More good news for rapamycin users:
Two years ago, LUMC researchers discovered that infections with Salmonella can increase the risk of colon cancer. New research sheds light on how this bacterium, which sickens millions of people every year, can cause this. The findings provide new leads for new treatments.
How can salmonella infection lead to colon cancer?
It all revolves around a protein complex located in our cells called mTOR. This protein helps the cell decide what to do based on available energy and nutrients. You can think of mTOR as the central regulator in the cell. The protein ensures that metabolism (the process by which a cell converts substances into energy) and cell growth and division occur in a controlled manner.
The researchers found that when Salmonella infects a cell, the bacteria use nutrients from that cell to multiply. This disrupts the normal balance present in the cell, and mTOR becomes severely dysregulated. As a result, the cell becomes cancerous: the cell grows faster and begins to divide uncontrollably. “What is striking is that even when the bacteria are gone, the cell remains in a cancerous state. This increases the chances of forming tumors,” says Dr. Virginie Stévenin, who coordinated the study together with Prof. Dr. Jacques Neefjes.
Reversing damage caused by salmonella infection
The good news is that the scientists may also have found a solution to this problem. "We discovered a way to influence the multistep process of cancer formation with a previously discovered inhibitor, a substance (inhibitor) that can temporarily block the action of mTOR. After a while, we saw that this caused the cells to return to their normal state. Our laboratory research suggests that there is a way to reverse the harmful effects of Salmonella infection", Stévenin (photo) explains.
Even though she adds: “These findings remain to be tested in complex pre-clinical models to see if the inhibitor will also work on more advance stage of tumor formation. As such mTOR inhibitors are already used in clinical trials for cancer treatment, they could be used in the future as most effective treatment for colon cancer induced by Salmonella infection, and maybe from other bacteria as well.”
Open Access paper
Multi-omics analyses of cancer-linked clinical salmonellae reveal bacterial-induced host metabolic shift and mTOR-dependent cell transformation
Summary
Salmonellae are associated epidemiologically and experimentally with colon cancer. To understand how Salmonellainduces cell transformation, we performed multi-omics and phenotypic analyses of Salmonella clinical strains isolated from patients later diagnosed with colon cancer (case strains) and control strains from patients without cancer. We show that high transformation efficiency is a frequent intrinsic feature of clinical (case and control) salmonellae, yet case strains showed higher transformation efficiency than control strains. Transformation efficiency correlates with gene expression, nutrient utilization, and intracellular virulence, but not with genetic features, suggesting a phenotypic convergence of Salmonella strains resulting in cell transformation. We show that both bacterial entry and intracellular replication are required for host cell transformation and are associated with hyperactivation of the mTOR pathway. Strikingly, transiently inactivating mTOR through chemical inhibition reverses the transformation phenotype instigated by Salmonella infection. This suggests that targeting the mTOR pathway could prevent the development of Salmonella-induced tumors.
https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01282-8
