Biology subjects

Huh, W. J.

Publications and source records attributed to Huh, W. J..

3 recordsLinked to original sources

bioRxiv2023

Transcriptomic Profiling Reveals Claudin 18.2 as a Diagnostic Biomarker of Menetrier Disease and the Role of Hedgehog Signaling in Pathogenesis

Both Menetriers disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer development. MD is an acquired disease without known causative mutations. MD patients are characterized by an increased expression of EGF receptor (EGFR) ligand and transforming growth factor alpha (TGF-) in the stomach. JPS is inherited in an autosomal dominant pattern and is caused by BMPR1A or SMAD4 mutations. It is characterized by multiple polyps throughout the gastrointestinal tract along with certain SMAD4 mutations that can result in gastric polyposis. Although there are many distinct clinico- endoscopic and histopathologic features that differ between the two diseases, they also share similar features that often lead to misdiagnosis. This study aimed to identify markers that can help distinguish MD from JPS and to better understand the pathogenesis of MD by comparing differential gene expression patterns. Upon examination of MD and JPS microscopically, we found almost all cases have patchy areas mimicking each other, making it difficult to make a correct diagnosis with histopathologic examination alone. Comparative analysis between MD and JPS using ingenuity pathway analysis (IPA) revealed both common and differential gene signatures. Common gene signatures included estrogen receptor signaling, integrin signaling, mTOR signaling, and others, which may be responsible for histopathologic similarities. Among differential gene signatures, we found that claudin 18 (CLDN18) is upregulated in MD and confirmed that CLDN18.2 (isoform of CLDN18) protein expression is higher in MD than JPS by immunohistochemistry. Comparative analysis between MD and normal control revealed the hedgehog (Hh) signaling pathway is upregulated in MD. Treatment with a hedgehog pathway inhibitor partially rescued the histopathologic phenotypes in a MD mouse model. The current study provides valuable insight into the potential underlying mechanism of why MD and JPS show similar clinico-pathologic features. We also identified a diagnostic marker CLDN18.2 that can help distinguish MD from JPS, genetically. Furthermore, it also shows that Hh signaling plays an important role in the pathogenesis of MD and can function as a potential therapeutic target.

pathology↗

bioRxiv2022

Lrig3 restricts the size of the colon stem cell compartment

The cellular census of the colonic crypt is tightly regulated, yet the molecular mechanisms that regulate this census are not fully understood. Lrig3, a transmembrane protein, is expressed in colonic crypt epithelial cells, including the stem, progenitor, and differentiated cell types. Mice missing Lrig3 have a disruption in their cellular census: using a novel Lrig3-/- mouse we demonstrate that Lrig3-/- mice have more cells per crypt, a greater mucosal area, and longer colons compared to wildtype mice, suggesting the expression of Lrig3 is required for both the total number of epithelial cells in the mouse colon, as well as colon length. In addition, we show Lrig3-/- mice have significantly more stem, progenitor, and deep crypt secretory cells, yet harbor a normal complement of enteroendocrine, Tuft, and absorptive cells. Lrig3-/- mice also have a concomitant decrease in phosphorylated Extracellular signal-related kinases, indicating the loss of Lrig3 leads to an expansion of the colonic stem cell compartment, in an Erk-dependent manner. Our study describes the expression of Lrig3 within the colon, defines perturbations in mice lacking Lrig3, and supports a role for Lrig3 in the establishment of both colonic crypt structure and cellular census, defined as the epithelial cell type and number in colon crypts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/483523v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@244c29org.highwire.dtl.DTLVardef@1045457org.highwire.dtl.DTLVardef@13d4134org.highwire.dtl.DTLVardef@83db4e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors

Most colorectal cancers (CRCs) develop from either adenomas (ADs) or sessile serrated lesions (SSLs). The origins and molecular landscapes of these histologically distinct pre-cancerous polyps remain incompletely understood. Here, we present an atlas at single-cell resolution of sporadic conventional tubular/tubulovillous ADs, SSLs, hyperplastic polyps (HPs), microsatellite stable (MSS) and unstable (MSI-H) CRC, and normal colonic mucosa. Using single-cell transcriptomics and multiplex imaging, we studied 69 datasets from 33 participants. We also examined separate sets of 66 and 274 polyps for RNA and targeted gene sequencing, respectively. We performed multiplex imaging on a tissue microarray of 14 ADs and 15 CRCs, and we integrated pre-cancer polyp data with published single-cell and The Cancer Genome Atlas (TCGA) bulk CRC data to establish potential polyp-cancer relationships. Striking differences were observed between ADs and SSLs that extended to MSS and MSI-H CRCs, respectively, reflecting their distinct origins and trajectories. ADs arose from WNT pathway dysregulation in stem cells, which aberrantly expanded and expressed a Hippo and ASCL2 regenerative program. In marked contrast, SSLs were depleted of stem cell-like populations and instead exhibited a program of gastric metaplasia in the setting of elevated cytotoxic inflammation. Using subtype-specific gene regulatory networks and shared genetic variant analysis, we implicated serrated polyps, including some HPs conventionally considered benign, as arising from a metaplastic program in committed absorptive cells. ADs and SSLs displayed distinct patterns of immune cell infiltration that may influence their natural history. Our multi-omic atlas provides novel insights into the malignant potential of colorectal polyps and serves as a framework for precision surveillance and prevention of sporadic CRC.

cancer biology↗