The large majority of cancer-caused deaths (>90%) do not result from the primary tumor, but from the spread of cancer cells from their location of origin to other sites of the body - a process known as metastasis. Despite this understanding, most cancer treatments are designed to target the primary tumor, not metastatic lesions. A major limitation in developing targeted anti-metastatic therapies is a lack of understanding of the biological drivers of this process in cancer cells. It has been demonstrated by a number of recent studies that epigenetic marks identifying gene enhancer elements across a cell's genome are highly predictive of cell-type-specific patterns of gene expression and are therefore highly informative of cellular behavior. One such study applying epigenetic enhancer profiling to the study of cancer has revealed unprecedented insight into the molecular alterations that drive tumor formation. In the proposed studies, this approach will be applied to investigate epigenetic alterations driving the process of metastasis in the most common primary tumor of bone, osteosarcoma. This is a highly aggressive solid tumor that commonly affects adolescents, often resulting in death from metastatic progression to the lung. Unfortunately, long-term outcomes for these patients have not improved for over 30 years. Through application of this epigenetic approach, this project seeks to gain insight into the molecular underpinnings of osteosarcoma metastasis with the goal of identifying metastatic drivers that may serve as suitable therapeutic targets as well as molecular signatures predictive of metastatic risk in osteosarcoma patients. Successful completion of these studies not only offer the potential to improve outcomes for osteosarcoma patients, but also to gain insight into the process of metastasis, in general, that may inform the study of other types of cancer.
Metastatic progression is the leading cause of cancer-related deaths worldwide. Indeed, >90% of cancer deaths result from metastasis, not the primary tumor. Osteosarcoma patients are no exception. Despite the development of numerous treatment modalities targeting the primary tumor, 40% of osteosarcoma patients ultimately 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 epigenomic regulation of cellular function to the study of tumor metastasis in osteosarcoma. Successful completion of the proposed studies offer the potential for development of targeted anti-metastatic 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.
|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|
|Cohen, Andrea J; Saiakhova, Alina; Corradin, Olivia et al. (2017) Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome. Nat Commun 8:14400|
|Morrow, James J; Mendoza, Arnulfo; Koyen, Allyson et al. (2016) mTOR Inhibition Mitigates Enhanced mRNA Translation Associated with the Metastatic Phenotype of Osteosarcoma Cells In Vivo. Clin Cancer Res 22:6129-6141|
|Lizardo, Michael M; Morrow, James J; Miller, Tyler E et al. (2016) Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression. Neoplasia 18:699-710|
|Morrow, James J; Khanna, Chand (2015) Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies. Crit Rev Oncog 20:173-97|
|Ren, Ling; Mendoza, Arnulfo; Zhu, Jack et al. (2015) Characterization of the metastatic phenotype of a panel of established osteosarcoma cells. Oncotarget 6:29469-81|
|Acquavella, Nicolas; Clever, David; Yu, Zhiya et al. (2015) Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest. Cancer Immunol Res 3:37-47|