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Studies on a new conditional mouse model reveal that ETS transcription factors, which are often mutated in prostate cancer, cause transformation by altering the androgen-receptor cistrome, priming the prostate epithelium to respond to upstream signals such as PTEN loss. Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1 -translocated, PTEN -deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN -deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.

Mitochondria are important and unique organelles in the cell that are mainly responsible for energy metabolism. However, due to its unique property of having its own DNA, it also is involved in many other cellular processes. Due to this major role of mitochondria in the cell, the organelle also plays important roles in many diseases, including mitochondria-inherited diseases, metabolic diseases, and cancer. Recently, more research has been targeted at elucidating the role of mitochondria and mitochondrial DNA in cancer and how mitochondrial dysfunction can be drug targeted. The work presented here aims to further investigate the role of specific mitochondrial DNA mutations and heteroplasmy in mitochondrial function and cancer traits.Chapter one is a review of the current knowledge of mitochondrial genetics and the involvement of mitochondrial dysfunction in various human diseases. It also summarizes the contemporary knowledge about the role of mitochondria and heteroplasmy in cancer and tumor progression, with an emphasis on breast cancer. Furthermore, it goes into using drugs to target mitochondrial DNA and metabolic dysfunction.Chapter two describes the initial investigation done on a non-pathogenic high heteroplasmy mutation in a colon cancer cell line and its correlation with mitochondrial membrane potential. Even though no association was found between heteroplasmy and membrane potential, it did shift the direction of my investigation toward finding pathogenic non-synonymous mutations that can be segregated into distinct heteroplasmy groups.Chapters three and four of my dissertation focuses on the effects of low and high heteroplasmy of two amino acid changing mutations on mitochondrial function and cancer phenotype in both tripe negative breast cancer cell lines and a cybrid cell line. Using various cancer specific assays, I was able to show that high heteroplasmy influences anchorage-independent growth and for the cybrid cell line, invasiveness as well. When examining differences in mitochondrial function, the high heteroplasmy samples showed a higher oxygen consumption rate than the low heteroplasmy groups. Furthermore, when examining nuclear gene expression changes, there were significant differences between the high vs low group in various cancer promoting and inhibiting pathways, respectively.

Aberrant activation of MAPK signaling leads to the activation of oncogenic transcriptomes. How MAPK signaling is coupled with the transcriptional response in cancer is not fully understood. In 2 MAPK-activated tumor types, gastrointestinal stromal tumor and melanoma, we found that ETV1 and other Pea3-ETS transcription factors are critical nuclear effectors of MAPK signaling that are regulated through protein stability. Expression of stabilized Pea3-ETS factors can partially rescue the MAPK transcriptome and cell viability after MAPK inhibition. To identify the players involved in this process, we performed a pooled genome-wide RNAi screen using a fluorescence-based ETV1 protein stability sensor and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 or DET1 loss led to decoupling between MAPK signaling and the downstream transcriptional response, where MAPK inhibition failed to destabilize Pea3 factors and fully inhibit the MAPK transcriptome, thus resulting in decreased sensitivity to MAPK pathway inhibitors. We identified multiple COP1 and DET1 mutations in human tumors that were defective in the degradation of Pea3-ETS factors. Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling-dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition.

ABSTRACT Even after total resection of glioblastoma core lesions by surgery and aggressive post-surgical treatments, life-threatening tumors inevitably recur. A characteristic obstacle in effective treatment is high intratumoral heterogeneity, both longitudinally and spatially. Recurrence occurs predominantly at the brain parenchyma-tumor core interface, a region termed tumor edge. Given the difficulty of accessing it surgically, the composition of the tumor edge, harboring both cancerous and non-cancerous cells, remains largely unknown. Here, to identify phenotypic diversity among heterogeneous glioblastoma core and edge lesions, we uncovered the existence of three phenotypically-distinct clonal subpopulations within individual tumors from glioblastoma patients. Clones from the tumor core shared the same phenotype, exclusively generating tumor-core cells. In contrast, two distinct clonal subtypes were identified at the tumor edge: one generated only edge-lesion cells and the other expanded more broadly to establish both edge- and core-lesions. Using multiple xenograft experimental models in mouse brains, tumor edge development was found to require that both somatic and tumor cells express the NADase CD38, combinedly elevating glioblastoma malignancy. In vitro data suggested that intracellular NADase activity at the edge was provoked through intercellular communication between edge clones and normal astrocytes. Systemic treatment of tumor-bearing mice with 78c, a small-molecule CD38 inhibitor, attenuated the formation of glioblastoma edge lesions, suggesting its clinical potential to pharmacologically eliminate tumor-edge lesions. Collectively, these findings provide novel phenotypic and mechanistic insights into clonal heterogeneity within glioblastoma, particularly in the surgically unresectable, currently understudied tumor edge. Competing Interest Statement The authors have declared no competing interest.