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 (US) |
|---|---|
| Pages (from-to) | 3789-3806.e17 |
| Journal | Cell |
| Volume | 185 |
| Issue number | 20 |
| DOIs | |
| State | Published - Sep 29 2022 |
Keywords
- biomarkers
- cancer
- fungi
- liquid biopsy
- metagenomics
- metatranscriptomics
- microbial interactions
- tumor microbiome
- tumor mycobiome
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. / Narunsky-Haziza, Lian; Sepich-Poore, Gregory D.; Livyatan, Ilana et al.
In: Cell, Vol. 185, No. 20, 29.09.2022, p. 3789-3806.e17.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions
AU - Narunsky-Haziza, Lian
AU - Sepich-Poore, Gregory D.
AU - Livyatan, Ilana
AU - Asraf, Omer
AU - Martino, Cameron
AU - Nejman, Deborah
AU - Gavert, Nancy
AU - Stajich, Jason E.
AU - Amit, Guy
AU - González, Antonio
AU - Wandro, Stephen
AU - Perry, Gili
AU - Ariel, Ruthie
AU - Meltser, Arnon
AU - Shaffer, Justin P.
AU - Zhu, Qiyun
AU - Balint-Lahat, Nora
AU - Barshack, Iris
AU - Dadiani, Maya
AU - Gal-Yam, Einav N.
AU - Patel, Sandip Pravin
AU - Bashan, Amir
AU - Swafford, Austin D.
AU - Pilpel, Yitzhak
AU - Knight, Rob
AU - Straussman, Ravid
N1 - Funding Information: 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 . Funding Information: 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. Publisher Copyright: © 2022 The Authors
PY - 2022/9/29
Y1 - 2022/9/29
N2 - 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.
AB - 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.
KW - biomarkers
KW - cancer
KW - fungi
KW - liquid biopsy
KW - metagenomics
KW - metatranscriptomics
KW - microbial interactions
KW - tumor microbiome
KW - tumor mycobiome
UR - http://www.scopus.com/inward/record.url?scp=85138486612&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138486612&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2022.09.005
DO - 10.1016/j.cell.2022.09.005
M3 - Article
C2 - 36179670
AN - SCOPUS:85138486612
VL - 185
SP - 3789-3806.e17
JO - Cell
JF - Cell
SN - 0092-8674
IS - 20
ER -