Distant metastases cause more than 90% of cancer-related mortality. Children suffering from osteosarcoma, where the typical route of spread is from bone to lung, are no exception. Despite the development of numerous treatment modalities targeting the primary tumor, 40% of patients still die from metastatic progression. There is therefore a pressing clinical need to determine the factors responsible for lung metastasis in osteosarcoma to facilitate development of novel anti- metastatic therapies and prognostic biomarkers. This proposal tests the central hypothesis that epigenetic alterations at distal enhancer loci underlie metastatic competence in osteosarcoma. Based on the fundamental principle that gene enhancer elements determine cellular identity and are key in mediating cellular responses to exogenous stimuli, we mapped enhancer elements genome wide through ChIP-seq of enhancer-histone marks. Compared to non-metastatic progenitors, metastatic cells show somatic acquisition and loss of enhancer- histone marks at thousands of loci across the epigenome. We call these Metastatic Variant Enhancer Loci, or Met-VELs. Using a lung explant mouse model of pulmonary metastasis, we show that gained and lost Met-VELs converge on prometastatic transcriptional programs that are uniquely activated or repressed as the metastatic cells colonize the lung microenvironment. The findings suggest that an osteosarcoma cell's metastatic success depends on its capacity to dynamically activate and repress pro- and anti-metastatic genes in the lung microenvironment, and that this ability is encoded in the epigenome at the level of gene enhancer elements.
Aim 1 tests the hypothesis that Met-VELs are ubiquitous and predictive of metastatic transcription in osteosarcoma cell lines and in patient samples.
Aim 2 tests the hypothesis that Met-VEL gene activation and repression is driven by dynamic changes in the epigenetic state of enhancers and promoters, dictated by the tumor microenvironment.
Aim 3 tests the hypothesis that Met-VEL clusters define metastasis-dependency genes. Successful completion of these aims will provide conclusive evidence that osteosarcoma cells hijack enhancers to metastasize to the lungs, and could reveal commonalities among metastatic cells exploitable as therapeutic targets and prognostic biomarkers in human patients.

Public Health Relevance

Most cancer deaths result from spread of the primary tumor to distant sites, a process called metastasis. Patients with osteosarcoma are no exception. Despite the development of numerous treatment modalities targeting the primary tumor, 40% of osteosarcoma patients will succumb to metastatic progression. A major limitation in the development of targeted anti-metastatic therapies in osteosarcoma and other types of cancer is a lack of understanding of the biological drivers of this process. This study seeks to apply recent advances in the understanding of epigenetic regulation of cellular function to the study of tumor metastasis in osteosarcoma. Completion of the proposed studies will offer the potential for development of targeted therapies and prognostic biomarkers for osteosarcoma patients and may also provide insights to the molecular underpinnings of metastasis that will inform the study and treatment of other types of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193677-05
Application #
9878064
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Ault, Grace S
Project Start
2016-03-02
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Berger, Nathan A; Scacheri, Peter C (2018) Targeting Epigenetics to Prevent Obesity Promoted Cancers. Cancer Prev Res (Phila) 11:125-128
Mack, Stephen C; Pajtler, Kristian W; Chavez, Lukas et al. (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101-105
Karnuta, Jaret M; Scacheri, Peter C (2018) Enhancers: bridging the gap between gene control and human disease. Hum Mol Genet 27:R219-R227
Morrow, James J; Bayles, Ian; Funnell, Alister P W et al. (2018) Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nat Med 24:176-185
Patten, Darren K; Corleone, Giacomo; Gy?rffy, Bal√°zs et al. (2018) Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer. Nat Med 24:1469-1480
Forrest, Megan E; Saiakhova, Alina; Beard, Lydia et al. (2018) Colon Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis. Sci Rep 8:7324
Yao, Hui; Hill, Sophie F; Skidmore, Jennifer M et al. (2018) CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development. JCI Insight 3:
Ferguson, James; Devarajan, Mahima; DiNuoscio, Gregg et al. (2018) PRC2 Is Dispensable in Vivo for ?-Catenin-Mediated Repression of Chondrogenesis in the Mouse Embryonic Cranial Mesenchyme. G3 (Bethesda) 8:491-503
Sahni, Jennifer M; Gayle, Sylvia S; Webb, Bryan M et al. (2017) Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors. Cancer Res 77:5395-5408
Cohen, Andrea J; Saiakhova, Alina; Corradin, Olivia et al. (2017) Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome. Nat Commun 8:14400

Showing the most recent 10 out of 15 publications