About Our Laboratory, TranSiR

1) Molecular Basis of Gastric Cancer Development in Helicobacter pylori-Infected Individuals

  Gastric cancer remains a major global health concern, causing over 720,000 deaths annually. Infection with Helicobacter pylori is the most decisive risk factor for gastric cancer. Among its virulence factors, the bacterial oncoprotein CagA is known to induce malignant transformation in host cells (Cell Host Microbe, 15:306–16, 2014). However, only about 3% of H. pylori-infected individuals develop gastric cancer (Nat. Rev. Gastroenterol. Hepatol., 15:458–460, 2018), suggesting that cancer development occurs selectively in a subset of infected hosts.

    Our research aims to elucidate the molecular mechanisms that determine why certain H. pylori-infected individuals progress to gastric cancer.

We have previously demonstrated that the emergence of CD44v9-positive cancer stem-like cells in H. pylori-infected gastric mucosa is significantly associated with metachronous recurrence of gastric cancer. Furthermore, we discovered that while CagA is normally degraded via autophagy, its accumulation occurs in cells overexpressing CAPZA1, due to impaired autophagy caused by suppressed LAMP1 expression.

Importantly, these CAPZA1-overexpressing cells not only stabilize CagA but also acquire CD44v9-positive stem-like properties. We propose that the emergence of CAPZA1-overexpressing cells in the infected gastric mucosa represents a critical early selection step toward gastric carcinogenesis.

Currently, our research focuses on two key questions:

1. What signaling mechanisms in the gastric environment induce CAPZA1 overexpression?

2. What is the original physiological role of CAPZA1-overexpressing cells?

(References)

1. Tsugawa H, Kato C, Mori H, Matsuzaki J, Kameyama K, Saya H, Hatakeyama M, Suematsu M, Suzuki H. Cancer stem-cell marker CD44v9-positive cells arise from Helicobacter pylori-infected CAPZA1-overexpressing cells. Cell. Mol. Gastroenterol. Hepatol., 8(3): 319-334, 2019. 

2. Tsugawa H, Mori H, Matsuzaki J, Sato A, Saito Y, Imoto M, Suematsu M, Suzuki H. CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobcater pylori CagA-degraded autophagy. Autophagy, 15(2): 242-258, 2019. 

3. Hirata K, Suzuki H, Imaeda H, Matsuzaki J, Tsugawa H, Nagano O, Asakura K, Saya H, Hibi T. CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. Br. J. Cancer, 109(2):379-386, 2013. 

4. Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, Nagano O, Matsuzaki J, Hibi T. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe, 12(6):764-777, 2012. 

2) Molecular Insights into the Role of Gut Commensal Pathobiont Bacteria on Systemic Disesase

  Aging leads to a decline in immune system function, significantly impairing the body's ability to combat pathogens. As a result, elderly individuals are more vulnerable to various infections, some of which can become life-threatening. Understanding the molecular mechanisms underlying age-related changes that promote susceptibility to infection is a critical step toward developing technologies to protect older adults from infectious diseases.

   Klebsiella pneumoniae is a gut-resident commensal bacterium that also exists in natural environments such as soil, water, and plants. In healthy young individuals, it typically remains non-pathogenic. However, in immunocompromised or elderly individuals, it can cause severe systemic infections, including pneumonia, liver abscesses, and urinary tract infections. Most K. pneumoniae infections originate from strains residing in the gut, and liver abscesses are believed to result from direct translocation of these bacteria from the intestine to the liver.

   Our previous studies have revealed that intestinal macrophages play a crucial role in recognizing K. pneumoniae and preventing its dissemination to the liver. Building on these findings, we are now investigating the molecular mechanisms by which K. pneumoniae contributes to systemic infections beyond the initial site of colonization.

(References)

1. Tsugawa H*, Tsubaki S, Tanaka R, Nashimoto S, Imai J, Matsuzaki J, Hozumi K. Macrophage-depleted young mice are beneficial in vivo models to assess the translocation of Klebsiella　pneumonia from the gastrointestinal tract to the liver in the elderly. Microbes Infect., 26:105371, 2024.

2. Tanaka R, Imai J, Sugiyama E, Tsubaki S, Hozumi K, Tsugawa H*. Cyclic-di-AMP confers an invasive phenotype on Escherichia coli through elongation of flagellin filaments. Gut Pathogens, 16: 6, 2024. 

3. Tsugawa H*, Ohki T, Tsubaki S, Tanaka R, Matsuzaki J, Suzuki H, Hozumi K. Gas6 ameliorates intestinal mucosal immunosenescence to prevent the translocation of a gut pathobiont, Klebsiella pneumoniae, to the liver. PLoS Pathogens, 19(6): e1011139, 2023. 

4. Tanaka R, Imai J, Tsugawa H, Eap Bil K, Yazawa M, Kaneko M, Ohno M, Sugihara K, Kitamoto S, Nagao-Kitamoto H, Barnich N, Matsushima M, Suzuki T, Kagawa T, Nishizaki Y, Suzuki H, Kamada N, Hozumi K. Adherent-invasive E. coli – induced specific IgA limits pathobiont localization to the epithelial niche in the gut. Frontiers in Microbiology, 14: 1031997, 2023. 

5. Tsugawa H, Kabe Y, Kanai A, Sugiura Y, Hida S, Taniguchi S, Takahashi T, Matsui H, Yasukawa Z, Itou H, Takubo K, Suzuki H, Honda K, Handa H, Suematsu M. Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection. PLoS Biology, 18(9): e3000813, 2020.