Publications by authors named "Timothy C Wang"

308 Publications

Stem cells and origins of cancer in the upper gastrointestinal tract.

Cell Stem Cell 2021 Jun 10. Epub 2021 Jun 10.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address:

The esophagus and stomach, joined by a unique transitional zone, contain actively dividing epithelial stem cells required for organ homeostasis. Upon prolonged inflammation, epithelial cells in both organs can undergo a cell fate switch leading to intestinal metaplasia, predisposing to malignancy. Here we discuss the biology of gastroesophageal stem cells and their role as cells of origin in cancer. We summarize the interactions between the stromal niche and gastroesophageal stem cells in metaplasia and early expansion of mutated stem-cell-derived clones during carcinogenesis. Finally, we review new approaches under development to better study gastroesophageal stem cells and advance the field.
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http://dx.doi.org/10.1016/j.stem.2021.05.012DOI Listing
June 2021

Intestinal organoids: roadmap to the clinic.

Am J Physiol Gastrointest Liver Physiol 2021 Jul 5;321(1):G1-G10. Epub 2021 May 5.

Center for Stem Cell and Organoid Medicine, grid.239573.9Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Recent advances in intestinal organoid research, along with encouraging preclinical proof-of-concept studies, have revealed significant therapeutic potential for induced pluripotent stem cell (iPSC)-derived organoids in the healing and replacement of severely injured or diseased bowel (Finkbeiner et al. 4: 1462-1472, 2015; Kitano et al. 8: 765, 2017; Cruz-Acuna et al. 19: 1326-1335, 2017). To fully realize the tremendous promise of stem cell organoid-based therapies, careful planning aligned with significant resources and efforts must be devoted demonstrating their safety and efficacy to meet critical regulatory requirements. Early recognition of the inherent preclinical and clinical obstacles that occur with the novel use of pluripotent stem cell-derived products will accelerate their bench-to-bedside translation (Neofytou et al. 125: 2551-2557, 2015; O'Brien et al. 6: 146, 2015; Ouseph et al. Cytotherapy 17: 339-343, 2015). To overcome many of these hurdles, a close and effective collaboration is needed between experts from various disciplines, including basic and clinical research, product development and manufacturing, quality assurance and control, and regulatory affairs. Therefore, the purpose of this article is to outline the critical areas and challenges that must be addressed when transitioning laboratory-based discovery, through an investigational new drug (IND) application to first-in-human clinical trial, and to encourage investigators to consider the required regulatory steps from the earliest stage of the translational process. The ultimate goal is to provide readers with a draft roadmap that they could use while navigating this exciting cell therapy space.
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http://dx.doi.org/10.1152/ajpgi.00425.2020DOI Listing
July 2021

Reply.

Gastroenterology 2021 Apr 19. Epub 2021 Apr 19.

Columbia University, New York, New York.

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http://dx.doi.org/10.1053/j.gastro.2021.04.027DOI Listing
April 2021

Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma.

Carcinogenesis 2021 Apr 20. Epub 2021 Apr 20.

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.

Barrett´s Esophagus (BE) is the main known precursor condition of Esophageal Adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease (GERD) and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is likely mediated by chronic esophageal inflammation, secondary to GERD in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, while both NSAIDs were effective chemoprevention agents in the accelerated HFD fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL-1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.
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http://dx.doi.org/10.1093/carcin/bgab032DOI Listing
April 2021

Randomized Controlled Trial of the Gastrin/CCK Receptor Antagonist Netazepide in Patients with Barrett's Esophagus.

Cancer Prev Res (Phila) 2021 Jun 29;14(6):675-682. Epub 2021 Mar 29.

Department of Medicine, Columbia University Irving Medical Center, New York, New York.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm, SD 620.7; placebo: +307.8 Ki67+ cells/mm, SD 640.3; = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype () and certain cancer-associated markers (), and decreased expression of intestinal markers , and No serious adverse events related to study drug occurred. The gastrin/CCK receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus. Treatment of patients with Barrett's esophagus with a gastrin/CCK receptor antagonist did not have obvious chemopreventive effects.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0050DOI Listing
June 2021

Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.

Sci Rep 2021 Feb 24;11(1):4509. Epub 2021 Feb 24.

Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
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http://dx.doi.org/10.1038/s41598-021-84011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904766PMC
February 2021

Nerves on tr[ac]k to support pancreatic cancer metabolism.

Cell Res 2021 04;31(4):381-382

Department of Medicine, Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.

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http://dx.doi.org/10.1038/s41422-020-00462-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115560PMC
April 2021

Reply.

Gastroenterology 2021 Apr 13;160(5):1900-1901. Epub 2021 Jan 13.

Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York.

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http://dx.doi.org/10.1053/j.gastro.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833954PMC
April 2021

Famotidine and Coronavirus Disease 2019.

Gastroenterology 2021 07 30;161(1):360-361. Epub 2020 Dec 30.

Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, New York.

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http://dx.doi.org/10.1053/j.gastro.2020.12.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833856PMC
July 2021

Acute Intestinal Inflammation Depletes/Recruits Histamine-Expressing Myeloid Cells From the Bone Marrow Leading to Exhaustion of MB-HSCs.

Cell Mol Gastroenterol Hepatol 2021 26;11(4):1119-1138. Epub 2020 Nov 26.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Electronic address:

Background & Aims: Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed.

Methods: We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC-green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC-tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan-Meier survival analysis was performed to assess the effect on survival.

Results: In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis.

Conclusions: Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.
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http://dx.doi.org/10.1016/j.jcmgh.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903065PMC
November 2020

The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

Gastroenterology 2021 Mar 14;160(4):1224-1239.e30. Epub 2020 Nov 14.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.

Background & Aims: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored.

Methods: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC.

Results: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5 intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis.

Conclusions: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.
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http://dx.doi.org/10.1053/j.gastro.2020.11.011DOI Listing
March 2021

PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice.

Gastroenterology 2021 02 29;160(3):781-796. Epub 2020 Oct 29.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York. Electronic address:

Background & Aims: Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1.

Methods: Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage.

Results: When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8 T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs.

Conclusions: In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8 T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.
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http://dx.doi.org/10.1053/j.gastro.2020.10.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878361PMC
February 2021

Bone Marrow-Derived Myofibroblasts Promote Gastric Cancer Metastasis by Activating TGF-β1 and IL-6/STAT3 Signalling Loop.

Onco Targets Ther 2020 16;13:10567-10580. Epub 2020 Oct 16.

Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China.

Background: Murine bone marrow-derived myofibroblasts (BMFs) have previously been shown to promote gastric cancer growth. However, whether BMFs promote gastric cancer cell metastasis remains largely unknown.

Methods: Wound healing assay, Transwell invasion and migration assay and 3D organotypic co-culture systems were conducted to study the effects of BMFs on invasion and migration of gastric cancer cells and the invasion and migration ability of gastric cancer stem cell-like cells (CSC-LCs) induced by BMFs. We employed two animal model to study the role of BMFs on the in vivo metastasis of gastric cancer cells and the metastatic ability of gastric BMF-induced CSC-LCs. A human gastric cancer tissue microarray and TCGA gastric cancer database were analysed to study the relationship between the expression of IL-6 and TGF-β1 and clinicopathological characteristics and survival in gastric cancer.

Results: We found that BMFs promoted the in vitro migration and invasion of gastric cancer cells. BMFs promoted liver, lung, subcutaneous, and splenic metastases of MKN28 cells in the spleen injection liver metastasis model and co-injection of caudal vein (IOCV) mouse model. BMFs reprogrammed non-gastric cancer stem cell (CSC) to CSC-LCs and enhanced CSC-LC migration and metastasis. BMF-derived IL-6 and gastric cancer cell-secreted TGF-β1 mediated the interaction between BMFs and gastric cancer cells, promoting tumour metastasis. BMFs enhanced the expressions of STAT3 and p-STAT3 in co-cultured gastric cancer cells. A combination of Napabucasin and Galunisertib exhibited the strongest inhibition of cell migration compared to when administered alone. Gastric cancer tissue array and TCGA database indicated that the overexpression of IL-6 and TGF-β1 was associated with gastric cancer metastasis.

Conclusion: Our results demonstrated that BMFs promote gastric cancer metastasis through the activation of the TGF-β1 and IL-6/STAT3 signalling pathways. Targeting the inhibition of these interactions may be a potent therapeutic strategy for addressing gastric cancer metastasis.
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http://dx.doi.org/10.2147/OTT.S266506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585554PMC
October 2020

Elimination of NF-κB signaling in Vimentin+ stromal cells attenuates tumorigenesis in a mouse model of Barrett's Esophagus.

Carcinogenesis 2021 04;42(3):405-413

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.

Chronic inflammation induces Barrett's Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.
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http://dx.doi.org/10.1093/carcin/bgaa109DOI Listing
April 2021

A DNA Hypomethylating Drug Alters the Tumor Microenvironment and Improves the Effectiveness of Immune Checkpoint Inhibitors in a Mouse Model of Pancreatic Cancer.

Cancer Res 2020 11 14;80(21):4754-4767. Epub 2020 Aug 14.

Division of Gastroenterology and Hepatology, Department of Medicine, New York University, New York, New York.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that has proven refractory to immunotherapy. Previously, treatment with the DNA hypomethylating drug decitabine (5-aza-dC; DAC) extended survival in the KPC-Brca1 mouse model of PDAC. Here we investigated the effects of DAC in the original KPC model and tested combination therapy with DAC followed by immune checkpoint inhibitors (ICI). Four protocols were tested: PBS vehicle, DAC, ICI (anti-PD-1 or anti-VISTA), and DAC followed by ICI. For each single-agent and combination treatment, tumor growth was measured by serial ultrasound, tumor-infiltrating lymphoid and myeloid cells were characterized, and overall survival was assessed. Single-agent DAC led to increased CD4 and CD8 tumor-infiltrating lymphocytes (TIL), PD1 expression, and tumor necrosis while slowing tumor growth and modestly increasing mouse survival without systemic toxicity. RNA-sequencing of DAC-treated tumors revealed increased expression of Chi3l3 (Ym1), reflecting an increase in a subset of tumor-infiltrating M2-polarized macrophages. While ICI alone had modest effects, DAC followed by either of ICI therapies additively inhibited tumor growth and prolonged mouse survival. The best results were obtained using DAC followed by anti-PD-1, which extended mean survival from 26 to 54 days ( < 0.0001). In summary, low-dose DAC inhibits tumor growth and increases both TILs and a subset of tumor-infiltrating M2-polarized macrophages in the KPC model of PDAC, and DAC followed by anti-PD-1 substantially prolongs survival. Because M2-polarized macrophages are predicted to antagonize antitumor effects, targeting these cells may be important to enhance the efficacy of combination therapy with DAC plus ICI. SIGNIFICANCE: In a pancreatic cancer model, a DNA hypomethylating drug increases tumor-infiltrating effector T cells, increases a subset of M2 macrophages, and significantly prolongs survival in combination with immune checkpoint inhibitors..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0285DOI Listing
November 2020

Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice.

Gut 2021 Apr 24;70(4):654-665. Epub 2020 Jul 24.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA

Background And Aims: The gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation.

Methods: We used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with . We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells.

Results: In both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing.

Conclusion: Gastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.
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http://dx.doi.org/10.1136/gutjnl-2020-320742DOI Listing
April 2021

Clinically Actionable Strategies for Studying Neural Influences in Cancer.

Cancer Cell 2020 07 11;38(1):11-14. Epub 2020 Jun 11.

Center for Neuroscience at the University of Pittsburgh, Pittsburgh Center for Pain Research and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.
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http://dx.doi.org/10.1016/j.ccell.2020.05.023DOI Listing
July 2020

Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series.

Gut 2020 09 4;69(9):1592-1597. Epub 2020 Jun 4.

Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

Objective: Treatment options for non-hospitalised patients with coronavirus disease 2019 (COVID-19) to reduce morbidity, mortality and spread of the disease are an urgent global need. The over-the-counter histamine-2 receptor antagonist famotidine is a putative therapy for COVID-19. We quantitively assessed longitudinal changes in patient reported outcome measures in non-hospitalised patients with COVID-19 who self-administered high-dose famotidine orally.

Design: Patients were enrolled consecutively after signing written informed consent. Data on demographics, COVID-19 diagnosis, famotidine use, drug-related side effects, temperature measurements, oxygen saturations and symptom scores were obtained using questionnaires and telephone interviews. Based on a National Institute of Health (NIH)-endorsed Protocol to research Patient Experience of COVID-19, we collected longitudinal severity scores of five symptoms (cough, shortness of breath, fatigue, headaches and anosmia) and general unwellness on a four-point ordinal scale modelled on performance status scoring. All data are reported at the patient level. Longitudinal combined normalised symptom scores were statistically compared.

Results: Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80 mg three times daily (n=6) for a median of 11 days (range: 5-21 days). Famotidine was well tolerated. All patients reported marked improvements of disease related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2) and device recorded activity (n=1) increased.

Conclusions: The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient-reported outcomes in non-hospitalised patients with COVID-19.
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http://dx.doi.org/10.1136/gutjnl-2020-321852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299656PMC
September 2020

Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study.

Gastroenterology 2020 09 22;159(3):1129-1131.e3. Epub 2020 May 22.

Division of Digestive and Liver Diseases, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, New York. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.05.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242191PMC
September 2020

Charge Transport in Zirconium-Based Metal-Organic Frameworks.

Acc Chem Res 2020 06 13;53(6):1187-1195. Epub 2020 May 13.

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.

Metal-organic frameworks (MOFs) are a class of crystalline porous materials characterized by inorganic nodes and multitopic organic linkers. Because of their molecular-scale porosity and periodic intraframework chemical functionality, MOFs are attractive scaffolds for supporting and/or organizing catalysts, photocatalysts, chemical-sensing elements, small enzymes, and numerous other functional-property-imparting, nanometer-scale objects. Notably, these objects can be installed after the synthesis of the MOF, eliminating the need for chemical and thermal compatibility of the objects with the synthesis milieu. Thus, postsynthetically functionalized MOFs can present three-dimensional arrays of high-density, yet well-separated, active sites. Depending on the application and corresponding morphological requirements, MOF materials can be prepared in thin-film form, pelletized form, isolated single-crystal form, polycrystalline powder form, mixed-matrix membrane form, or other forms. For certain applications, most obviously catalytic hydrolysis and electro- or photocatalytic water splitting, but also many others, an additional requirement is water stability. MOFs featuring hexa-zirconium(IV)-oxy nodes satisfy this requirement. For applications involving electrocatalysis, charge storage, photoelectrochemical energy conversion, and chemiresistive sensing, a further requirement is electrical conductivity, as embodied in electron or hole transport. As most MOFs, under most conditions, are electrically insulating, imparting controllable charge-transport behavior is both a chemically intriguing and chemically compelling challenge.Herein, we describe three strategies to render zirconium-based metal-organic frameworks (MOFs) tunably electrically conductive and, therefore, capable of transporting charge on the few nanometers (i.e., several molecular units) to few micrometers (i.e., typical dimensions for MOF microcrystallites) scale. The first strategy centers on redox-hopping between periodically arranged, chemically equivalent sites, essentially repetitive electron (or hole) self-exchange. Zirconium nodes are electrically insulating, but they can function as grafting sites for (a) redox-active inorganic clusters or (b) molecular redox couples. Alternatively, charge hopping based on linker redox properties can be exploited. Marcus's theory of electron transfer has proven useful for understanding/predicting trends in redox-hopping based conductivity, most notably, in accounting for variations as great as 3000-fold depending on the direction of charge propagation through structurally anisotropic MOFs. In MOF environments, propagation of electronic charge via redox hopping is necessarily accompanied by movement of charge-compensating ions. Consequently, rates of redox hopping can depend on both the identity and concentration of ions permeating the MOF. In the context of electrocatalysis, an important goal is to transport electronic charge fast enough to match or exceed the inherent activity of MOF-based or MOF-immobilized catalysts.Bandlike electronic conductivity is the focus of an alternative strategy: one based on the introduction of molecular guests capable of forming donor-acceptor charge transfer complexes with the host framework. Theory again can be applied predictively to alter conductivity. A third strategy similarly emphasizes electronic conductivity, but it makes use of added bridges in the form of molecular oligomers or inorganic clusters that can then be linked to span the length of a MOF crystallite. For all strategies, retention of molecular-scale porosity is emphasized, as this property is key to many applications. Finally, while our focus is on Zr-MOFs, the described approaches clearly are extendable to other MOF compositions, as has already been demonstrated, in part, in studies by others.
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http://dx.doi.org/10.1021/acs.accounts.0c00106DOI Listing
June 2020

Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression.

Gut 2021 Feb 10;70(2):330-341. Epub 2020 May 10.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA

Objective: Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression.

Design: We crossed LSL- ;-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples.

Results: KC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8 T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1 B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival.

Conclusion: We show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.
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http://dx.doi.org/10.1136/gutjnl-2019-319912DOI Listing
February 2021

Adult Pancreatic Acinar Progenitor-like Populations in Regeneration and Cancer.

Trends Mol Med 2020 08 30;26(8):758-767. Epub 2020 Apr 30.

Division of Digestive and Liver Disease, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address:

The bulk of the pancreas primarily comprises long-lived acinar cells that are not considered a bona fide source for stem cells. However, certain acinar subpopulations have a repopulating capacity during regeneration, raising the hypothesis as to the presence of regenerative progenitor-like populations in the adult pancreas. Here, we describe recent discoveries based on fate-mapping techniques that support the existence of progenitor-like acinar subpopulations, including active progenitor-like cells that maintain tissue homeostasis and facultative progenitor-like cells that drive tissue regeneration. A possible link between progenitor-like acinar cells and cancer initiators is proposed. Further analysis of these cellular components is needed, because it would help uncover possible cellular sources for regeneration and cancer, as well as potential targets for therapy.
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http://dx.doi.org/10.1016/j.molmed.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395864PMC
August 2020

Hypergastrinemia Expands Gastric ECL Cells Through CCK2R Progenitor Cells via ERK Activation.

Cell Mol Gastroenterol Hepatol 2020 21;10(2):434-449.e1. Epub 2020 Apr 21.

Division of Digestive and Liver Diseases, Department of Medicine. Electronic address:

Background & Aims: Enterochromaffin-like (ECL) cells in the stomach express gastrin/cholecystokinin 2 receptor CCK2R and are known to expand under hypergastrinemia, but whether this results from expansion of existing ECL cells or increased production from progenitors has not been clarified.

Methods: We used mice with green fluorescent protein fluorescent reporter expression in ECL cells (histidine decarboxylase [Hdc]-green fluorescent protein), as well as Cck2r- and Hdc-driven Tamoxifen inducible recombinase Cre (Cck2r-CreERT2, Hdc-CreERT2) mice combined with Rosa26Sor-tdTomato (R26-tdTomato) mice, and studied their expression and cell fate in the gastric corpus by using models of hypergastrinemia (gastrin infusion, omeprazole treatment).

Results: Hdc-GFP marked the majority of ECL cells, located in the lower third of the gastric glands. Hypergastrinemia led to expansion of ECL cells that was not restricted to the gland base, and promoted cellular proliferation (Ki67) in the gastric isthmus but not in basal ECL cells. Cck2r-CreERT2 mice marked most ECL cells, as well as scattered cell types located higher up in the glands, whose number was increased during hypergastrinemia. Cck2r-CreERT2 isthmus progenitors, but not Hdc mature ECL cells, were the source of ECL cell hyperplasia during hypergastrinemia and could grow as 3-dimensional spheroids in vitro. Moreover, gastrin treatment in vitro promoted sphere formation from sorted Cck2rHdc cells, and increased chromogranin A and phosphorylated- extracellular signal-regulated kinase expression in CCK2R-derived organoids. Gastrin activates extracellular signal-regulated kinase pathways in vivo and in vitro, and treatment with the Mitogen-activated protein kinase kinase 1 inhibitor U0126 blocked hypergastrinemia-mediated changes, including CCK2R-derived ECL cell hyperplasia in vivo as well as sphere formation and chromogranin A expression in vitro.

Conclusions: We show here that hypergastrinemia induces ECL cell hyperplasia that is derived primarily from CCK2R progenitors in the corpus. Gastrin-dependent function of CCK2R progenitors is regulated by the extracellular signal-regulated kinase pathway.
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http://dx.doi.org/10.1016/j.jcmgh.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371950PMC
July 2021

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

Roadmap for the Emerging Field of Cancer Neuroscience.

Cell 2020 04;181(2):219-222

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, DKTK & Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany.

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.
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http://dx.doi.org/10.1016/j.cell.2020.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286095PMC
April 2020

Gastrointestinal Symptoms and Coronavirus Disease 2019: A Case-Control Study From the United States.

Gastroenterology 2020 Jul 12;159(1):373-375.e2. Epub 2020 Apr 12.

Division of Digestive and Liver Diseases, Columbia University Irving Medical Center-New York Presbyterian Hospital, New York, New York. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152871PMC
July 2020

Generation and Characterization of Patient-Derived Head and Neck, Oral, and Esophageal Cancer Organoids.

Curr Protoc Stem Cell Biol 2020 06;53(1):e109

Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

Esophageal cancers comprise adenocarcinoma and squamous cell carcinoma, two distinct histologic subtypes. Both are difficult to treat and among the deadliest human malignancies. We describe protocols to initiate, grow, passage, and characterize patient-derived organoids (PDO) of esophageal cancers, as well as squamous cell carcinomas of oral/head-and-neck and anal origin. Formed rapidly (<14 days) from a single-cell suspension embedded in basement membrane matrix, esophageal cancer PDO recapitulate the histology of the original tumors. Additionally, we provide guidelines for morphological analyses and drug testing coupled with functional assessment of cell response to conventional chemotherapeutics and other pharmacological agents in concert with emerging automated imaging platforms. Predicting drug sensitivity and potential therapy resistance mechanisms in a moderate-to-high throughput manner, esophageal cancer PDO are highly translatable in personalized medicine for customized esophageal cancer treatments. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Generation of esophageal cancer PDO Basic Protocol 2: Propagation and cryopreservation of esophageal cancer PDO Basic Protocol 3: Imaged-based monitoring of organoid size and growth kinetics Basic Protocol 4: Harvesting esophageal cancer PDO for histological analyses Basic Protocol 5: PDO content analysis by flow cytometry Basic Protocol 6: Evaluation of drug response with determination of the half-inhibitory concentration (IC ) Support Protocol: Production of RN in HEK293T cell conditioned medium.
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http://dx.doi.org/10.1002/cpsc.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350550PMC
June 2020

Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis.

Cell Stem Cell 2020 05 5;26(5):739-754.e8. Epub 2020 Mar 5.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address:

Cancer is believed to arise from stem cells, but mechanisms that limit the acquisition of mutations and tumor development have not been well defined. We show that a +4 stem cell (SC) in the gastric antrum, marked by expression of Cck2r (a GPCR) and Delta-like ligand 1 (DLL1), is a label-retaining cell that undergoes predominant asymmetric cell division. This +4 antral SC is Notch1/ Numb and repressed by signaling from gastrin-expressing endocrine (G) cells. Chemical carcinogenesis of the stomach is associated with loss of G cells, increased symmetric stem cell division, glandular fission, and more rapid stem cell lineage tracing, a process that can be suppressed by exogenous gastrin treatment. This hormonal suppression is associated with a marked reduction in gastric cancer mutational load, as revealed by exomic sequencing. Taken together, our results show that gastric tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling.
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http://dx.doi.org/10.1016/j.stem.2020.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214188PMC
May 2020

GPR30-Expressing Gastric Chief Cells Do Not Dedifferentiate But Are Eliminated via PDK-Dependent Cell Competition During Development of Metaplasia.

Gastroenterology 2020 05 4;158(6):1650-1666.e15. Epub 2020 Feb 4.

Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, Japan.

Background & Aims: Gastric chief cells, a mature cell type that secretes digestive enzymes, have been proposed to be the origin of metaplasia and cancer through dedifferentiation or transdifferentiation. However, studies supporting this claim have had technical limitations, including issues with the specificity of chief cell markers and the toxicity of drugs used. We therefore sought to identify genes expressed specifically in chief cells and establish a model to trace these cells.

Methods: We performed transcriptome analysis of Mist1-CreERT-traced cells, with or without chief cell depletion. Gpr30-rtTA mice were generated and crossed to TetO-Cre mice, and lineage tracing was performed after crosses to R26-TdTomato mice. Additional lineage tracing experiments were performed using Mist1-CreERT, Kitl-CreERT, Tff1-Cre, and Tff2-Cre mice crossed to reporter mice. Mice were given high-dose tamoxifen or DMP-777 or were infected with Helicobacter pylori to induce gastric metaplasia. We studied mice that expressed mutant forms of Ras in gastric cells, using TetO-Kras, LSL-Kras, and LSL-Hras mice. We analyzed stomach tissues from GPR30-knockout mice. Mice were given dichloroacetate to inhibit pyruvate dehydrogenase kinase (PDK)-dependent cell competition.

Results: We identified GPR30, the G-protein-coupled form of the estrogen receptor, as a cell-specific marker of chief cells in gastric epithelium of mice. Gpr30-rtTA mice crossed to TetO-Cre;R26-TdTomato mice had specific expression of GPR30 in chief cells, with no expression noted in isthmus stem cells or lineage tracing of glands. Expression of mutant Kras in GPR30 chief cells did not lead to the development of metaplasia or dysplasia but, instead, led to a reduction in labeled numbers of chief cells and a compensatory expansion of neck lineage, which was derived from upper Kitl clones. Administration of high-dose tamoxifen, DMP-777, or H pylori decreased the number of labeled chief cells. Chief cells were eliminated from epithelia via GPR30- and PDK-dependent cell competition after metaplastic stimuli, whereas loss of GRP30 or inhibition of PDK activity preserved chief cell numbers and attenuated neck lineage cell expansion.

Conclusions: In tracing studies of mice, we found that most chief cells are lost during metaplasia and therefore are unlikely to contribute to gastric carcinogenesis. Expansion of cells that coexpress neck and chief lineage markers, known as spasmolytic polypeptide-expressing metaplasia, does not occur via dedifferentiation from chief cells but, rather, through a compensatory response from neck progenitors to replace the eliminated chief cells.
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http://dx.doi.org/10.1053/j.gastro.2020.01.046DOI Listing
May 2020

antibiotic eradication coupled with a chemically defined diet in INS-GAS mice triggers dysbiosis and vitamin K deficiency resulting in gastric hemorrhage.

Gut Microbes 2020 07 19;11(4):820-841. Epub 2020 Jan 19.

Division of Comparative Medicine, Massachusetts Institute of Technology , Cambridge, MA, USA.

Infection with causes chronic inflammation and is a risk factor for gastric cancer. Antibiotic treatment or increased dietary folate prevents gastric carcinogenesis in male INS-GAS mice. To determine potential synergistic effects, -infected male INS-GAS mice were fed an amino acid defined (AAD) diet with increased folate and were treated with antibiotics after 18 weeks of infection. Antibiotic therapy decreased gastric pathology, but dietary folate had no effect. However, the combination of antibiotics and the AAD diet induced anemia, gastric hemorrhage, and mortality. Clinical presentation suggested hypovitaminosis K potentially caused by dietary deficiency and dysbiosis. Based on current dietary guidelines, the AAD diet was deficient in vitamin K. Phylloquinone administered subcutaneously and via a reformulated diet led to clinical improvement with no subsequent mortalities and increased hepatic vitamin K levels. We characterized the microbiome and menaquinone profiles of antibiotic-treated and antibiotic-free mice. Antibiotic treatment decreased the abundance of menaquinone producers within orders and . PICRUSt predicted decreases in canonical menaquinone biosynthesis genes, and . Reduction of from , and were confirmed in antibiotic-treated mice. The fecal menaquinone profile of antibiotic-treated mice had reduced MK5 and MK6 and increased MK7 and MK11 compared to antibiotic-free mice. Loss of menaquinone-producing microbes due to antibiotics altered the enteric production of vitamin K. This study highlights the role of diet and the microbiome in maintaining vitamin K homeostasis.
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http://dx.doi.org/10.1080/19490976.2019.1710092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524293PMC
July 2020