic adenocarcinomas, but absent from normal tissues. His laboratory was the first to establish that AGR2 expression is required to maintain the transformed phenotype of adenocarcinoma cell lines. Subsequent studies established that AGR2 expression affected both the Hippo and EGFR signaling pathways by respectively activating the coactivator YAP1 and inducing expression of the EGFR ligand Amphiregulin. His group defined the mechanism of action for AGR2 and discovered that it serves as a thioredoxin within the endoplasmic reticulum, and that its major substrate is the Epidermal Growth Factor Receptor (EGFR). Within the endoplasmic reticulum, AGR2 physically interacts with EGFR and enables its transport to the cell surface where cell signaling is initiated. Without AGR2 expression, they established that EGFR signaling is not possible, and thus represents a novel and likely dominant mechanism for regulating EGFR signaling. The Lowe laboratory recently established in a murine pancreatitis model that AGR2 expression is induced and is responsible for initiating EGFR signaling and tissue regeneration, without which mice are unable to recover and die. The work represents the first definitive assessment of EGFR function in adult vertebrates, namely tissue regeneration, and supports a close relationship between tissue regeneration and the development of pancreatic cancer. From a translational perspective, identification of genes whose expression is induced by AGR2 expression has identified novel biomarkers for pancreatic cysts and cancer. Dr. Lowe is currently focused on exploring how this pathway can be manipulated for therapeutic purposes.

Dr. Lowe has an active collaboration with Dr. Walter Park of the PCRG.

Selected relevant publications (Stanford PCRG members in bold):

  1. Lowe, A.W., Olsen, M., Hao, Y., Lee, S.P., Lee, K-T., Chen, X., van de Rijn, M., and P.O. Brown. Gene Expression Patterns in Pancreatic Tumors, Cells and Tissues. Plos One 2007 Mar 28;2:e323.
  2. Wang, Z., Hao, Y., Lowe, A.W. The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res. 2008:68(2):492-497.
  3. Park WG, Wu M,.. Visser BC, Poultsides GA,..Lowe AW, et al. Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine. Gastrointest Endosc. 2013.
  4. Tun MT, Pai RK, ... Visser BC,..Poultsides GA.,..Lowe, AW, Park, WG. Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts. BMC Gastroenterol. 2012;12(1):15.
  5. Dong A, Wodziak D, Lowe AW. Epidermal Growth Factor Receptor (EGFR) Signaling Requires a Specific Endoplasmic Reticulum Thioredoxin for the Post-translational Control of Receptor Presentation to the Cell Surface. J Biol Chem. 2015;290(13):8016-27.
  6. Wodziak D, Dong A, Basin MF, Lowe AW. Anterior Gradient 2 (AGR2) Induced Epidermal Growth Factor Receptor (EGFR) Signaling Is Essential for Murine Pancreatitis-Associated Tissue Regeneration. PLoS One. 2016;11(10):e0164968.