An in vivo metastasis screen of chromatin modifiers reveals a potential role for dopamine in adrenal and brain colonization.
Abstract: Metastasis is the ultimate and fatal stage of malignant progression responsible for the vast majority of cancer deaths. Experimentally we know that metastasis is a highly inefficient process with adaptation to the secondary site being the rate limiting step. Experimental systems able to recapitulate colonization of multiple organs are lacking. To better understand this process I establis... read morehed a novel in vivo model for the study of systemic metastasis by a breast cancer tumor cell line. Ultrasound guided intracardiac injection coupled with non-invasive imaging allowed me to seed all of the organs in the body and track the establishment and growth of the resulting brain, adrenal, ovarian and other tumors. This cell line was established from a metastasis to the brain and I describe the neurotropic properties it gained during adaptation to this environment including a previously unknown, and importantly clinically addressable, response to dopamine which increases tumor cell viability in vitro. Additionally I leveraged this new model to globally address metastatic organ tropism. While cancer has long been acknowledged as a genetic disease, it is now recognized that the number of epigenetic abnormalities exceeds those of a genetic nature. Clinically, metastases in breast cancer may manifest years or decades after surgery implying a period of dormancy for the tumor seeds sowed by the primary tumor. Aberrant chromatin modification has been established as a driver of malignancy and I hypothesized that chromatin modification may be involved in the transition from a covert dormant cell or micro metastasis to a full blown secondary tumor. I performed a comprehensive screen knocking down all human chromatin modifiers singly to gauge the effect on metastatic organ tropism. Analysis of the hits in the nonadrenal tumors identified four genes EHMT1, JMJD5, PRDM14 and SIRT3 that were targeted above the noise threshold and by more than one hairpin. Additional experimentation using the system described herein may elucidate metastatic mechanisms of these genes in colonization of the brain and other organs.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisors: Charlotte Kuperwasser, and Grace Gill.
Committee: Philip Hinds, and James Schwob.
Keywords: Biology, Oncology, and Cellular biology.read less