An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors

Tao Wang, Rong Lu, Payal Kapur, Bijay S. Jaiswal, Raquibul Hannan, Ze Zhang, Ivan Pedrosa, Jason J. Luke, He Zhang, Leonard D. Goldstein, Qurratulain Yousuf, Yi Feng Gu, Tiffani McKenzie, Allison Joyce, Min S. Kim, Xinlei Wang, Danni Luo, Oreoluwa Onabolu, Christina Stevens, Zhiqun XieMingyi Chen, Alexander Filatenkov, Jose Torrealba, Xin Luo, Wenbin Guo, Jingxuan He, Eric Stawiski, Zora Modrusan, Steffen Durinck, Somasekar Seshagiri, James Brugarolas

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors. SIGNIfICANCE: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis.

Original languageEnglish (US)
Pages (from-to)1142-1155
Number of pages14
JournalCancer Discovery
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2018

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Tumor Microenvironment
Renal Cell Carcinoma
Neoplasms
Inflammation
RNA Sequence Analysis
Thrombocytosis
Regulatory T-Lymphocytes
Stromal Cells
Genomics
Heterografts
Natural Killer Cells
Medical Records
Dissection
Anemia
Neutrophils
B-Lymphocytes
Macrophages
Pathology
T-Lymphocytes
Survival

ASJC Scopus subject areas

  • Oncology

Cite this

An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors. / Wang, Tao; Lu, Rong; Kapur, Payal; Jaiswal, Bijay S.; Hannan, Raquibul; Zhang, Ze; Pedrosa, Ivan; Luke, Jason J.; Zhang, He; Goldstein, Leonard D.; Yousuf, Qurratulain; Gu, Yi Feng; McKenzie, Tiffani; Joyce, Allison; Kim, Min S.; Wang, Xinlei; Luo, Danni; Onabolu, Oreoluwa; Stevens, Christina; Xie, Zhiqun; Chen, Mingyi; Filatenkov, Alexander; Torrealba, Jose; Luo, Xin; Guo, Wenbin; He, Jingxuan; Stawiski, Eric; Modrusan, Zora; Durinck, Steffen; Seshagiri, Somasekar; Brugarolas, James.

In: Cancer Discovery, Vol. 8, No. 9, 01.09.2018, p. 1142-1155.

Research output: Contribution to journalArticle

Wang, T, Lu, R, Kapur, P, Jaiswal, BS, Hannan, R, Zhang, Z, Pedrosa, I, Luke, JJ, Zhang, H, Goldstein, LD, Yousuf, Q, Gu, YF, McKenzie, T, Joyce, A, Kim, MS, Wang, X, Luo, D, Onabolu, O, Stevens, C, Xie, Z, Chen, M, Filatenkov, A, Torrealba, J, Luo, X, Guo, W, He, J, Stawiski, E, Modrusan, Z, Durinck, S, Seshagiri, S & Brugarolas, J 2018, 'An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors', Cancer Discovery, vol. 8, no. 9, pp. 1142-1155. https://doi.org/10.1158/2159-8290.CD-17-1246
Wang, Tao ; Lu, Rong ; Kapur, Payal ; Jaiswal, Bijay S. ; Hannan, Raquibul ; Zhang, Ze ; Pedrosa, Ivan ; Luke, Jason J. ; Zhang, He ; Goldstein, Leonard D. ; Yousuf, Qurratulain ; Gu, Yi Feng ; McKenzie, Tiffani ; Joyce, Allison ; Kim, Min S. ; Wang, Xinlei ; Luo, Danni ; Onabolu, Oreoluwa ; Stevens, Christina ; Xie, Zhiqun ; Chen, Mingyi ; Filatenkov, Alexander ; Torrealba, Jose ; Luo, Xin ; Guo, Wenbin ; He, Jingxuan ; Stawiski, Eric ; Modrusan, Zora ; Durinck, Steffen ; Seshagiri, Somasekar ; Brugarolas, James. / An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors. In: Cancer Discovery. 2018 ; Vol. 8, No. 9. pp. 1142-1155.
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abstract = "By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65{\%} of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors. SIGNIfICANCE: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis.",
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T1 - An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors

AU - Wang, Tao

AU - Lu, Rong

AU - Kapur, Payal

AU - Jaiswal, Bijay S.

AU - Hannan, Raquibul

AU - Zhang, Ze

AU - Pedrosa, Ivan

AU - Luke, Jason J.

AU - Zhang, He

AU - Goldstein, Leonard D.

AU - Yousuf, Qurratulain

AU - Gu, Yi Feng

AU - McKenzie, Tiffani

AU - Joyce, Allison

AU - Kim, Min S.

AU - Wang, Xinlei

AU - Luo, Danni

AU - Onabolu, Oreoluwa

AU - Stevens, Christina

AU - Xie, Zhiqun

AU - Chen, Mingyi

AU - Filatenkov, Alexander

AU - Torrealba, Jose

AU - Luo, Xin

AU - Guo, Wenbin

AU - He, Jingxuan

AU - Stawiski, Eric

AU - Modrusan, Zora

AU - Durinck, Steffen

AU - Seshagiri, Somasekar

AU - Brugarolas, James

PY - 2018/9/1

Y1 - 2018/9/1

N2 - By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors. SIGNIfICANCE: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis.

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