Investigating gastric inflammation and preneoplastic progression driven by Helicobacter pylori infection

研究幽门螺杆菌感染驱动的胃部炎症和癌前进展

• 批准号: 10661588
• 负责人: Valerie Phoebe O'Brien
• 金额: $ 16.78万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661588
• 关键词: Abnormal Cell; Acceleration; Alleles; Atrophic Gastritis; Bacteria; Bacterial Infections; Cancer Etiology; Carcinoma; Cell Line; Cell Lineage; Cells; Cessation of life; Chronic; Colorectal Cancer; Cytotoxin; Development; Disease; Disease Progression; Dysplasia; Environment; Gastric Acid; Gastric Chief Cells; Gastric Metaplasia; Gastric Parietal Cells; Gastritis; Gene Expression; Gene Expression Profile; Genes; Gland; Goals; Guanosine Triphosphate Phosphohydrolases; Helicobacter Infections; Helicobacter pylori; Human; Immune; Immune response; Immunity; Immunotherapy; In Situ Hybridization; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intestinal Metaplasia; Intestines; KRAS2 gene; MUC4 mucin; Malignant Neoplasms; Mediating; Metaplasia; Modeling; Morphology; Mucous body substance; Mus; Mutation; Normal Cell; Oncogenic; PTPRC gene; Pathway interactions; Peptidyltransferase; Phenotype; Preneoplastic Change; Proliferating; Protein Secretion; Proteins; Research; Role; Sampling; Series; Signal Pathway; Signaling Protein; Source; Splenocyte; Stomach; Surface; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; T-cell inflamed; Tamoxifen; Techniques; Testing; Tissues; Toxin; Transgenic Organisms; Type IV Secretion System Pathway; Variant; Virulence; Virulence Factors; cancer immunotherapy; cancer risk; cell transformation; cell type; congenic; disease phenotype; experimental study; genetic approach; immunopathology; inflammatory modulation; insight; malignant stomach neoplasm; mouse model; mutant; novel; polarized cell; premalignant; prevent; progenitor; programs; protein expression; repaired; single cell sequencing; single-cell RNA sequencing; stem cells; tumor progression

Project Summary Many cancers are attributed to chronic inflammation, which can cause mutations and activate oncogenic signaling pathways. An important example is gastric cancer, the fourth-leading cause of cancer death worldwide. At least 80% of gastric cancer cases are attributed to stomach infection with the bacterium Helicobacter pylori (Hp), which causes lifelong chronic inflammation that does not eradicate the infection. In some individuals, this inflammation can cause gastric atrophy, metaplasia (conversion of one normal cell type to another), dysplasia (presence of abnormal cells) and finally cancer, but the specific mechanism(s) through which Hp triggers this cascade are not well understood. Similar preneoplastic changes are recapitulated in a mouse model through tamoxifen-induced expression of active KRAS in the chief cells of the stomach (KRAS+ mice). I found that Hp infection of KRAS+ mice exacerbated disease: compared to Hp-KRAS+ mice, Hp+KRAS+ mice had an altered trajectory of metaplasia and accelerated dysplasia. Hp+KRAS+ mice also had expansion of “variant” pit cells (surface mucous cells) that expressed metaplasia- and cancer-related genes like the mucin Muc4. In accordance with the hypothesis that Hp causes cancer through eliciting chronic inflammation, Hp+KRAS+ mice had severe inflammation marked by a ten- fold increase in T cells vs. Hp-KRAS+ mice. In this proposal I will investigate the mechanism(s) through which Hp worsens disease in KRAS+ mice, with a broader goal of better understanding how Hp infection and its associated chronic inflammation cause cancer. I hypothesize that Hp modulates the inflammatory response to prevent Hp eradication from the stomach, and this deleterious immune response leads to metaplasia and dysplasia. In Aim 1 I will perform targeted depletion of CD4+ and CD8α+ T cell subsets to assess whether immune perturbation impacts metaplasia, dysplasia and Hp colonization. I will also assess whether T cells traffic to the stomach in Hp+KRAS+ mice or proliferate locally. Finally, I will test whether Hp+ human samples have increased T cells relative to Hp- samples. In Aim 2 I will investigate candidate Hp virulence factors that modulate inflammation: the cag type IV secretion system and two proteins that modulate T cells, the toxin VacA and the transpeptidase gGT. I will determine whether virulence factor mutants can elicit the same inflammatory and disease progression phenotypes in KRAS+ mice as wild-type Hp does. In Aim 3 I will test whether variant pit cells arise from gastric progenitor cells, and will assess disease phenotypes in Hp+KRAS+MUC4- mice to determine whether Muc4 expression drives pit cell transformation. I will also perform spatial single-cell RNA sequencing in +/- Hp, +/- KRAS mice to discover whether variant pit cells share a gene expression signature with Muc4-expressing cells in the “first gland” of the stomach, a morphologically distinct gland that is believed to be a source of reparative cell lineages. Taken together, the results of these studies will provide new understanding of how Hp infection and inflammation cause gastric preneoplastic progression and may reveal new targets for gastric immunotherapy. These findings may also be applicable to other cancers associated with bacterial infection and/or inflammation, like colorectal cancer.

项目总结