NF-κB–dependent lymphoid enhancer co-option promotes renal carcinoma metastasis

Paulo Rodrigues, Saroor A. Patel, Louise Harewood, Ioana Olan, Erika Vojtasova, Saiful Effendi Syafruddin, M. Nazhif Zaini, Emma K. Richardson, Johanna Burge, Anne Y. Warren, Grant D. Stewart, Kourosh Saeb-Parsy, Shamith A. Samarajiwa, Sakari Vanharanta

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identi fied, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis–associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB–driven lymphoid element, as a mediator of metastasis in vivo. We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states. SIGNIFICANCE: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer.

Original languageEnglish
Pages (from-to)850-865
Number of pages16
JournalCancer Discovery
Volume8
Issue number7
DOIs
Publication statusPublished - 1 Jul 2018

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Kidney Neoplasms
Neoplasm Metastasis
Carcinoma
Kidney
Neoplasms
Gene Expression
Regulator Genes
Epigenomics
Genes
Phenotype
Mutation
Mortality
Population

ASJC Scopus subject areas

  • Oncology

Cite this

Rodrigues, P., Patel, S. A., Harewood, L., Olan, I., Vojtasova, E., Syafruddin, S. E., ... Vanharanta, S. (2018). NF-κB–dependent lymphoid enhancer co-option promotes renal carcinoma metastasis. Cancer Discovery, 8(7), 850-865. https://doi.org/10.1158/2159-8290.CD-17-1211

NF-κB–dependent lymphoid enhancer co-option promotes renal carcinoma metastasis. / Rodrigues, Paulo; Patel, Saroor A.; Harewood, Louise; Olan, Ioana; Vojtasova, Erika; Syafruddin, Saiful Effendi; Zaini, M. Nazhif; Richardson, Emma K.; Burge, Johanna; Warren, Anne Y.; Stewart, Grant D.; Saeb-Parsy, Kourosh; Samarajiwa, Shamith A.; Vanharanta, Sakari.

In: Cancer Discovery, Vol. 8, No. 7, 01.07.2018, p. 850-865.

Research output: Contribution to journalArticle

Rodrigues, P, Patel, SA, Harewood, L, Olan, I, Vojtasova, E, Syafruddin, SE, Zaini, MN, Richardson, EK, Burge, J, Warren, AY, Stewart, GD, Saeb-Parsy, K, Samarajiwa, SA & Vanharanta, S 2018, 'NF-κB–dependent lymphoid enhancer co-option promotes renal carcinoma metastasis', Cancer Discovery, vol. 8, no. 7, pp. 850-865. https://doi.org/10.1158/2159-8290.CD-17-1211
Rodrigues, Paulo ; Patel, Saroor A. ; Harewood, Louise ; Olan, Ioana ; Vojtasova, Erika ; Syafruddin, Saiful Effendi ; Zaini, M. Nazhif ; Richardson, Emma K. ; Burge, Johanna ; Warren, Anne Y. ; Stewart, Grant D. ; Saeb-Parsy, Kourosh ; Samarajiwa, Shamith A. ; Vanharanta, Sakari. / NF-κB–dependent lymphoid enhancer co-option promotes renal carcinoma metastasis. In: Cancer Discovery. 2018 ; Vol. 8, No. 7. pp. 850-865.
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