Abstract
Cancer-microbe associations have been explored for centuries, but cancer-associated fungi have rarely been examined. Here, we comprehensively characterize the cancer mycobiome within 17,401 patient tissue, blood, and plasma samples across 35 cancer types in four independent cohorts. We report fungal DNA and cells at low abundances across many major human cancers, with differences in community compositions that differ among cancer types, even when accounting for technical background. Fungal histological staining of tissue microarrays supported intratumoral presence and frequent spatial association with cancer cells and macrophages. Comparing intratumoral fungal communities with matched bacteriomes and immunomes revealed co-occurring bi-domain ecologies, often with permissive, rather than competitive, microenvironments and distinct immune responses. Clinically focused assessments suggested prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers, and synergistic predictive performance with bacteriomes.
| Original language | English |
|---|---|
| Pages (from-to) | 3789-3806.e17 |
| Journal | Cell |
| Volume | 185 |
| Issue number | 20 |
| DOIs | |
| State | Published - 29 Sep 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors
Funding
G.D.S-P. was supported by a fellowship from the US National Institutes of Health, National Cancer Institute ( F30 CA243480 ) during this work. R.K. is funded in part by grants from the National Cancer Institute within the National Institutes of Health ( R01 CA255206 and U24 CA248454 ). R.K. is also funded in part by the National Institutes of Health ( NIH DP1AT010885 ). R.S. is funded by the Israel Science Foundation (grant no. 2927/21 ), the Binational Science Foundation (grant no. 2013332 ), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 818086 ), the Fabrikant-Morse Families Research Fund for Humanity , the Knell Family Center for Microbiology , the Moross Integrated Cancer Center , the Swiss Society Institute for Cancer Prevention Research at the Weizmann Institute of Science , the Rising Tide Foundation , the Dr. Dvora and Haim Teitelbaum Endowment Fund , the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program , and a partnership of the Israel Cancer Research Fund and City of Hope (COH) as supported by The Harvey L. Miller Family Foundation . J.P.S. is funded by SD IRACDA — Professors of the Future — 5K12GM068524-17 . The Seven Bridges Cancer Genomics Cloud was used during the course of this work and has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health , contract no. HHSN261201400008C , and ID/IQ agreement no. 17X146 under contract no. HHSN261201500003I . Samples re-analyzed for the UCSD plasma cohort were collected under the following grants: R00 AA020235 , R01 DA026334 , P30 MH062513 , P01 DA012065 , and P50 DA026306 . We thank C. Sepich-Poore for providing critical review and feedback on the manuscript and figures. We also thank all members of the Straussman laboratory as well as E. Segal, N. Shlezinger, N. Osherov, and D. Mirelman for fruitful discussions; N. Osherov, S. Covo, D. Mirelman, and O. Yarden for giving us fungal species that were used as positive controls; and D. Peeper and C. Blank for providing some of the melanoma samples that were used in this study. The authors also wish to acknowledge the patients and their families who have helped contribute toward a better understanding of this field. G.D.S-P. was supported by a fellowship from the US National Institutes of Health, National Cancer Institute (F30 CA243480) during this work. R.K. is funded in part by grants from the National Cancer Institute within the National Institutes of Health (R01 CA255206 and U24 CA248454). R.K. is also funded in part by the National Institutes of Health (NIH DP1AT010885). R.S. is funded by the Israel Science Foundation (grant no. 2927/21), the Binational Science Foundation (grant no. 2013332), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 818086), the Fabrikant-Morse Families Research Fund for Humanity, the Knell Family Center for Microbiology, the Moross Integrated Cancer Center, the Swiss Society Institute for Cancer Prevention Research at the Weizmann Institute of Science, the Rising Tide Foundation, the Dr. Dvora and Haim Teitelbaum Endowment Fund, the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, and a partnership of the Israel Cancer Research Fund and City of Hope (COH) as supported by The Harvey L. Miller Family Foundation. J.P.S. is funded by SD IRACDA—Professors of the Future—5K12GM068524-17. The Seven Bridges Cancer Genomics Cloud was used during the course of this work and has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, contract no. HHSN261201400008C, and ID/IQ agreement no. 17X146 under contract no. HHSN261201500003I. Samples re-analyzed for the UCSD plasma cohort were collected under the following grants: R00 AA020235, R01 DA026334, P30 MH062513, P01 DA012065, and P50 DA026306. Conceptualization, R.S. L.N.-H. G.D.S.-P. R.K. I.L. and Y.P.; Methodology, L.N.-H. G.D.S.-P. I.L. O.A. C.M. J.E.S. A.B. Q.Z. G.A. and A.M.; Investigation, L.N.-H. G.D.S.-P. I.L. O.A. C.M. D.N. N.G. J.E.S. G.A. A.G. S.W. G.P. R.A. A.M. J.P.S. N.B.-L. S.P.P. A.B. and R.S.; Visualization, L.N.-H. N.G. D.N. R.A. G.D.S.-P. C.M. J.E.S. and I.L.; Funding acquisition, R.S. and R.K.; Supervision, R.S. R.K. Y.P. A.D.S. A.B. S.P.P. I.B. M.D. and E.N.G.-Y.; Writing – original draft: G.D.S.-P. R.S. L.N.-H. I.L. and G.A.; Writing – review & editing, R.S. L.N.-H. I.L. G.D.S.-P. R.K. A.D.S. G.P. S.P.P. J.P.S. C.M. D.N. N.G. Y.P. and J.E.S. G.D.S.-P. and R.K. are inventors on a US patent application (PCT/US2019/059647) submitted by The Regents of the University of California and licensed by Micronoma; that application covers methods of diagnosing and treating cancer using multi-domain microbial biomarkers in blood and cancer tissues. G.D.S.-P. and R.K. are founders of and report stock interest in Micronoma. G.D.S.-P. has filed several additional US patent applications on cancer bacteriome and mycobiome diagnostics that are owned by The Regents of the University of California. R.K. additionally is a member of the scientific advisory board for GenCirq, holds an equity interest in GenCirq, and can receive reimbursements for expenses up to US $5,000 per year. S.W. is an employee of Micronoma. R.S. received a grant from Merck EMD Serono, is a member of the scientific advisory board for Micronoma and reports stock interest in Micronoma, CuResponse, and Biomica, and is a paid adviser to Biomica, CuResponse, and BiomX. R.S. Y.P. I.L. and L.N.-H. are co-inventors on an Israeli provisional patent application (#284860) submitted by Yeda Research and Development, the Weizmann Institute of Science, that covers methods of diagnosing and treating cancer using mycobial biomarkers in cancer tissues.
| Funders | Funder number |
|---|---|
| Dr. Dvora and Haim Teitelbaum Endowment Fund | |
| Fabrikant-Morse Families Research Fund for Humanity | |
| Israel Cancer Research Fund and City of Hope | HHSN261201500003I, HHSN261201400008C, 17X146, 5K12GM068524-17 |
| Merck EMD Serono | 284860 |
| Moross Integrated Cancer Center | |
| Swiss Society Institute for Cancer Prevention Research | |
| National Institutes of Health | DP1AT010885 |
| National Institute on Drug Abuse | P50DA026306 |
| National Cancer Institute | F30 CA243480, U24 CA248454, R01 CA255206 |
| University of California | |
| Horizon 2020 Framework Programme | |
| European Commission | |
| Weizmann Institute of Science | |
| United States-Israel Binational Science Foundation | 2013332 |
| Israel Science Foundation | 2927/21 |
| Horizon 2020 | 818086 |
| Rising Tide Foundation |
Keywords
- biomarkers
- cancer
- fungi
- liquid biopsy
- metagenomics
- metatranscriptomics
- microbial interactions
- tumor microbiome
- tumor mycobiome
