tbuckley/cabot-search huggingface dataset:
Abstract 2726: Nuclear checkpoints for melanoma and breast cancer lung metastasis
Authors: Francesco Roncato, Ofer Regev, Nehora Levi, Sara W. Feigelson, Gabi Gerlitz, Ronen Alon
Journal: Cancer Research (2020)

Abstract Introduction Metastasis involves cancer cell intravasation and extravasation from blood vessels at target organs. The mechanisms by which the nuclei of metastatic tumor cells squeeze through different vascular and epithelial barriers are poorly understood. The nuclear lamina attaches chromatin domains to the nuclear periphery and controls the mechanical properties of the nucleus and its crosstalk with the cell cytoskeleton. A-type lamins, lamin A and its splice variant lamin C, are key nuclear lamina proteins that control nucleus stiffness and regulate chromatin conformation. Reduced lamin A was reported in some aggressive cancers. Results and Discussion Using a new in vitro transendothelial migration (TEM) assay we found that melanoma and breast cancer cells slowly squeeze their nuclei and complete TEM through endothelial junctions irrespective of their relative lamin A/C levels, suggesting that lamin A/C dependent nuclear stiffening is not a rate-limiting step for cancer cell squeezing through endothelial cells in vitro. In contrast, reduced lamin A/C enhanced cancer cell squeezing through rigid pores. Tumor emigration analysis across blood vessels in vivo was performed by new 3D imaging of fluorescently labeled cancer cells with high and low lamin A/C levels. This imaging was based on light sheet microscopy of lipid-cleared lungs of recipient mice in situ labeled with anti-vascular CD31 mAb. Using this technology, we found that reduced lamin A/C expression did not enhance the emigration of circulating murine melanoma and breast cancer cells across lung capillaries in vivo. Lower lamin A/C levels reduced the constitutive, transcriptionally repressed, heterochromatin in both melanoma and breast cancer cells. Decreased lamin A/C expression did not enhance however, nuclear rupture in the tumor cells that entered the lung parenchyma. The outcomes of the epigenetic and mechanical changes resulting of lamin A/C suppression on tumor growth and metastasis are under current investigation. Conclusions Our results suggest that subsets of tumor cells may benefit from reducing their nuclear content of lamin A/C mainly at the level of rigid barrier crossing (e.g. dense interstitial spaces), but not at the level of extravasation or post extravasation survival at target organs. How alterations in lamin A/C content contribute to tumor heterogeneity and metastatic potential of singular cancer cells remains an open question. Citation Format: Francesco Roncato, Ofer Regev, Nehora Levi, Sara W. Feigelson, Gabi Gerlitz, Ronen Alon. Nuclear checkpoints for melanoma and breast cancer lung metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2726.
A global investment framework for the elimination of hepatitis B
Authors: Jessica Howell, Alisa Pedrana, Sophia E. Schroeder, Nick Scott, Lisa Aufegger, Rifat Atun, Ricardo Baptista-Leite, Gottfried Hirnschall, Ellen ‘t Hoen, Sharon J. Hutchinson, Jeffrey V. Lazarus, Lesi Olufunmilayo, Raquel Peck, Manik Sharma, Annette H. Sohn, Alexander Thompson, Mark Thursz, David Wilson, Margaret Hellard
Journal: Journal of Hepatology (2020)
Abstract 1848: NUC-3373 induces ER stress and the release of damage associated molecular patterns in colorectal cancer cells
Authors: Fiona G. McKissock, Oliver J. Read, David J. Harrison
Journal: Cancer Research (2020)

Abstract Background: NUC-3373 is a ProTide transformation of fluorodeoxyuridine monophosphate (FUDR-MP), the active anti-cancer metabolite of 5-fluorouracil (5-FU). NUC-3373 can overcome key cancer resistance mechanisms and the rapid degradation known to impact 5-FU's clinical utility. Clinical studies are currently investigating NUC-3373 as monotherapy (solid tumors) and in combination with agents commonly used to treat patients with colorectal cancer (CRC). Previous studies revealed ultrastructural adaptations in CRC cell lines exposed to NUC-3373 that were indicative of endoplasmic reticulum (ER) stress. NUC-3373 was also shown to induce the formation of long-lasting ternary thymidylate synthase (TS) complexes. The induction of ER stress may promote the release of damage-associated molecular patterns (DAMPs) which have the potential to evoke immunogenic cell death (ICD). This study examines the ability of NUC-3373 to induce both ER stress and the release of DAMPs in CRC. Methods: Immunoglobulin-binding protein (BiP) was used as a marker of ER stress induction. BiP and TS (free and ternary complex) expression were measured by Western blot and quantified using Licor Odyssey. TS was knocked down using TYMS-targeting siRNA and lipofectamine-based transfection. DAMPs, active release of nuclear high mobility group box protein 1 (HMGB1) and cell surface exposure of calreticulin (CRT), were assessed by fluorescence microscopy and flow cytometry respectively. Results: NUC-3373 resulted in the rapid formation of TS ternary complexes, which was associated with ER stress as assessed by BiP protein expression. siRNA knockdown studies confirmed that TS ternary complex formation is necessary for the induction of ER stress. A strong correlation between BiP and TS ternary complex formation (R2=0.97) was observed. Furthermore, NUC-3373 induced the release of DAMPs, with increased expression of CRT at the cell surface and concomitant loss of nuclear HMGB1. Conclusions: NUC-3373, a potent inhibitor of TS activity, also induces ER stress, upregulates cell surface CRT, and decreases nuclear HMGB1 in CRC cells. The aforementioned DAMPs have been shown to cause ICD. In addition to being an effective cytotoxic agent, these findings suggest that NUC-3373 has the potential to evoke a host immune response and enhance the clinical utility of immunotherapy. Citation Format: Fiona G. McKissock, Oliver J. Read, David J. Harrison. NUC-3373 induces ER stress and the release of damage associated molecular patterns in colorectal cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1848.
Abstract 3954: Validation of the extracellular matrix protein fibulin-3 as a molecular target in malignant pleural mesothelioma
Authors: Arivazhagan Roshini, Chandra Goparaju, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Joan Chou, Frank A. Middleton, Harvey I. Pass, Mariano S. Viapiano
Journal: Cancer Research (2020)

Abstract Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor of the pleura with poor prognosis and limited therapeutic options. Fibulin-3 (gene EFEMP1) is an extracellular matrix protein found in the parenchyma and pleural effusions of MPM, which has been proposed as prognostic biomarker complementing diagnostic biomarkers -such as mesothelin- for this cancer type. However, the functions and potential mechanisms of fibulin-3 in MPM remain completely unknown. To further define the relevance of fibulin-3 in MPM we performed gain- and loss-of-function experiments by respectively overexpressing fibulin-3 in normal mesothelial cells or knocking down its expression in MPM cells, followed by evaluation of cell viability, colony formation, invasion and chemoresistance. We also evaluated changes in gene expression and signaling mechanisms after fibulin-3 downregulation. Furthermore, a novel anti-fibulin-3 antibody was developed and tested for its ability to recognize fibulin-3 in mesothelioma, inhibit pro-tumoral signaling, and disrupt tumor growth in orthotopic MPM models. Fibulin-3 downregulation decreased viability, clonogenic capacity, and invasiveness of MPM cell lines, whereas overexpression of this protein increased the same phenotypic traits in normal mesothelial cells. At the molecular level, fibulin-3 regulated the activation of PI3K/Akt and NFkB signaling and correlated with a gene expression signature required for cell adhesion and motility, matching its cellular effects. Loco-regional delivery of anti-fibulin-3 had a marked cytostatic effect and significantly increased median survival and the number of long-term surviving animals with stable disease. Our work reveals that fibulin-3 is a relevant therapeutic target in mesothelioma, adding to its relevance as prognostic biomarker and encouraging further development of anti-fibulin-3 targeted therapies for this cancer type. Citation Format: Arivazhagan Roshini, Chandra Goparaju, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Joan Chou, Frank A. Middleton, Harvey I. Pass, Mariano S. Viapiano. Validation of the extracellular matrix protein fibulin-3 as a molecular target in malignant pleural mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3954.
EPISCORE: cell type deconvolution of bulk tissue DNA methylomes from single-cell RNA-Seq data
Authors: Andrew E. Teschendorff, Tianyu Zhu, Charles E. Breeze, Stephan Beck
Journal: Genome biology (2020)

Abstract Cell type heterogeneity presents a challenge to the interpretation of epigenome data, compounded by the difficulty in generating reliable single-cell DNA methylomes for large numbers of cells and samples. We present EPISCORE, a computational algorithm that performs virtual microdissection of bulk tissue DNA methylation data at single cell-type resolution for any solid tissue. EPISCORE applies a probabilistic epigenetic model of gene regulation to a single-cell RNA-seq tissue atlas to generate a tissue-specific DNA methylation reference matrix, allowing quantification of cell-type proportions and cell-type-specific differential methylation signals in bulk tissue data. We validate EPISCORE in multiple epigenome studies and tissue types.
Association Between Urinary Epidermal Growth Factor and Renal Prognosis in Lupus Nephritis
Authors: Juan M. Mejia‐Vilet, John P. Shapiro, Xiaolan L. Zhang, Cristino Cruz, Grant Zimmerman, R. Angélica Méndez‐Pérez, Mayra L. Cano‐Verduzco, Samir V. Parikh, Haikady N. Nagaraja, Luis E. Morales‐Buenrostro, Brad H. Rovin
Journal: Arthritis & Rheumatology (2020)

Objective To evaluate the role of urinary epidermal growth factor (EGF) as a biomarker of chronic kidney damage in lupus nephritis (LN). Methods A proteomics approach was used to identify urinary EGF as a biomarker of interest in a discovery cohort of patients with LN. The expression of urinary EGF was characterized in 2 large multiethnic LN cohorts, and the association between urinary EGF levels at the time of flare and kidney outcomes was evaluated in a subset of 120 patients with long‐term follow‐up data. For longitudinal studies, the expression of urinary EGF over time was determined in 2 longitudinal cohorts of patients with LN from whom serial urine samples were collected. Results Discovery analysis showed the urinary EGF levels as being low in patients with active LN (median peptide count 8.4, interquartile range [IQR] 2.8–12.3 in patients with active LN versus median 48.0, IQR 45.3–64.6 in healthy controls). The peptide sequence was consistent with that of proEGF, and this was confirmed by immunoblotting. The discovery findings were verified by enzyme‐linked immunosorbent assay. Patients with active LN had a significantly lower level of urinary EGF compared to that in patients with active nonrenal systemic lupus erythematosus (SLE), patients with inactive SLE, and healthy kidney donors (each P &lt; 0.05). The urinary EGF level was inversely correlated with the chronicity index of histologic features assessed in kidney biopsy tissue (Spearman’s r = −0.67, P &lt; 0.001). Multivariate survival analysis showed that the urinary EGF level was associated with time to doubling of the serum creatinine level (DSCr), a marker of future end‐stage kidney disease (ESKD) (hazard ratio 0.88, 95% confidence interval 0.77–0.99, P = 0.045). Patients whose LN symptoms progressed to DSCr and those who experienced progression to ESKD had a lower urinary EGF level at the time of flare, and urinary EGF levels decreased over the 12 months following flare. All patients who experienced progression to ESKD were identified based on a urinary EGF cutoff level of &lt;5.3 ng/mg. Conclusion Urinary EGF levels are correlated with histologic kidney damage in patients with LN. Low urinary EGF levels at the time of flare and decreasing urinary EGF levels over time are associated with adverse long‐term kidney outcomes.
Abstract 4538: A safe and potent agonist ADG106 targeting a unique epitope of CD137 with novel mechanism of actions
Authors: Guizhong Liu, Felix Du, Xiaohong She, Yi Zhu, Anthony W. Tolcher, Peter Luo
Journal: Cancer Research (2020)

Abstract Antagonist antibodies targeting immune checkpoint co-inhibitory receptor such as PD-1/PD-L1 have achieved great clinical success in cancer immunotherapy. However, agonistic antibodies targeting the co-stimulatory T cell receptors in the TNFR superfamily, and CD137 in particular, has suffered significant setback due to either dose-dependent severe liver toxicity by Urelumab, or modest clinical anti-tumor activity by Utomilumab. ADG106, a safe and potent antibody targeting a unique epitope of CD137, is shown to hold the great promise to achieve much better efficacy and safety profile for immunotherapy in preclinical and phase 1 studies. ADG106, a fully human agonistic anti-CD137 IgG4 mAb, binds to a unique and conserved epitope with multiple cross-species reactivity, and overlaps with CD137 ligand binding site. This unique antibody acts in a novel mechanism with the following attributes: 1) it agonizes CD137 in a natural ligand-like fashion; 2) it blocks ligand to disable its reverse signaling; 3) it exhibits strong but specific Fc receptor mediated crosslinking in comparison with Utomilumab. ADG106 shows robust dose-dependent single agent anti-tumor activity in multiple syngeneic mouse tumor models and induces durable antigen-specific memory immunity that protects animals from the same re-challenged tumor cells. Consistent with the preclinical observations, ongoing phase I trial shows that the same antibody, ADG106, is well-tolerated in cancer patients in dose escalation from 0.03 to 3 mg/kg; and it also shows single agent activity on circulating T cell activation and clonal expansion in anti-tumor activity. Furthermore, ADG106 has also induced complete remission of the liver metastatic lesion in a lymphoma patient at 1mg/kg dose. Preclinical studies demonstrate that ADG106 enhances activation and inflammatory cytokine release of primed T cells alone or together with other immunomodulatory agents in vitro, as well as exhibits synergistic in vivo anti-tumor activity in combination with variety of other cancer therapies, including checkpoint inhibitors, chemotherapies and targeted agents. Mechanistic analyses suggest that ADG106 stimulates tumor infiltration and expansion of CD4+ and CD8+ T cells, thereby promoting the antitumor responses. These findings support that ADG106-boosted immune response could offer an effective but alternative solution for cancer immunotherapy in single and combination therapies, especially for non-responders to current PD-1/PD-L1 based immunotherapies. Citation Format: Guizhong Liu, Felix Du, Xiaohong She, Yi Zhu, Anthony W. Tolcher, Peter Luo. A safe and potent agonist ADG106 targeting a unique epitope of CD137 with novel mechanism of actions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4538.
Abstract 4140: Dissecting the structural basis for rational inhibitor design: Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1
Authors: Lan Lan, Minli Xing, Maithri Kashipathy, Justin Douglas, Philip Gao, Kevin Battaile, Robert Hanzlik, Scott Lovell, Liang Xu
Journal: Cancer Research (2020)

Abstract RNA-binding proteins (RBPs) are key regulators of cellular functions, especially in post-transcriptional regulations. Dysregulation of RBPs is implicated in many diseases including cancer. One of the RBPs that is overexpressed in a variety of human cancer is Musashi-2 (MSI2). Elevated MSI2 expression is associated with ectopic oncogenic pathways including but not limited to NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, making MSI2 a promising therapeutic target for cancer. Protein structure is critical for drug discovery and structure-based rational design. Both MSI1 and MSI2 proteins contain two N-terminal RNA recognition motifs and play roles in post-transcriptional regulation of target mRNAs. We have identified several inhibitors of MSI1, all of which bind to MSI2 as well. In order to design MSI2 specific inhibitors and compare the differences of binding mode of the inhibitors, we set out to solve the structure of MSI2-RRM1, the key motif that is responsible for the binding. Here we report the crystal structure and the first NMR solution structure of MSI2-RRM1, and compare these to the structures of MSI1-RBD1 and other RNA binding proteins. A high degree of structural similarity was observed between the crystal and solution NMR structures. MSI2-RRM1 shows a highly similar overall folding topology to MSI1-RBD1 and other RNA binding proteins. The structural information of MSI2-RRM1 will be helpful for understanding MSI2-RNA interaction and for guiding rational design of MSI2 specific inhibitors. Citation Format: Lan Lan, Minli Xing, Maithri Kashipathy, Justin Douglas, Philip Gao, Kevin Battaile, Robert Hanzlik, Scott Lovell, Liang Xu. Dissecting the structural basis for rational inhibitor design: Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4140.
Abstract LB-005: Senescence reprogramming in primary tumors initiates prostate cancer metastases
Authors: Ilaria Guccini, Ajinkya Revandkar, Mariantonietta D'Ambrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Andrea Alimonti
Journal: Cancer Research (2020)

Abstract Recent studies have raised fundamental questions about the possibility that senescence induced either by oncogene activation or chemotherapy, while initially restricting tumorigenesis, may promote cancer metastases at a late stage. This coexisting dichotomy remains unclear due to the lack of evidence on the mechanism by which senescent tumor cells initiate metastases, a fatal and therapeutically challenging hallmark of cancer. Here, we put forward the hypothesis that the genetic make-up of the tumors accounts for the distinct outcomes of senescence in cancer. Using different genetically engineered mouse models we demonstrate that inactivation of Timp1 is capable to switch senescence driven by the loss of PTEN and chemotherapy from a tumor-suppressive into a tumor-promoting response that drives metastases. Of note, depletion of senescent tumor cells by the senolytic compound ABT263 or p53 genetic inactivation significantly impeded metastases formation in Ptenpc-/-; Timp1-/- mice, indicating the involvement of senescence in the metastatic process. Moreover, enhancement of senescence by Docetaxel therapy decreased the proliferation of prostate tumors in Ptenpc-/- mice, whereas it accelerated metastases formation in Ptenpc-/-; Timp1-/- mice. Mechanistically, TIMP1-loss in PTEN-deficient cells reprogrammed the senescent-secretome significantly changing the levels of GDF15, FGF and IGFBP thereby promoting cellular invasion, migration and the up-regulation of a metastases-associated gene signature. In prostate cancer patients, we found that TIMP1 is commonly lost in combination with PTEN in advanced and metastatic prostate tumors and that TIMP1 inactivation is associated with TIMP1 promoter methylation. Altogether, these findings highlight the crucial role of TIMP1 as the gatekeeper that limits the pro-metastatic function of senescent tumor cells, implying that senescence inducing therapies should be administered with caution in patients affected by cancers with TIMP1 inactivation. Citation Format: Ilaria Guccini, Ajinkya Revandkar, Mariantonietta D'Ambrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Andrea Alimonti. Senescence reprogramming in primary tumors initiates prostate cancer metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-005.
Abstract 1598: Reprogramming of immunosuppressive tumor microenvironments by multifunctional nanoemulsion and enhance immune checkpoint blockade therapy
Authors: Seung Mo Jin, Sang Nam Lee, Yong Taik Lim
Journal: Cancer Research (2020)

Abstract The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Toll-like receptor (TLR) 7/8 agonist-based adjuvants have been widely used to activate antigen-presenting cells (APCs) and induce antigen-specific therapeutic T cells. However, the incorporation of TLR 7/8 agonists also induces immunosuppressive factors, such as Indoleamine 2,3-dioxygenase (IDO) in APCs and tumor cells, which results in the formation of immunosuppressive TME. In this research, we report the assemblable immune-modulating suspension (AIMS) consisting of TLR 7/8 agonist and IDO inhibitor, which was designed to down-regulate the immune-suppressive factors (TGF-β, IL-10, myeloid-derived suppressor cells, regulatory T cells) and to increase the infiltration of cytotoxic T lymphocytes. The best combination of immune-modulating agents in AIMS, we called supra-adjuvant, was selected by screening possible combinations of commercialized TLR 7/8 agonists and IDO inhibitors based on the ratio of pro- and anti-inflammatory cytokines. Paclitaxel was also introduced into AIMS to induce immunogenic cell death (ICD) and in situ vaccination efficacy with TLR 7/8 agonist at the tumor bed. Local administration of AIMS increased infiltrated T cells in both local and distant tumors, and inhibited the metastasis of tumors to lung significantly. AIMS also reshaped the TME from ‘cold tumor' to ‘hot tumor' successfully, and increased the responsive rate of immune checkpoint blockade therapy (ICBT) significantly. Taken together, the AIMS composed of supra-adjuvant and ICD-inducer is expected to be used as a platform for the re-programming of immunosuppressive TME and the induction of synergistic cancer immunotherapy with ICBT. Citation Format: Seung Mo Jin, Sang Nam Lee, Yong Taik Lim. Reprogramming of immunosuppressive tumor microenvironments by multifunctional nanoemulsion and enhance immune checkpoint blockade therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1598.