Exploiting activation of senescence tumour suppressor mechanisms by Salmonella enterica for the treatment of cancer

Details

Background

Typhoid toxin is a DNase-like virulence factor of the human pathogen Salmonella Javiana, which intoxicates cells throughout the microenvironment. We discovered that the toxin induces DNA damage responses in cultured cells that activates a senescence tumour suppressor mechanism (https://doi.org/10.1038/s41467-019-12064-1). Cells undergoing toxin-induced senescence undergo permanent cell-cycle arrest and release a secretome (https://doi.org/10.1016/j.celrep.2023.113181), which causes paracrine senescence and attracts immune cells to eliminate senescent cells. Despite these advances, toxin-induced senescence by Salmonella has not been investigated in an animal infection model. Senescence is a major defence against cancer, which causes 10 million deaths annually. Bacterial cancer therapy (BCT) shows promise for treatment of solid tumours, of which, attenuated Salmonella Typhimurium is the best studied. Salmonella is extremely tumour tropic, selectively colonising tumour-tissue over healthy tissue, and activates innate immune responses. However, Salmonella Typhimurium does not encode typhoid toxin and, thus, we hypothesise that treating cancerous tissue with attenuated Salmonella Javiana instead would enhance BCT through the typhoid toxin that would cause senescence and further inhibit tumour development.

Objectives

Thus, we seek an enthusiastic PhD student to: (i) Study toxin-induced senescence in a human cell and mouse infection models, and (ii) investigate whether toxin-induced senescence can be exploited to improve BCT.

Novelty and Timeliness

The project will advance understanding of Salmonella-induced senescence by revealing the mechanism in vivo and how this can be exploited to improve health. This aligns with MRC Research Priorities in securing better health, ageing, wellbeing, and combatting infections. Chemotherapy and radiotherapy are life savers following cancer diagnosis but they damage healthy tissues – novel treatment strategies are required. The project is timely given the phase-1 trials using Salmonella to treat bladder cancer and the rise in cancer diagnoses. For example, the colon is the natural host tissue of Salmonella, and colon cancer is the fourth most common cause of cancer death in the UK with over 40,000 new cases diagnosed in 2024.

Experimental approach

Biochemical and molecular approaches will purify typhoid toxin and engineer attenuated Salmonella Javiana, which will induce senescence in mouse cancer cells in vitro prior to injection into a mouse before assessing effects on metastasis. AOM/DSS model of Colitis-Associated Cancer will be used to determine whether Salmonella infection reduces the number of tumours in a toxin-dependent manner. The effect of senescence on metastasis and tumour development will be quantified and imaged using IVIS Imaging, and senescence analysed using microbiology, immunoblotting, RNA sequencing and fluorescence microscopy.

Funding Notes

Self-funded applicants desired

References

Supervisor references

Srour et al. 2025, EMBO Mol Med (https://doi.org/10.1038/s44321-025-00347-8)

ElGhazaly et al., 2023, Cell Reports (https://doi.org/10.1016/j.celrep.2023.113181)

Ibler et al. 2023, Nat Commun (https://doi.org/10.1038/s41467-019-12064-1)

Relevant review on BCT

Badie et al 2021, Frontiers in Oncology, (10.3389/fonc.2021.624759)