We study the identity of intestinal stem cells (ISC) and investigate the signaling crosstalk orchestrating their function. Our analyses focus on understanding the intestinal niche behavior in homeostasis and analyzing its changes following injury, such as irradiation damage. To this aim, the lab takes advantage of engineered mouse models and –omics technologies to characterize intestinal epithelial and stromal heterogeneity. Of particular interest is the role of the innervating nervous system in regulating ISC function and regeneration.
Our laboratory has been studying stomach cancer for thirty years, focused initially on the role of H. pylori infection as an initiating and promoting factor. In collaboration with MIT, we have helped to develop the first Helicobacter-dependent mouse models of gastric cancer and discovered the key role of chronic inflammation in driving gastric carcinogenesis. The lab has gone on to develop multiple models of gastric cancer, which allowed our group to uncover the stem cell origins of both metaplasia and cancer. We have recently identified key alterations to niche cells, including nerves, endothelial cells, innate lymphoid cells, myeloid cells, tuft cells and endocrine cells. Changes in these niche cells lead to expansion of stem/progenitor cells, as well as suppression of tumor immunity, allowing for progression to dysplasia and cancer.
The Wang lab is interested in the role of hematopoietic stem cells (HSCs) in inflammation, regeneration, and cancer biology. We have previously identified the gene histidine decarboxylase (Hdc) as a marker for a population of HSCs that are biased towards becoming immature myeloid cells (IMCs), and histidine as being an important regulator of these cells’ differentiation. IMCs are a class of leukocytes that have been implicated in inflammation and regeneration in the gut in response to certain inflammatory signals. We have shown that exhaustion of these Hdc+ cells in the bone marrow contributes to the progression of conditions such as colitis, but this exhaustion can be reversed using histamine receptor agonists. We will continue to study the role of these cells in intestinal injury and cancer with the goal of elucidating their contributions to different pathologies.
To gain insight into the pathogenesis of Barrett’s Esophagus (BE) progression into esophageal adenocarcinoma (EAC), our lab generated a transgenic mouse model of BE and EAC, that closely resembles human disease. We have combined lineage tracing in mice and 3D organoid modeling to demonstrate that the gastric cardia stem/progenitor (i.e., Lgr5+ and CCK2R+) cells can generate BE. Our lab has been among the pioneers in the identification and study of stem/progenitor populations at the squamocolumnar junction (SCJ), the likely site of initiation of BE/EAC. We will continue to address fundamental biology research on BE/EAC progression, including cell of origin, cellular function affected by genetic determinants, risk factors, clonal evolution, and niche cell function.
Nerves and the Tumor Microenvironment
Pancreatic cancer is one of the most life-threatening diseases and that effective treatment remain limited. Our laboratory aims to identify the cellular origins of pancreatic cancer to better understand the mechanism of cancer development and progression. We have focused on acinar cell origins and acinar-to-ductal metaplasia and have used single cell methods to confirm the heterogeneity of acinar cells and have identified several subsets that behave as active or facultative progenitors. In particular, using mouse models, we have found that Dclk1-positive cells plays an important role in the mechanisms of pancreatic regeneration and tumorigenesis. In addition, we have focused extensively on the role of neuronal signals in modulating these and other progenitors in response to injury and Kras mutation. Our group has shown important roles for alterations in sympathetic and parasympathetic signaling in the progression of pancreatic cancer, and further studies are underway, including clinical trials in patients, based on these discoveries.