Written by Nicolas Kim '26
Edited by Surya Khatri '24
Description: Genetically engineered Salmonella target tumor cells
Source: Science News
Introduction
Cancer afflicts millions worldwide every year. In spite of its prevalence, scientists are still not close to developing therapeutic measures that can unilaterally treat the variegated forms of the disease without adverse side effects. From chemotherapy to immunotherapy, current means of treating cancer are beset by their poor selectivity for tumor cells, off-target effects, and general inability to cause cancer recurrence.
Besides the common obstacles to their clinical efficacy, these treatments also target similar hallmarks of cancer cells that differentiate them from normal tissues (e.g., increased vascularization, low oxygen, low extracellular pH, etc.). As a result, these hallmarks have also served as a target for researchers seeking to develop new therapeutics able to minimize cancer progression.
History: Bacteria As Anti-Cancer Agents
In the search for a suitable therapeutic, bacteria were selected as the optimal anti-cancer agent. It was known since the 19th century that the live entrance of bacteria into cancer patients (whether intravenously or by other means) tends to reduce tumor size, but the true mechanisms behind tumor regression have not been well elucidated until now. Recently however, the emergence of new methods in computational genetics has brought the field of synthetic biology to the fore as a means to diagnose and develop new means for treating cancer [1, 2]. As a result, synthetic biology has started to be leveraged as a way to engineer the genetic circuits of bacteria to deliver therapeutic payloads (e.g., tumor inhibiting enzymes) to tumor cells, using their natural propensity for colonizing tumors as an aid (also reducing the need for additional measures to make them selective for tumors) [3].
In particular, the use of probiotic bacteria, live bacteria that have beneficial properties when ingested, has been especially explored for cancer treatments due to their “safeness” and/or anticancer properties in certain contexts. For example, S. typhimurium is a bacterium that selectively colonizes cancer cells due to its attraction to metabolites produced on their surface. Post-colonization, S. typhimurium can induce mass cancer cell death by means ranging from programmed cell death to rupturing the cell membrane. These anticancer properties are not restricted to S. typhimurium; other species ranging from Salmonella, Listeria, to Clostridium also target tumors through various means, whether it be through the release of cytotoxic proteins within cancerous cells or the recruitment of immune cells to the area of tumor growth [4, 5].
Current Advancements: E. Coli as a Diagnostic Tool
In 2015, researchers took advantage of the selectivity of a strain of bacteria, E. coli Nissle 1917, to develop a natural, orally ingested, diagnostic tool for measuring the amount of cancer metastasis in liver cells. First, they engineered the strain by inserting an external piece of genetic material (a plasmid) specifically constructed to express a light-emitting enzyme (lac-Z) into the bacterial cells [6]. The luminescent properties of this enzyme are caused by its cleavage of its specific substrate, or biological molecule, that it binds to in order to speed up a biological process (i.e., light emittance). Since lac-Z solely has specificity for a substrate (IPTG) released by metastatic tumors in the liver, it will only produce cleaved substrates that give off light upon contact with said tumors.
Knowing this, the researchers then made their experimental group of mice ingest the bacteria (with the engineered plasmid expressing lac-Z) orally, while simultaneously injecting a strain of metastatic tumor cells into them, thus making it possible for the probiotics to amplify selectively within their liver. The release of lac-Z by the bacteria then allowed for the cleavage of substrates that were then filtered out through the liver, leading to the presence of cleavage products in the urine of the mice (that were then detectable by fluorescent imaging). The results of this study ultimately showed that the E. coli Nissle 1917 did not colonize healthy tissues in the mice, nor did they produce negative health effects on the mice over a long period of time. Moreover, the diagnostic proved the potential for probiotics to be engineered to deliver therapeutics to tumors within the body.
Future Steps
However, in spite of the success of this study, there are still momentous challenges in the clinical development of bacteria-engineered therapeutics. From continued off-target effects on healthy tissues to their inability to fully eradicate tumors within the body, the variegated means for engineering live organisms to colonize and kill tumors has still a long way to go before entering the mainstream wave of cancer treatments [1]. However, the future looks bright for these new therapeutics stealing the scene, especially as it uplifts the organisms traditionally pathologized to the fore of human medicine.
References
1. Bao, Y., Cheng, Y., Liu, W., Luo, W., Zhou, P., & Qian, D. (2022). Bacteria-Based Synergistic Therapy in the Backdrop of Synthetic Biology. Frontiers in oncology, 12, 845346. https://doi.org/10.3389/fonc.2022.845346
2. Sieow, B. F., Wun, K. S., Yong, W. P., Hwang, I. Y., & Chang, M. W. (2021). Tweak to Treat: Reprogramming Bacteria for Cancer Treatment. Trends in cancer, 7(5), 447–464. https://doi.org/10.1016/j.trecan.2020.11.004
3. Harimoto, T., Singer, Z. S., Velazquez, O. S., Zhang, J., Castro, S., Hinchliffe, T. E., Mather, W., & Danino, T. (2019). Rapid screening of engineered microbial therapies in a 3D multicellular model. Proceedings of the National Academy of Sciences of the United States of America, 116(18), 9002–9007. https://doi.org/10.1073/pnas.1820824116
4. Leventhal, D. S., Sokolovska, A., Li, N., Plescia, C., Kolodziej, S. A., Gallant, C. W., Christmas, R., Gao, J. R., James, M. J., Abin-Fuentes, A., Momin, M., Bergeron, C., Fisher, A., Miller, P. F., West, K. A., & Lora, J. M. (2020). Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nature communications, 11(1), 2739.
5. Wei, C., Xun, A. Y., Wei, X. X., Yao, J., Wang, J. Y., Shi, R. Y., Yang, G. H., Li, Y. X., Xu, Z. L., Lai, M. G., Zhang, R., Wang, L. S., & Zeng, W. S. (2016). Bifidobacteria Expressing Tumstatin Protein for Antitumor Therapy in Tumor-Bearing Mice. Technology in cancer research & treatment, 15(3), 498–508. https://doi.org/10.1177/1533034615581977https://doi.org/10.1038/s41467-020-16602-0
6. Danino, T., Prindle, A., Kwong, G. A., Skalak, M., Li, H., Allen, K., Hasty, J., & Bhatia, S. N. (2015). Programmable probiotics for detection of cancer in urine. Science translational medicine, 7(289), 28984. https://doi.org/10.1126/scitranslmed.aaa3519
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