Introduction Understanding which genes restrain gastric tumor growth—and how host factors like Helicobacter pylori shape tumor biology—remains central to precision prevention and therapy. CRISPR-Cas9 loss-of-function screening offers a scalable way to discover tumor suppressors, but most screens are performed in vitro and miss key in vivo pressures such as immunity and microbial influences.
Introduction
Understanding which genes restrain gastric tumor growth—and how host factors like Helicobacter pylori shape tumor biology—remains central to precision prevention and therapy. CRISPR-Cas9 loss-of-function screening offers a scalable way to discover tumor suppressors, but most screens are performed in vitro and miss key in vivo pressures such as immunity and microbial influences. This study builds an organoid-based in vivo CRISPR platform to identify gastric tumor suppressors in both ectopic (subcutaneous) and orthotopic (stomach) settings.
Summary (≈200 words)
Using murine gastric organoids, the authors performed in vivo CRISPR knockout screening with (1) a custom library targeting 49 putative gastric tumor suppressors and (2) a genome-scale “cancer” library targeting ~5000 genes. Screens were conducted across immunocompetent and immunodeficient mice, with and without H pylori infection, and in both subcutaneous and surgically implanted orthotopic tumor models. Recurrently enriched guides identified Pten, Fbxw7, and multiple TGF-β pathway components (Smad4, Tgfbr1, Tgfbr2, Acvr2a) as consistent tumor suppressor hits across models; genome-scale screening confirmed these and revealed additional candidates. The top hits were individually validated in vivo. Mechanistically, Pten loss drove large, highly vascular tumors with neutrophil recruitment and T-cell exclusion, highlighting an immune-evasive, pro-angiogenic state. In contrast, loss of Smad4, Tgfbr1, or Acvr2a produced lesions resembling early gastric precancer states, including Alcian blue–positive intestinal metaplasia and compensatory hyperplasia. Notably, H pylori did not change the tumor mutational landscape; instead, it primarily reshaped the tumor microenvironment, promoting influx of tumour-supporting SiglecF⁺ neutrophils. Overall, the work introduces a versatile in vivo organoid-CRISPR platform that separates tumor genetics from host factors while capturing clinically relevant gastric cancer biology.
Introduction: Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with poor prognosis and limited treatment options. While ICC has traditionally been considered a malignancy of biliary epithelial cells, increasing evidence suggests that hepatocytes can...
Introduction: Liver fibrosis is the key determinant of long-term outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Activated hepatic stellate cells (HSCs) drive fibrogenesis, but effective antifibrotic therapies remain unavailable. This study investigated whether blocking the succinate–GPR91...
Introduction: The progression from metabolic dysfunction-associated fatty liver (MAFL) to metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex interactions between hepatocytes and immune cells. This study identifies a novel spatial mechanism in the periportal (PP)...
Introduction: Cardiovascular–Kidney–Metabolic (CKM) syndrome recognizes the close interaction between obesity, type 2 diabetes, chronic kidney disease, and cardiovascular disease. This review highlights the emerging role of the gut microbiome, particularly butyrate-producing bacteria, as a central...
• Small intestinal adenocarcinoma (SIA) is a rare gastrointestinal cancer with limited disease-specific prognostic biomarkers and generally poor outcomes. • This nationwide Dutch population-based study evaluated whether three routinely available immunohistochemical markers—CK7, CK20, and CDX2—have...
Introduction: Metabolic dysfunction–associated steatotic liver disease (MASLD) is closely linked to insulin resistance and type 2 diabetes, with the liver traditionally viewed as a key regulator of blood glucose through hepatic glucose production. However, emerging...
We are pioneers in clinical intelligence, dedicated to helping gastroenterologists harness the power of artificial intelligence to drive precision, efficiency, and patient growth.