Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment. ETS1 was regulated by p44/42 MAP kinase signaling activated in the OC cells interacting with mesothelial cells at the metastatic site. Human OC tumors had increased expression of ETS1, which predicted poor prognosis. ETS1 regulated OC metastasis both in vitro and in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis and functional rescue experiments revealed FAK as the key transcriptional target and downstream effector of ETS1. Taken together, our results indicate that ETS1 is an essential transcription factor induced in OC cells by the microenvironment, which promotes metastatic colonization though the transcriptional upregulation of its target FAK.

Ewing sarcoma (ES) is an aggressive, primary bone malignancy with occasional soft tissue extension. Purely extra­osseous ES is rare. A primary intraspinal, intradural ES without bone involvement is exceedingly rare. ES may be differentiated from other primitive neuroectodermal tumors by molecular analysis. The authors report the case of a 14-year-old female who suffered an acute neurologic decline from a hemorrhagic, intraspinal, intradural ES. The patient has been tumor free for 2 years after the initial emergency surgery. Our management of the patient and a review of the literature are provided. Considering only those cases with molecular or genetic confirmation of ES, our patient is the fifth pediatric case reported in the English literature.

Several studies have analyzed the efficacy of AngioVac for percutaneous intracardiac vegetectomy, but impact on surgical candidacy or clinical efficacy for infectious endocarditis (IE) is currently unknown. This is a single-arm, retrospective study on IE vegetectomy with impact on surgical risk scores. Analysis included 32 patients who underwent AngioVac vegetectomy for right heart IE at a single institution. The primary endpoint was improvement in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) scores. Secondary endpoints included technical success, improved leukocytosis, procedural safety, 30-day mortality, and 60-day mortality. Findings demonstrate 90.6% (n = 29) technically successful debulking. There was improvement in mean NSQIP scores from 34.6 to 27.9 ( P = .007). Zero cases of 30-day all-cause mortality. One patient experienced a major post-procedural complication of pneumothorax, a Class D Adverse Event. 20.5% (n = 5) of valvular vegetation patients went on to have surgical tricuspid valve repair. All indwelling intracardiac devices were removed. Findings suggest that percutaneous vegetectomy improves surgical candidacy, as measured by ACS NSQIP scores, in patients with IE and right heart vegetations and is associated with low complication rates.

Metastatic colonization of ovarian cancer involves productive paracrine/juxtacrine interactions with the microenvironment. The resulting induction of an adaptive response in the cancer cells enables them to establish themselves in the new microenvironment and take advantage of the new factors available. A key feature of this adaptation is induced changes in gene expression through transcriptional regulation as a result of microenvironmental cues. However, the identities of transcription factors induced by the metastatic microenvironment in ovarian cancer and their mechanism of action are poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1, a member of the ETS family of TFs, as an essential driver of metastatic colonization. Increased ETS1 expression was induced in metastasizing ovarian cancer cells interacting with the mesothelial cells covering the surface of the omentum. The mechanism of upregulation was through the activation of p44/42 MAP kinase signaling in the cancer cells induced by TGFbeta from the microenvironment. We also found an increased ETS1 expression in human ovarian cancer samples as compared to normal fallopian tubes using a tissue microarray. Moreover, higher expression of ETS1 was a predictor of poor prognosis in ovarian cancer patients. Knocking down ETS1 decreased migration, proliferation, and colony formation as well as invasion through and colonization of the organotypic 3D culture. Overexpression of ETS1 had the opposite effect. CRISPR/Cas9-mediated knockout of ETS1 resulted in decreased tumor burden in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis revealed that ETS1 promoted an EMT phenotype and FAK was identified as a novel transcriptional target. Inhibition of FAK functionally mimicked the effects of ETS1 inhibition in the ovarian cancer cells. Moreover, functional rescue experiments established FAK as a downstream effector of ETS1 during ovarian cancer metastasis. Taken together, our results indicate that ETS1 is an essential transcription factor induced in ovarian cancer cells by the microenvironment, which promotes metastatic colonization. This is the first report establishing FAK as a transcriptional target and functional effector of ETS1 in establishing metastatic tumors. Citation Format: Sunil Tomar, Joshua P. Plotnik, James Haley, Joshua Scantland, Zahir Sheikh, Robert Emerson, Dean Lenz, Peter C. Hollenhorst, Anirban K. Mitra. Induction of a novel ETS1/FAK pathway in metastasizing ovarian cancer cells by the omental microenvironment primes them for metastatic colonization. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A34.