Juanita L Merchant

• M.D., Ph.D.
• Professor (Full) at University of Michigan

The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early ons...

e16104 Background: Gastric adenocarcinoma (GAC) is the fifth most common cancer worldwide with significant morbidity and mortality. Recently, southern Arizona has seen a concerning surge in incidence of GAC due to ineffective H. pylori screening and treatment. Moreover, peri-operative chemotherapy treatment in stage IB-III GAC represents an area of...

Background: Neuroendocrine tumors (NETs) represent heterogenous malignancies whose origins and etiology remain poorly understood. Men1-driven reprogramming of neural crest-derived glial cells was recently implicated in NET development. In these studies, aberrant Sonic hedgehog (SHH) pathway activation known to pattern neural cell fate coincided wit...

Significance Multiphoton microscopy (MPM) is a useful biomedical imaging tool for its ability to probe labeled and unlabeled depth-resolved tissue biomarkers at high resolution. Automated MPM tile scanning allows for whole-slide image acquisition but can suffer from tile-stitching artifacts that prevent accurate quantitative data analysis. Aim We...

Gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor‐derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone‐secreting and non‐functional GEP‐NETs....

Significance Lineage tracing using fluorescent reporters is a common tool for monitoring the expression of genes and transcription factors in stem cell populations and their progeny. The zinc-binding protein 89 (ZBP-89/Zfp148 mouse gene) is a transcription factor that plays a role in gastrointestinal (GI) stem cell maintenance and cellular differen...

Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NET) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure–function relationship of clinical multiple endocrine neoplasia, type 1 (MEN1)...

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor-derived signals from the surrounding microenvironment by applying Nanostring Digital Spatial Profiling (DSP) to hormone-secreting and non-functiona...

Introduction MDSCs express SCHLAFEN 4 (SLFN4) in Helicobacter-infected stomachs coincident with spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor of gastric cancer. We aimed to characterize SLFN4⁺ cell identity and the role of Slfn4 in these cells. Methods Single-cell RNA sequencing was performed on immune cells sorted from PBMCs a...

The incidence of early onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of...

MENIN regulation of gastrin gene expression in gastrin‐expressing cells versus MENIN regulation of cell specification genes in neuroendocrine tumors. Left panel: Enteroendocrine cells in the gastric antrum respond to activation of the epidermal growth factor receptor (EGFR) upon binding by EGFR ligands such as amphiregulin (AREG), epiregulin (EREG)...

Pancreatic neuroendocrine tumors (PNETs) are a rare but increasingly more prevalent cancer with heterogeneous clinical and pathological presentation. Surgery is the preferred treatment for all hormone-expressing PNETs and any PNET greater than 2 cm, but difficulties arise when tumors are multifocal, metastatic, or small in size due to lack of effec...

182 Background: About 10 percent of all colorectal cancers are in subjects who are not yet 50 (EO-CRC) and the occurrence of early onset colorectal cancer (EO-CRC) is rising in the US. Patients with CRC are twice as likely to have diabetes or be overweight. Using targeted exome sequencing of germline DNA from EO-CRC subjects, we identified a missen...

Small intestinal neuroendocrine tumor SI-NETs are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan...

Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NETs) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure– function relationship of clinical Multiple Endocrine Neoplasia, type 1 ( MEN...

Background: Duodenal gastrinomas (DGASTs) are neuroendocrine tumors that develop in the submucosa of the duodenum and produce the hormone gastrin. Surgical resection of DGASTs is complicated by the small size of these tumors and the tendency for them to develop diffusely in the duodenum. Endoscopic mucosal resection of DGASTs is an increasingly po...

BACKGROUND & AIMS Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine...

Menin is the protein product of the Multiple Endocrine Neoplasia 1 ( MEN1 ) gene locus at 11q13 and is a known tumor suppressor of neuroendocrine neoplasms (NENs). Gastrin-expressing NENs (gastrinomas) comprise the most frequent and malignant of the MEN1-dependent endocrine tumors. When gastrinomas are part of the MEN1 syndrome, they exhibit a grea...

Background and Aims A subset of MDSCs that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter-inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that individuals with a more robust response to damage-activated molecular patterns (DAMPs) and increas...

Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune mi...

BACKGROUND & AIMS Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive model systems that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a role for enteric glia in neuroendocrine cell specifica...

Background and Aims A subset of MDSCs that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter -inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that individuals with a more robust response to damage-activated molecular patterns (DAMPs) and increa...

(1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL proliferation, and effector function, thus promoting tumor cell evasion from immu...

Abetted by widespread usage of acid-suppressing proton pump inhibitors, the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the s...

Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 5...

Objective Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups. Aim To identify the possible derivation of GEP-NETs using genome-wide analyses...

Tumors evade immune surveillance by expressing Programmed Death-Ligand 1 (PD-L1), subsequently inhibiting CD8+ cytotoxic T lymphocyte function. Response of gastric cancer to immunotherapy is relatively low. Our laboratory has reported that Helicobacter pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Hedgehog (Hh) si...

Background & Aims Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized...

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell im...

The myeloid differentiation factor Schlafen4 (Slfn4) marks a subset of myeloid-derived suppressor cells (MDSCs) in the stomach during Helicobacter -induced spasmolytic polypeptide-expressing metaplasia (SPEM). Objective To identify the gene products expressed by Slfn4 ⁺ -MDSCs and to determine how they promote SPEM. Design We performed transcript...

https://www.sciencedirect.com/science/article/pii/S0016508519390146?via%3Dihub

Cholangiopathies, which affect extrahepatic bile ducts (EHBDs), include biliary atresia, primary sclerosing cholangitis, and cholangiocarcinoma. They have no effective therapeutic options. Tools to study EHBD are very limited. Our purpose was to develop an organ-specific, versatile, adult stem cell-derived, preclinical cholangiocyte model that can...

Hedgehog (HH) signaling participates in hepatobiliary repair after injury and is activated in patients with cholangiopathies. Cholangiopathies are associated with bile duct (BD) hyperplasia, including expansion of peribiliary glands, the niche for biliary progenitor cells. The inflammation‐associated cytokine interleukin (IL)‐33 is also up‐regulate...

The enteric nervous system (ENS) consists of neurons and enteric glial cells (EGCs) that reside within the smooth muscle wall, submucosa and lamina propria. EGCs play important roles in gut homeostasis through the release of various trophic factors and contribute to the integrity of the epithelial barrier. Most studies of primary enteric glial cult...

Lgr5-expressing intestinal stem cells (ISCs) maintain continuous and rapid generation of the intestinal epithelium. Here, we present evidence that dedifferentiation of committed enteroendocrine cells (EECs) contributes to maintenance of the epithelium under both basal conditions and in response to injury. Lineage-tracing studies identified a subset...

ZBP-89 (Zfp148, ZNF148) is a Kruppel-type zinc-finger family transcription factor that binds to GC-rich DNA elements. Earlier studies in cell lines demonstrated that ZBP-89 cooperates with Wnt β-catenin signaling by inducing β-catenin gene expression. Since β-catenin levels are normally highest at the crypt base, we examined whether ZBP-89 is requi...

Background & aims: The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors (NETs) such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes...

Purpose of review: Neuroendocrine tumors (NETs) were initially identified as a separate entity in the early 1900s as a unique malignancy that secretes bioactive amines. GI-NETs are the most frequent type and represent a unique subset of NETs, because at least 75% of these tumors represent gastrin stimulation of the enterochromaffin-like cell locat...

Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocyt...

BUTYRATE REGULATES TRANSCRIPTION FACTOR ZBP-89 AND SUSTAINS PROLIFERATION UNDER LOW GLUCOSE CONDITIONS Ramon Ocádiz-Ruiz, Michael M. Hayes, Juanita L. Merchant Background: ZBP-89 (ZNF148, Zfp148) is a transcription factor that binds to GC-rich elements. We previously reported that butyrate stimulates ZBP-89 protein expression suggest- ing interacti...

TRANSCRIPTION FACTOR ZBP-89 COOPERATES WITH B-CATENIN IN THE LGR5+ STEM CELL Ramon Ocádiz-Ruiz, Michael M. Hayes, Juanita L. Merchant Background: ZBP-89 (ZNF148, Zfp148) is a transcription factor that binds to GC-rich elements. We recently reported that conditional deletion of Zfp148 in a mouse model of intestinal polyps from deleted Apc reduced po...

Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses three HH ligands with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastro...

Methods: Inbred C57BL/6J strain, a 50:50 hybrid (B6SJLF1/J) strain and mice on a highly mixed genetic background were fed four diets: standard chow (STD, 6% fat), STD with 200 ppm OM (STD+O), a high-energy chow (HiE, 11% fat) and HiE chow with OM (HiE+O) for 17 weeks. Metabolic analysis, body composition and fecal microbiota composition were analy...

Gastric cancer remains one of the leading neoplasms and currently ranks third in cancer mortality worldwide.1 Helicobacter pylori ( H. pylori ) infection, and the subsequent chronic inflammation that the organism induces, is a major risk factor for stomach cancer,2 along with smoking and a diet high in salt and nitrates (http://www.cancer.org/cance...

In colorectal cancer (CRC), APC-mediated induction of unregulated cell growth involves post-translational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10 percent of colorectal tumors also exhibit increased CTNNB1 mRNA. Here we show in CRC that incr...

This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C...

Chronic Helicobacter pylori infection triggers neoplastic transformation of the gastric mucosa in a small subset of patients, but the risk factors that induce progression to gastric metaplasia have not been identified. Prior to cancer development, the oxyntic gastric glands atrophy and are replaced by metaplastic cells in response to chronic gastri...

Background: Intestinal metaplasia (IM) is a gastric cancer precursor lesion (GCPL) and an extremely high risk factor for progression to gastric cancer (GC). Clinical guidelines recommend that patients with extensive IM undergo a gastroscopy every 3 years. However, protein biomarkers that indicate a transition from IM to GC are lacking. Our group r...

Background Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffu...

Gastric adenocarcinoma is the third most common cause of cancer-related death worldwide. Here we report a novel, highly-penetrant mouse model of invasive gastric cancer arising from deregulated Hedgehog/Gli2 signaling targeted to Lgr5-expressing stem cells in adult stomach. Tumor development progressed rapidly: three weeks after inducing the Hh pat...

Background & aims: Dual oxidase 2 (DUOX2), a hydrogen-peroxide generator at the apical membrane of gastrointestinal epithelia, is upregulated in patients with inflammatory bowel disease (IBD) before the onset of inflammation, but little is known about its effects. We investigated the role of DUOX2 in maintaining mucosal immune homeostasis in mice....