Microbial signals in primary and metastatic brain tumors
Golnaz Morad, Ashish Damania, Brenda Melendez, Bharat Singh, Fabiana J. Veguilla, Rebecca Soto, Yasmine Hoballah, Pranoti Sahasrabhojane, Matthew C. Wong, Mona M. Ahmed, Rene N. Rico, Kaitlyn N. Lewis, Khalida Wani, Diana Shamsutdinova, Rossana N. Lazcano Segura, Davis R. Ingram, Eric A. Goethe, Abderrahman Day, Ivonne I. Flores, Lauren McDaniel, Manoj Chelvanambi, Sarah B. Johnson, Florentia Dimitriou, Pravesh Gupta, Shivangi Oberai, Malgorzata Anna Zal, Phoebe Doss, Mohamed A. Jamal, Eiko Hayase, Chetna Wathoo, Lisa Norberg, Stephanie L. Jenkins, Sara Nass, Joy Gumin, Lihong Long, Jing Yang, Gina R. Bradley, Mahesh Bekal, Antonio Dono, Pavel S. Pichardo‐Rojas, Samuel W. Andrewes, Leomar Y. Ballester, Jillian Losh, Jiyong Liang, Longfei Huo, Douglas C. Nielsen, Brittany C. Parker Kerrigan, Priscilla K. Brastianos, Natalie W. Fowlkes, Chia‐Chi Chang, Robert R. Jenq, Candelaria Gomez‐Manzano, Jason T. Huse, Michael A. Davies, Alexander J. Lazar, Krishna Bhat, Nitin Tandon, Yoshua Esquenazi, Christine B. Peterson, Vinay K. Puduvalli, Frederick F. Lang, Christopher D. Johnston, Susan Bullman, Nadim J. Ajami, Sherise D. Ferguson, Jennifer A. Wargo
Abstract
Gliomas and brain metastases are associated with poor prognosis, necessitating a deeper understanding of brain tumor biology and the development of effective therapeutic strategies. Although our group and others have demonstrated microbial presence in various tumors, recent controversies regarding cancer-type-specific intratumoral microbiota emphasize the importance of rigorous, orthogonal validation. This prospective, multi-institutional study included a total of 243 samples from 221 patients, comprising 168 glioma and brain metastases samples and 75 non-cancerous or tumor-adjacent tissues. Using stringent fluorescence in situ hybridization, immunohistochemistry and high-resolution spatial imaging, we detected intracellular bacterial 16S rRNA and lipopolysaccharides in both glioma and brain metastases samples, localized to tumor, immune and stromal cells. Custom 16S and metagenomic sequencing workflows identified taxa associated with intratumoral bacterial signals in the tumor microenvironment; however, standard culture methods did not yield readily cultivable microbiota. Spatial analyses revealed significant correlations between bacterial 16S signals and antimicrobial and immunometabolic signatures at regional, neighborhood and cellular levels. Furthermore, intratumoral 16S bacterial signals showed sequence overlap with matched oral and gut microbiota, suggesting a possible connection with distant communities. Together, these findings introduce microbial elements as a component of the brain tumor microenvironment and lay the foundation for future mechanistic and translational studies.