tbuckley/cabot-search huggingface dataset:
Abstract A063: What can we learn from a retrospective evaluation of HER2, P53 and P16INK4A protein expression in rare ovarian tumors?
Authors: Kavitha M. Advikolanu-Rao, Anthony M. Magliocco, Andrew W. Maksymiuk
Journal: Cancer Research (2024)

Abstract In this retrospective study, we examined the incidence and prevalence of HER2, P53, and P16INK4A protein accumulation patterns in patients diagnosed with rare ovarian cancer. The population-based study included a total of thirteen patients diagnosed at the Saskatoon Cancer Centre during the years 1983-1995. Immunohistochemistry for evaluation of HER2, P53 and P16INK4A protein expression and ploidy status in paraffin-embedded tissue (PET) specimens were correlated with clinicopathologic variables. Immunoexpression studies were with the following rabbit monoclonal antibodies: Erb-B2, 485 and P16INK4A, G175-405, 13251A, except for P53, mouse monoclonal antibody, D07. DNA status was assessed by flow-cytometric analysis. The most prevalent histologic subtype was sex-cord stromal, followed by three germ-cell, while the remaining two tumors were malignant Brenner. The patients’ ages ranged between (15-77 years). The data on stage was unavailable in five patients, two patients had undifferentiated tumor, one had grade 2-3, and data on grade was unavailable in the remaining six cases. Two of the 13 patients died: one patient in stage IV, grade 3, granulosa-theca, P53 immunonegative and near-tetraploid DNA status; the other patient with malignant Brenner histologic subtype, P53 overexpression, and diploid DNA status. Tumor tissues were available in nine of 13 randomly selected patients. Except for one case with P53 overexpression, the remaining 89% tumor specimens had low to zero P53, P16INK4A, and Erb-B2 expression. The nonsignificance of the immunoexpression studies and preclusion from prognostic prediction is likely due to the restricted sample size. Thus, immunoexpression of P53, P16INK4A, and Erb-B2 have not been associated with rare ovarian tumors. Moreover, the observation that malignant Brenner had P53 overexpression and diploid DNA status in one of the patients is a significant finding of this retrospective study. Additionally, these findings argue for routine use of P53 protein expression and ploidy status in the assessment of malignant Brenner tumors. The vast majority of tumors with P53 mutations progress rapidly. Therefore, the subset of patients with malignant Brenner tumors that have P53 protein disruption will likely benefit from therapy using PARP inhibitors. A. Geissel and J. L. Griffin, “Preparation of nuclei for flow cytometry,” in AFIP Advances in Laboratory methods in Histology and Pathology, ed. Mikel UV (Washington DC: American Registry of Pathology, 1944), 111-121. Citation Format: Kavitha M. Advikolanu-Rao, Anthony M. Magliocco, Andrew W. Maksymiuk. What can we learn from a retrospective evaluation of HER2, P53 and P16INK4A protein expression in rare ovarian tumors? [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A063.
Abstract A069: High-resolution volumetric imaging of primary and metastatic high-grade serous ovarian cancer explants
Authors: Adele E. Connor, Joanne Lysaght, Donal J. Brennan, Jeremy C. Simpson, Antoinette S. Perry
Journal: Cancer Research (2024)

Abstract Introduction: As high-grade serous ovarian cancer (HGSOC) rarely shows symptoms, most patients present with metastases. Tumor heterogeneity between metastases may impede a patient’s response to therapy and thus impact survival. We aim to decipher the heterobiology of HGSOC lesions using high-resolution imaging of patient-derived explants (PDEs), to determine the differential treatment response between primary and metastatic tumors. Methods: PAX8, CK7, RAD51, γH2AX, Ki67, cPARP, and CD3 were chosen to enumerate tumor and T cells, and their activity. Antibodies were optimized in monolayer and spheroid cultures of HGSOC cell lines, COV318 and OVCAR4. CD3 was optimized in FFPE human tonsillitis tissue. Primary and metastatic HGSOC explants were cultured for 48h followed by 24h fixation. Several immunostaining and optical clearing protocols were tested on PDEs, which were imaged using a fully automated confocal high-content screening system. Results: Immunostaining and automated image analysis facilitated the identification of individual nuclei within PDEs without Refractive Index (RI) matching or optical clearing. However, high background impeded further image analysis, preventing the quantification of certain antibodies. Glycerol-based RI matching and ScaleS tissue clearing were implemented to try and overcome this. However, neither generated sufficiently high-quality images for analysis. A novel Clearing-enhanced 3D (Ce3D) immunostaining system recently developed for high-quality multiplex fluorescence microscopy of large tissue volumes was tested. While individual nuclei were recognized, as well as RAD51 foci and CK7 cytoskeleton staining, image analysis was still impeded due to high background. Conclusions: Protocols without RI matching and optical clearing can stain large, complex structures such as PDEs. However, high background impedes image analysis suggesting the need for optical clearing and RI matching. The inclusion of various RI matching and/or optical clearing steps failed to overcome high background staining. Further work is ongoing to refine immunostaining, RI matching, optical clearing, and mounting of PDEs to allow the quantification of all antibodies. Citation Format: Adele E. Connor, Joanne Lysaght, Donal J. Brennan, Jeremy C. Simpson, Antoinette S. Perry. High-resolution volumetric imaging of primary and metastatic high-grade serous ovarian cancer explants [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A069.
Abstract A072: Altering the ovarian cancer tumor microenvironment using car t cell therapy
Authors: Alexandra N. McMellen, Michael S. Leibowitz
Journal: Cancer Research (2024)

Abstract Ovarian cancer accounts for 12,810 deaths per year in the USA, making it the deadliest gynecologic malignancy. Unfortunately, patients who are resistant to standard of care treatments have very limited effective therapeutic options. Immunotherapies are an emerging class of treatments that utilize a patient’s immune system to recognize and destroy tumor cells and have resulted in dramatic responses in many hematologic malignancies. In particular, reprograming patient T cells to recognize specific surface antigen(s) known as chimeric antigen receptor (CAR) T cell therapy, has provided both pediatric and adult patients with relapsed or treatment-unresponsive hematologic malignancies novel and potentially curative treatment options. CAR T cell therapy received FDA approval in 2018 for the treatment of B cell leukemia, however despite significant efforts, has been largely ineffective in solid malignancies. This is due in part to the complex solid tumor immune microenvironment (TME) and how it may change in response to therapies. For example, there is evidence that an FDA approved treatment for ovarian cancer called poly(ADP) ribose polymerase inhibitors (PARP; PARPi) leads to increased immune cell infiltration and cancer sensitivity to immunotherapies. This proposal will delineate the immune composition of the ovarian cancer TME using mouse models that closely recapitulate ovarian cancer progression and examine the impact of CAR T cells on the TME. We will utilize mouse ovarian cancer models that are sensitive and resistant to PARP inhibition. The information derived from these studies will provide a better understanding of the evolution of ovarian cancer TME and provide insight on how CAR T cells may alter the TME. Ultimately, we hope this work will lead to the development of safer and more effective therapeutic options for ovarian cancer patients. Citation Format: Alexandra N. McMellen, Michael S. Leibowitz. Altering the ovarian cancer tumor microenvironment using car t cell therapy [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A072.
CD4+ T cell activation distinguishes response to anti-PD-L1+anti-CTLA4 therapy from anti-PD-L1 monotherapy
Authors: Amelie Franken, Michel Bila, Aurelie Mechels, Sam Kint, Jeroen Van Dessel, Valentina Pomella, Sebastiaan Vanuytven, Gino Philips, Orian Bricard, Jieyi Xiong, Bram Boeckx, Sigrid Hatse, Thomas Van Brussel, Rogier Schepers, Cedric Van Aerde, Sarah Geurs, Vincent Vandecaveye, Esther Hauben, Vincent Vander Poorten, Sara Verbandt, Katy Vandereyken, Junbin Qian, Sabine Tejpar, Thierry Voet, Paul M. Clement, Diether Lambrechts
Journal: Immunity (2024)
Beta-defensin index: A functional biomarker for oral cancer detection
Authors: Santosh K. Ghosh, Yuncheng Man, Arwa Fraiwan, Christopher Waters, Crist McKenzie, Cheng Lu, David Pfau, Hameem Kawsar, Natarajan Bhaskaran, Pushpa Pandiyan, Ge Jin, Farren Briggs, Chad C. Zender, Rod Rezaee, Fotinos Panagakos, Jason E. Thuener, Jay Wasman, Alice Tang, Hiba Qari, Trisha Wise-Draper, Thomas S. McCormick, Anant Madabhushi, Umut A. Gurkan, Aaron Weinberg
Journal: Cell Reports Medicine (2024)

There is an unmet clinical need for a non-invasive and cost-effective test for oral squamous cell carcinoma (OSCC) that informs clinicians when a biopsy is warranted. Human beta-defensin 3 (hBD-3), an epithelial cell-derived anti-microbial peptide, is pro-tumorigenic and overexpressed in early-stage OSCC compared to hBD-2. We validate this expression dichotomy in carcinoma in situ and OSCC lesions using immunofluorescence microscopy and flow cytometry. The proportion of hBD-3/hBD-2 levels in non-invasively collected lesional cells compared to contralateral normal cells, obtained by ELISA, generates the beta-defensin index (BDI). Proof-of-principle and blinded discovery studies demonstrate that BDI discriminates OSCC from benign lesions. A multi-center validation study shows sensitivity and specificity values of 98.2% (95% confidence interval [CI] 90.3-99.9) and 82.6% (95% CI 68.6-92.2), respectively. A proof-of-principle study shows that BDI is adaptable to a point-of-care assay using microfluidics. We propose that BDI may fulfill a major unmet need in low-socioeconomic countries where pathology services are lacking.
Abstract B007: NAD+ metabolism drives PARPi resistance in ovarian cancer cells
Authors: Subin Myong, Hardik Shah, Benedikt Nagele, Reshma Rajesh, Sridevi Challa
Journal: Cancer Research (2024)

Abstract NAD+ is a coenzyme for redox reactions and a cofactor for enzymes such as PARPs and Sirtuins. The nuclear enzyme PARP1 is a major consumer of NAD+, which is cleaved during the catalytic activation of PARP1 in response to DNA damage. PARP1 inhibitors compete with NAD+ for the catalytic site of PARP1 and reduce the catalytic activity of PARP1 and impair DNA damage repair. Recently PARP inhibitors (PARPi) have shown efficacy in the treatment of ovarian cancers and most patients with defects in homologous repair of DNA damage are now on PARPi maintenance. But, heterogeneous responses to PARPi is limiting their clinical efficacy. To identify the mechanisms of PARPi resistance, we generated a panel of ovarian cancer cells with acquired resistance to niraparib (PARPiR), an FDA approved PARP inhibitor. We demonstrated that the PARPiR cells are also resistant to other FDA approved PARP inhibitors rucaparib and olaparib. This data suggested that a common mechanism of resistance underlies poor response to the FDA approved PARP inhibitors. Since PARP1 activity is tightly controlled by the cellular NAD+ levels, we next investigated the role of NAD+ biosynthesis in PARPi resistance. Metabolomic profiling of the parental and PARPiR cells demonstrated that PARPiR cells have elevated levels of NAD+ metabolism. Indeed, treating the PARPiR cells with inhibitors of NAD+ synthesis restored the sensitivity to PARP inhibitors. Moreover, culturing the previously sensitive parental ovarian cancer cells in NAD+ precursors decreased their sensitivity to PARP inhibitors. These data collectively demonstrated that high levels of NAD+ metabolism causes PARP inhibitor resistance in ovarian cancer cells. Complementary to the metabolomic analysis, results from phenotypic assays in PARPiR cells revealed that high levels of NAD+ maintain cellular quiescence in PARPiR cells. In summary, our results demonstrated that high levels of NAD+ biosynthesis causes PARPi resistance by maintaining cellular quiescence. There is an urgent need to identify the mechanisms of resistance to PARP inhibitors to increase their clinical efficacy. Our study identified that maintenance of quiescence is a fundamental mechanism of PARPi resistance. We also demonstrated that inhibiting NAD+ biosynthesis reverses PARP inhibitor resistance. Citation Format: Subin Myong, Hardik Shah, Benedikt Nagele, Reshma Rajesh, Sridevi Challa. NAD+ metabolism drives PARPi resistance in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B007.
Abstract A088: Tumor innervation as a novel driver of ovarian cancer progression
Authors: Matthew Knarr, Hunter Reavis, Timothy Lippert, Priyanka Rawat, Paola Vermeer, Ronny Drapkin
Journal: Cancer Research (2024)

Abstract One of the main challenges currently faced in ovarian cancer treatment is that the primary platinum/taxane therapy used to treat patients does not meaningfully extend survival. The overall survival for ovarian cancer patients with advanced disease is less than 30% with most patients recurring within 5 years of initial therapy. Once resistant disease develops there are few second line therapy options, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surround and support the cancer cells within the tumor. Different strategies have evolved to target the TME, such as immune checkpoint inhibitors or angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. Most ovarian tumors have a microenvironment that is highly immunosuppressive and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME targeting therapies must be developed that can induce a therapeutic effect in ovarian tumors and can be used to treat most ovarian cancer patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains undefined. Here we show that Transient Receptor Potential cation channel subfamily V member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer growth and metastasis. Analysis of patient samples shows that sensory nerve fiber innervation is much higher in ovarian tumors vs benign reproductive tissue. In addition, ablation of TRPV1 sensory nerve fibers in vivo causes reduced tumor burden and prolongs survival in a syngeneic mouse model of ovarian cancer metastasis. Taken together, our results establish TRPV1+ sensory innervation as a novel driver of ovarian cancer growth/metastasis and a potential therapeutic target for ovarian cancer treatment. Citation Format: Matthew Knarr, Hunter Reavis, Timothy Lippert, Priyanka Rawat, Paola Vermeer, Ronny Drapkin. Tumor innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A088.
Abstract A047: Modeling the role of the fallopian tube in the prevention and spread of high grade serous cancer using a multi-organ platform
Authors: Joanna Burdette
Journal: Cancer Research (2024)

Abstract It is now recognized that a large percentage of high grade serous ovarian cancers arise in the fallopian tube and colonize the ovary as the primary metastatic step. One of the risk factors associated with ovarian cancer is the lifetime number of ovulations. Few models are currently available that allow the process of ovulation and the development of ovarian cancer to be studied. To address this gap, our team developed a microphysiological platform called PREDICT-multi-organ-system (MOS). PREDICT-MOS contains 30 wells for culturing organs and 60 pumps with precisely controlled flow rates. Human fallopian tube tissue can be grown in an air-liquid interface, while murine ovaries can be engineered to ovulate while producing and secreting physiological concentrations of hormones and proteins over the entire process of ovulation. Importantly, these secreted factors are contained in the device within the media and can therefore precisely model local concentration gradients and temporal exposure of the human fallopian tube tissues. First, we uncovered that the ovary secretes versican during the cycle to enhance ovarian migration, adhesion, and expansion within the ovarian microenvironment. We revealed that fallopian tube tumor cells stimulate the ovary to produce testosterone, which enhanced fallopian tube invasion and stem cell marker expression. Next, we profiled the expression of secreted extracellular vesicles that are produced by the fallopian tube on the platform. Extracellular vesicles may provide a new form of liquid biopsy, but understanding the cargo expressed from normal cells is critical for understanding the importance of cancer EV’s during progression. Finally, we have engineered the platform to allow for real-time invasion using an insert technology and a modified pump that allows for interaction between the organs. Overall, the integration of organ-on-chip technology with key human tissues allows for the in-depth analysis of the role of ovulation in the onset and spread of high-grade serous cancer from the fallopian tube. Citation Format: Joanna Burdette. Modeling the role of the fallopian tube in the prevention and spread of high grade serous cancer using a multi-organ platform [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A047.
Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression
Authors: Anthi C. Krontira, Cristiana Cruceanu, Leander Dony, Christina Kyrousi, Marie-Helen Link, Nils Rek, Dorothee Pöhlchen, Catarina Raimundo, Signe Penner-Goeke, Alicia Schowe, Darina Czamara, Marius Lahti-Pulkkinen, Sara Sammallahti, Elina Wolford, Kati Heinonen, Simone Roeh, Vincenza Sportelli, Barbara Wölfel, Maik Ködel, Susann Sauer, Monika Rex-Haffner, Katri Räikkönen, Marta Labeur, Silvia Cappello, Elisabeth B. Binder
Journal: Neuron (2024)

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.
Abstract A114: Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium
Authors: Victor Ho, Maggie Chan, Manreet Chehal, Alice Liang, Allen C Eaves, Sharon A Louis, John Stingl
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of epithelial ovarian cancer. Despite its name, HGSOC originates in the fallopian tube (FT), but metastasizes quickly in the adnexal region and is the most lethal gynecological cancer worldwide. Organoid culture is emerging as a powerful model for studying normal FT cell biology and ovarian cancer. To standardize primary human FT and HGSOC organoid culture, we have developed GyneCult Fallopian Tube Organoid Medium (FTOM), an optimized serum-free medium and a workflow that supports robust and representative FT organoid culture from freshly isolated or cryopreserved primary human FT cells. FT cultures were initiated by seeding 4000 fresh or cryopreserved single cells (8 donors) directly into 20 µL Corning® Matrigel® domes and overlaying them with FT Organoid Medium. Cultures were maintained with full-medium changes every 3 - 4 days and were passaged every 8 - 14 days into new 20 µL Matrigel® droplets, either at a passage ratio of 1:3 or by seeding at 4000 cells per droplet. Cultures were analyzed by immunocytochemistry (ICC) to detect secretory markers keratin 7 (KRT7), oviductal glycoprotein 1 (OVGP1), and PAX8, as well as ciliated cell markers acetylated alpha tubulin (TUBA1A) and FOXJ1. Across all donors, 16 ± 8% (mean ± SD) of dissociated EpCAM+ FT cells formed 50 - 300 µm diameter cystic organoids within 14 days of seeding (n = 8). Cultures can be maintained for at least 5 passages with 14 - 20 cumulative population doublings, at 3 - 4 doublings per passage. ICC analysis confirmed that organoids contained both polarized secretory cells (i.e., KRT7+, OVGP1+, PAX8+) and ciliated cells (i.e. acetylated TUBA1A+, FOXJ1+), indicating multilineage capacity (n = 5). We also tested the compatibility of GyneCult FTOM with culturing HGSOC samples and observed that one of three tumor samples tested generated organoids. These tumour organoids had a solid and irregular shaped morphology and were composed of PAX8+ cells. These cells underwent ≥ 5 cumulative population doublings over 5 passages, with 0.5 - 2 doublings per passage; this performance is consistent with recently published HGSOC organoid culture methods. These results demonstrate that GyneCult Fallopian Tube Organoid Medium is a robust medium for initiating and culturing FT epithelium as organoids, can support HGSOC organoid culture, and is a valuable tool for studying FT biology. Citation Format: Victor Ho, Maggie Chan, Manreet Chehal, Alice Liang, Allen C Eaves, Sharon A Louis, John Stingl. Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A114.