Colorectal cancer detection and treatment with engineered probiotics

Gurbatri, C. R.; Radford, G.; Vrbanac, L.; Coker, C.; Im, J.; Taylor, S. R.; Jang, Y.; Sivan, A.; Rhee, K.; Saleh, A. A.; Chien, T.; Zandkarimi, F.; Lia, I.; Lannagan, T. R.; Wang, T.; Wright, J. A.; Thomas, E.; Kobayashi, H.; Ng, J. Q.; Lawrence, M.; Sammour, T.; Thomas, M.; Lewis, M.; Papanicolas, L.; Perry, J.; Fitzsimmons, T.; Kaazan, P.; Lim, A.; Marker, J.; Ostroff, C.; Rogers, G.; Arpaia, N.; Worthley, D. L.; Woods, S. L.; Danino, T.

doi:10.1101/2023.04.03.535370

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bioRxiv · 10.1101/2023.04.03.535370

Colorectal cancer detection and treatment with engineered probiotics

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Abstract

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition. We show that, after oral administration, adenomas can be monitored over time by recovering EcN from stool. We also demonstrate specific colonization of EcN to solitary neoplastic lesions in an orthotopic murine model of CRC. We then exploit this neoplasia-homing property of EcN to develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate, and demonstrate that oral delivery of this strain results in significantly increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. We also assess EcN engineered to locally release immunotherapeutics at the neoplastic site. Oral delivery to mice bearing adenomas, reduced adenoma burden by [~]50%, with notable differences in the spatial distribution of T cell populations within diseased and healthy intestinal tissue, suggesting local induction of robust anti-tumor immunity. Together, these results support the use of EcN as an orally-delivered platform to detect disease and treat CRC through its production of screening and therapeutic molecules.

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Gurbatri, C. R., Radford, G., Vrbanac, L., Coker, C., Im, J., Taylor, S. R., Jang, Y., Sivan, A., Rhee, K., Saleh, A. A., Chien, T., Zandkarimi, F., Lia, I., Lannagan, T. R., Wang, T., Wright, J. A., Thomas, E., Kobayashi, H., Ng, J. Q., Lawrence, M., Sammour, T., Thomas, M., Lewis, M., Papanicolas, L., Perry, J., Fitzsimmons, T., Kaazan, P., Lim, A., Marker, J., Ostroff, C., Rogers, G., Arpaia, N., Worthley, D. L., Woods, S. L., Danino, T.. 2023-04-05. Colorectal cancer detection and treatment with engineered probiotics. https://doi.org/10.1101/2023.04.03.535370

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