Spatial meta-transcriptomics reveal associations of intratumor bacteria burden with lung cancer cells showing a distinct oncogenic signature
Abigail Wong-Rolle, Qiang Dong, Yunhua Zhu, Prajan Divakar, Jyh Liang Hor, Noemi Kedei, Madeline Wong, Desiree Tillo, Elizabeth A Conner, Arun Rajan, David S Schrump, Chengcheng Jin, Ronald N Germain, Chen Zhao, Abigail Wong-Rolle, Qiang Dong, Yunhua Zhu, Prajan Divakar, Jyh Liang Hor, Noemi Kedei, Madeline Wong, Desiree Tillo, Elizabeth A Conner, Arun Rajan, David S Schrump, Chengcheng Jin, Ronald N Germain, Chen Zhao
Abstract
Background: The lung intratumor microbiome influences lung cancer tumorigenesis and treatment responses, but detailed data on the extent, location, and effects of microbes within lung tumors are missing, information needed for improved prognosis and treatment.
Methods: To address this gap, we developed a novel spatial meta-transcriptomic method simultaneously detecting the expression level of 1,811 host genes and 3 microbe targets (bacteria, fungi, and cytomegalovirus). After rigorous validation, we analyzed the spatial meta-transcriptomic profiles of tumor cells, T cells, macrophages, other immune cells, and stroma in surgically resected tumor samples from 12 patients with early-stage lung cancer.
Results: Bacterial burden was significantly higher in tumor cells compared with T cells, macrophages, other immune cells, and stroma. This burden increased from tumor-adjacent normal lung and tertiary lymphoid structures to tumor cells to the airways, suggesting that lung intratumor bacteria derive from the latter route of entry. Expression of oncogenic β-catenin was strongly correlated with bacterial burden, as were tumor histological subtypes and environmental factors.
Conclusions: Intratumor bacteria were enriched with tumor cells and associated with multiple oncogenic pathways, supporting a rationale for reducing the local intratumor microbiome in lung cancer for patient benefit.
Trial registration number: NCT00242723, NCT02146170.
Keywords: lung neoplasms; translational medical research; tumor microenvironment.
Conflict of interest statement
Competing interests: PD is an employee and stockholder at NanoString Technologies. All other authors declare no competing interests. YZ is currently an employee at GlaxoSmithKline. All other authors declare no competing interests.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
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References
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7–30. 10.3322/caac.21590
- Thai AA, Solomon BJ, Sequist LV, et al. . Lung cancer. Lancet 2021;398:535–54. 10.1016/S0140-6736(21)00312-3
- Liu N-N, Ma Q, Ge Y, et al. . Microbiome dysbiosis in lung cancer: from composition to therapy. NPJ Precis Oncol 2020;4:33. 10.1038/s41698-020-00138-z
- Man WH, de Steenhuijsen Piters WAA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol 2017;15:259–70. 10.1038/nrmicro.2017.14
- Wong-Rolle A, Wei HK, Zhao C, et al. . Unexpected guests in the tumor microenvironment: microbiome in cancer. Protein Cell 2021;12:426–35. 10.1007/s13238-020-00813-8
- Dong Q, Chen ES, Zhao C, et al. . Host-Microbiome interaction in lung cancer. Front Immunol 2021;12:679829. 10.3389/fimmu.2021.679829
- Jin C, Lagoudas GK, Zhao C, et al. . Commensal microbiota promote lung cancer development via γδ T cells. Cell 2019;176:e101610.1016/j.cell.2018.12.040
- Nejman D, Livyatan I, Fuks G, et al. . The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368:973–80. 10.1126/science.aay9189
- Kalaora S, Nagler A, Nejman D, et al. . Identification of bacteria-derived HLA-bound peptides in melanoma. Nature 2021;592:138–43. 10.1038/s41586-021-03368-8
- Delorey TM, Ziegler CGK, Heimberg G, et al. . COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 2021;595:107–13. 10.1038/s41586-021-03570-8
- Merritt CR, Ong GT, Church SE, et al. . Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat Biotechnol 2020;38:586–99. 10.1038/s41587-020-0472-9
- Danaher P, et al. . Advances in mixed cell deconvolution enable quantification of cell types in spatially-resolved gene expression data. bioRxiv 2020.
- Lambrechts D, Wauters E, Boeckx B, et al. . Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med 2018;24:1277–89. 10.1038/s41591-018-0096-5
- Guo X, Zhang Y, Zheng L, et al. . Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med 2018;24:978–85. 10.1038/s41591-018-0045-3
- Zilionis R, Engblom C, Pfirschke C, et al. . Single-Cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 2019;50:1317–34. 10.1016/j.immuni.2019.03.009
- Krämer A, Green J, Pollard J, et al. . Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 2014;30:523–30. 10.1093/bioinformatics/btt703
- Valvani A, Martin A, Devarajan A, et al. . Postobstructive pneumonia in lung cancer. Ann Transl Med 2019;7:357. 10.21037/atm.2019.05.26
- Dieu-Nosjean M-C, Antoine M, Danel C, et al. . Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008;26:4410–7. 10.1200/JCO.2007.15.0284
- Lavin Y, Kobayashi S, Leader A, et al. . Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 2017;169:750–65. 10.1016/j.cell.2017.04.014
- Lin Z, Huang L, Li S, et al. . Pan-cancer analysis of genomic properties and clinical outcome associated with tumor tertiary lymphoid structure. Sci Rep 2020;10:21530. 10.1038/s41598-020-78560-3
- Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721–32. 10.1038/nrc1187
- Rutkowski MR, Conejo-Garcia JR. TLR5 signaling, commensal microbiota and systemic tumor promoting inflammation: the three parcae of malignant progression. Oncoimmunology 2015;4:e1021542. 10.1080/2162402X.2015.1021542
- Rubinstein MR, Wang X, Liu W, et al. . Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 2013;14:195–206. 10.1016/j.chom.2013.07.012
- Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231–5. 10.1038/nature14404
- Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015;5:2892–911.
- Cullin N, Azevedo Antunes C, Straussman R, et al. . Microbiome and cancer. Cancer Cell 2021;39:1317–41. 10.1016/j.ccell.2021.08.006
- McGranahan N, Rosenthal R, Hiley CT, et al. . Allele-Specific HLA loss and immune escape in lung cancer evolution. Cell 2017;171:1259–71. 10.1016/j.cell.2017.10.001
- Stämpfli MR, Anderson GP. How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol 2009;9:377–84. 10.1038/nri2530
Source: PubMed