TY - JOUR
T1 - The Tumor Microbiome Reacts to Hypoxia and Can Influence Response to Radiation Treatment in Colorectal Cancer
AU - for the exORIEN Consortium
AU - Benej, Martin
AU - Hoyd, Rebecca
AU - Kreamer, McKenzie
AU - Wheeler, Caroline E.
AU - Grencewicz, Dennis J.
AU - Choueiry, Fouad
AU - Chan, Carlos H.F.
AU - Zakharia, Yousef
AU - Ma, Qin
AU - Dodd, Rebecca D.
AU - Ulrich, Cornelia M.
AU - Hardikar, Sheetal
AU - Churchman, Michelle L.
AU - Tarhini, Ahmad A.
AU - Robinson, Lary A.
AU - Singer, Eric A.
AU - Ikeguchi, Alexandra P.
AU - McCarter, Martin D.
AU - Tinoco, Gabriel
AU - Husain, Marium
AU - Jin, Ning
AU - Tan, Aik C.
AU - Osman, Afaf E.G.
AU - Eljilany, Islam
AU - Riedlinger, Gregory
AU - Schneider, Bryan P.
AU - Benejova, Katarina
AU - Kery, Martin
AU - Papandreou, Ioanna
AU - Zhu, Jiangjiang
AU - Denko, Nicholas
AU - Spakowicz, Daniel
N1 - Publisher Copyright:
©2024 The Authors;
PY - 2024/7
Y1 - 2024/7
N2 - Tumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiation’s ability to kill cells. We hypothesized that some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. Therefore, we examined the RNA sequencing data from the Oncology Research Information Exchange Network database of patients with colorectal cancer treated with radiotherapy. We identified microbial RNAs for each tumor and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such as Fusobacterium nucleatum. The presence of other microbes, such as Fusobacterium canifelinum, predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To experimentally investigate this concept, we implanted CT26 colorectal cancer cells into immune-competent BALB/c and immune-deficient athymic nude mice. After growth, in which tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed a metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-tropic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Thus, hypoxia gene expression scores seem to associate with different microbial populations and elicit an adaptive transcriptional response in intratumoral microbes, potentially influencing clinical outcomes. Significance: Tumor hypoxia reduces radiotherapy efficacy. In this study, we explored whether some of the clinical effects of hypoxia could be due to interaction with the tumor microbiome. Hypoxic gene expression scores associated with certain microbes and elicited an adaptive transcriptional response in others that could contribute to poor clinical outcomes.
AB - Tumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiation’s ability to kill cells. We hypothesized that some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. Therefore, we examined the RNA sequencing data from the Oncology Research Information Exchange Network database of patients with colorectal cancer treated with radiotherapy. We identified microbial RNAs for each tumor and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such as Fusobacterium nucleatum. The presence of other microbes, such as Fusobacterium canifelinum, predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To experimentally investigate this concept, we implanted CT26 colorectal cancer cells into immune-competent BALB/c and immune-deficient athymic nude mice. After growth, in which tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed a metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-tropic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Thus, hypoxia gene expression scores seem to associate with different microbial populations and elicit an adaptive transcriptional response in intratumoral microbes, potentially influencing clinical outcomes. Significance: Tumor hypoxia reduces radiotherapy efficacy. In this study, we explored whether some of the clinical effects of hypoxia could be due to interaction with the tumor microbiome. Hypoxic gene expression scores associated with certain microbes and elicited an adaptive transcriptional response in others that could contribute to poor clinical outcomes.
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U2 - 10.1158/2767-9764.CRC-23-0367
DO - 10.1158/2767-9764.CRC-23-0367
M3 - Article
C2 - 38904265
AN - SCOPUS:85198677559
SN - 2767-9764
VL - 4
SP - 1690
EP - 1701
JO - Cancer Research Communications
JF - Cancer Research Communications
IS - 7
ER -