Periodic Reporting for period 4 - Tumor microbiome (The tumor microbial communities: Characterization, effects and translational opportunities)
Reporting period: 2023-11-01 to 2024-04-30
Bacteria are part of the human body, and their total number may exceed the number of human cells. While traditionally, bacteria were mostly described on the skin as well as in the gastrointestinal tract, over the last few years, it has been suggested that bacteria can also be found in human tumors. For example – our group demonstrated that bacteria can be found in human pancreatic tumors and may contribute to drug resistance. The bacteria were shown to ‘hide’ inside cancer cells, and protect the cancer cells from the commonly used anti-cancer drug gemcitabine by degrading and inactivating the drug.
In the current project, we suggested to greatly increase the characterization of the tumor microbiome, studying its effects on tumor biology, and capitalizing on the findings to introduce novel treatment modalities. We hypothesize that bacteria in tumors have a yet unknown influence on many aspects of tumor biology and that better characterization of these effects would thus lead to completely new treatment options.
In the current project, we suggested to greatly increase the characterization of the tumor microbiome, studying its effects on tumor biology, and capitalizing on the findings to introduce novel treatment modalities. We hypothesize that bacteria in tumors have a yet unknown influence on many aspects of tumor biology and that better characterization of these effects would thus lead to completely new treatment options.
During the project, we were able to characterize the bacteria that reside in human tumors in an unprecedented way. We explored a cohort of more than 1,500 human tumors originating from eight different solid tumor types. We showed that bacteria can be found in all of these tumor types and that each tumor type has a different signature of bacteria. We found that most of the bacteria in tumors are intra-cellular, mostly in cancer and immune cells, and also found some bacteria that are correlated with response to immunotherapy. We also explored the functions of bacteria in specific tumor types, looking for their correlations with clinical phenotypes. For example, we showed that in lung tumors from smokers, there is an enrichment for bacteria that can degrade nicotine as compared to lung tumors from non-smokers. We could also culture live bacteria from human tumors and are now studying these bacteria and their effects in mice cancer models.
We have done a few screens looking for the effect of bacteria on response to anti-cancer drugs and decided to follow an interesting finding in which bacteria that are present in lung cancer can reduce the sensitivity of lung cancer cells to commonly used anti-cancer treatment. We are now working on dissecting the molecular mechanism by which the bacteria mediate this effect.
We have also been using bacteria as a novel anti-cancer drug. We found that some bacteria home preferentially to tumors upon their intravenous (IV) injection. We thus use attenuated bacteria that we genetically engineer to deliver payloads to the tumor. We show that the presence of the bacteria in the tumors and the specific payloads that we add to them can activate the immune response and lead to tumor retraction in multiple mice cancer models.
We also explored the presence of fungi in tumors. In a comprehensive work that we published in 2022, we demonstrated that fungi can be found in almost all types of solid human tumors. We showed that tumor-type specific fungal signatures could be found and that the load and identity of the fungi in tumors may correlated to many clinical phenotypes, including overall survival. We were also found specific connections between bacteria, fungi, and immune cells in human tumors.
We have done a few screens looking for the effect of bacteria on response to anti-cancer drugs and decided to follow an interesting finding in which bacteria that are present in lung cancer can reduce the sensitivity of lung cancer cells to commonly used anti-cancer treatment. We are now working on dissecting the molecular mechanism by which the bacteria mediate this effect.
We have also been using bacteria as a novel anti-cancer drug. We found that some bacteria home preferentially to tumors upon their intravenous (IV) injection. We thus use attenuated bacteria that we genetically engineer to deliver payloads to the tumor. We show that the presence of the bacteria in the tumors and the specific payloads that we add to them can activate the immune response and lead to tumor retraction in multiple mice cancer models.
We also explored the presence of fungi in tumors. In a comprehensive work that we published in 2022, we demonstrated that fungi can be found in almost all types of solid human tumors. We showed that tumor-type specific fungal signatures could be found and that the load and identity of the fungi in tumors may correlated to many clinical phenotypes, including overall survival. We were also found specific connections between bacteria, fungi, and immune cells in human tumors.
Most of the tumors that we studied thus far were obtained pre-treatment. To study the effect of treatments on the microbial community in tumors, we are now studying cohorts from breast cancer patients in which the tumors were sampled both pre and post-treatment. We were able to identify bacteria that are highly enriched after therapy and are currently validating these results is additional cohorts as well as trying to understand why specific bacteria are enriched post treatment and the clinical importance of this observation.
We have previously demonstrated that specific bacteria can be found in human pancreatic tumors and can degrade the anti-cancer drug gemcitabine and thus confer drug resistance. Now, using advanced technology, which allows us to grow human tumors in the lab, we are exploring how addition to antibiotics can synergize with gemcitabine. We have also started recently a clinical trial in which we test the effect of antibiotic treatment on the response of pancreatic cancer patients to gemcitabine.
We have previously demonstrated that specific bacteria can be found in human pancreatic tumors and can degrade the anti-cancer drug gemcitabine and thus confer drug resistance. Now, using advanced technology, which allows us to grow human tumors in the lab, we are exploring how addition to antibiotics can synergize with gemcitabine. We have also started recently a clinical trial in which we test the effect of antibiotic treatment on the response of pancreatic cancer patients to gemcitabine.