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Bacteria-Tumor-Drug Interactions: Investigating Bacterial Tumor Colonization and Bacterial Evolved Resistance to Anti-Cancer Therapy

Sayin, Serkan
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Student Authors
Faculty Advisor
Amir Mitchell
Academic Program
Bioinformatics and Computational Biology
UMass Chan Affiliations
Document Type
Doctoral Dissertation
Publication Date
2023-09-25
Subject Area
Embargo Expiration Date
2025-10-10
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Abstract

The human microbiome has been extensively studied, yet remains elusive due to its complexity. Recent findings showed that many solid tumors may harbor a microbiome. Bacterial presence in tumors may cause cancer progression, modify the chemical structures of anti-cancer treatments or alter the immune responses. Basic principles of how bacteria initiate a population and expand in tumors, and how they adapt to anti-cancer therapies is an underexplored area. For instance, gamma-proteobacteria found in pancreatic ductal adenocarcinomas cause chemoresistance by converting gemcitabine to its inactive form by the cytidine deaminase enzyme. Here, I first focused on this drug-bacteria interaction to understand bacterial evolution to gemcitabine and how it could affect existing bacteria-drug interactions. Using a genome-wide genetic screen, I showed that many loss-of-function mutations can cause gemcitabine resistance. I found that one-third of the resistance mutations increase or decrease bacterial drug breakdown, which can decrease or increase the gemcitabine load in the local environment. I also found that the adaptation of E. coli to gemcitabine resulted in the inactivation of the nucleoside permease NupC, which increased the drug burden on co-cultured cancer spheroids. Secondly, I focused on exploring the bacterial colonization of tumors in vivo. Using an isogenic barcoded E. coli library, I showed the presence of a narrow bottleneck during tumor colonization and skewed bacterial dissemination in the tumor environment. Overall, this study sheds light on quantitative bacterial colonization principles in tumors and intra-species bacterial adaptation to anti-cancer drugs with implications to the cancer cells.

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DOI
10.13028/cmw7-bc66
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© 2023 Serkan Sayin