tbuckley/cabot-search huggingface dataset:
Abstract A079: G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous carcinoma
Authors: Hsuan Shun Huang, Tang-Yuan Chu
Journal: Cancer Research (2024)

Abstract The incidence and mortality burden of ovarian high-grade serous carcinoma (HGSC) is increasing rapidly in Taiwan and many urbanized countries. The etiology of HGSC, especially that responsible for the rapid and advanced seeding of the tumor in the peritoneum, which causes late diagnosis and poor prognosis, is elusive. Epidemiological and molecular studies have demonstrated incessant ovulation is the main culprit of ovarian cancer. Our previous studies also elucidated some transforming factors in the ovulatory follicular fluid (FF). We unveiled the oncogenic activities of ovulation on the malignant transformation of fallopian tube fimbria epithelial cells (FTEC), the primary origin of HGSC. We hypothesized that ovulation could also promote the intraperitoneal spreading of tube originated HGSC. First, in both human and mouse specimens, we observed a dramatic influx of neutrophils in the peritoneal fluid during ovulation after LH surge. Ovulatory FF from IVF women, when injected to the mouse peritoneum cavity, readily induced neutrophil influx and activated neutrophil extracellular trap (NET) formation (NETosis). Among the different neutrophil activators in FF, we found G-CSF is responsible for the ROS and PAD4 increases and histone citrullination in NETosis. This FF-GCSF-induced NETosis increases anchoring independent growth (AIG), cell adhesions, and matrigel invasion of STIC-mimicking FTEC and HGSC cells. Interestingly, while the AIG-promoting activity of the ovulation-activated NET showed cell autonomous, the adhesion and invasion activities were non-autonomous conferred by the conditioned medium of the activated neutrophils. Shown by a FF plus tumor cell i.p. coinjection mouse xenograft model, intraperitoneal seeding was increased by the coinjection and was inhibited by the inhibitor (GSK) of NETosis. Taken together, we disclosed an unprecedented intraperitoneal neutrophil influx/activation activity of ovulation. This activity, presumably acting as an antimicrobial to prevent ascending infection during fertilization, is utilized to aid the peritoneal seedings of tubal-origin HGSC. Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. G-CSF released from ovulation recruits and activates neutrophils in the peritoneum to aid transformation, seeding, and invasion of high-grade serous carcinoma [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 A079.
Abstract IA007: Distinct immune landscapes characterize highly and minimally invasive brain metastases
Authors: Peter Siegel
Journal: Cancer Research (2024)

Abstract Background: Cancer metastasis to the brain is a common complication of advanced disease with limited therapeutic options. Inefficient treatment is influenced, in part, by the unique composition of the brain microenvironment. Brain metastases (BrM) grow in two distinct patterns, either as minimally invasive (MI) masses with well-defined borders, or as tumors with highly invasive (HI) growth into surrounding brain tissue. HI BrM are associated with poor prognoses compared to MI BrM; however, differences in the tumor immune microenvironments (TIME) between these two lesion types remain largely unknown. Here, we investigate how the TIME differs between HI and MI BrM. Methods: We use Nanostring Digital Spatial Profiling coupled with the Cancer Transcriptome Atlas panel on 5 MI and 15 HI BrM patient samples (lung and breast cancer). This technique enables specific isolation of cancer cells at the tumor-brain interface and quantification of 1,825 cancer-specific RNA targets. Additionally, we perform imaging mass cytometry (IMC) on 119 BrM samples (lung cancer, breast cancer, melanoma, other) from 46 patients, encompassing over 350,000 cells. Samples represent BrM from various primary sites, including cancers of the lung, breast, and skin, and include patient-matched samples from the brain-tumor interface (‘margin’) or the centre of the metastatic lesion (‘core’). Results: The Nanostring Digital Spatial Profiling revealed a list of 106 and 73 differentially expressed genes in MI vs HI breast and lung BrM, respectively. Gene set enrichment analyses revealed that an interferon gamma (IFNγ) pathway signature was enriched in MI BrM and lost in HI BrM, which was confirmed by immunohistochemical staining for pSTAT1, consistent with an “immune hot” TIME in MI BrM when compared to HI lesions. Using IMC technology, we identified 20 different cell types, activation states, and spatially-defined cellular neighborhoods across our BrM patient samples. In comparison to MI samples, HI BrM have lower numbers of B cells, CD4+ T cells, and CD4- CD8- T cells in both the core and margin samples, and lower numbers of CD8+ T cells and regulatory T cells in the margin samples only. Conclusion: These data suggest that HI BrM invade into an immunosuppressed microenvironment while MI BrM are characterized by an active anti-tumor immune infiltrate. Together, this work suggests potential immune regulation of BrM invasion, which warrants further investigation. Citation Format: Peter Siegel. Distinct immune landscapes characterize highly and minimally invasive brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA007.
Abstract A035: Genome-wide CRISPRi screening reveals determinants of platinum sensitivity and resistance in high-grade serous ovarian cancer
Authors: Yi Wen Kong, Erika D. Handly, Robin A. Lu, Molly A. Bird, Hannah-Lou Schilling, Samkyu P. Yaffe, Michael B. Yaffe, David H. Koch
Journal: Cancer Research (2024)

Abstract Platinum-based chemotherapeutic drugs induce intra- and interstrand crosslinks between purine residues, resulting in DNA damage and tumor cell death. Although these drugs are widely used as front-line treatment for multiple human cancers, particularly high-grade serous ovarian cancer (HGSOC), the development of platinum resistance and tumor recurrence remains a common clinical problem due to an incomplete understanding of what governs the cellular response to platinum-induced DNA damage. Here we report the results from genome-wide CRISPRi-screens for modulators of sensitivity and resistance to two widely used platinum agents, cisplatin and oxaliplatin, using a cell-based approach that mimics clinical treatment protocols. Using this unbiased genomic approach, we demonstrate that lethality after cisplatin or oxaliplatin treatment in p53-defective ovarian cancer cells is markedly enhanced by suppressing genes in the Fanconi anemia (FA) and homologous recombination (HR) pathways, but considerably less enhanced by suppressing genes in the nucleotide excision repair (NER) pathway, despite the well-established importance of NER in reversing platinum-induced intrastrand crosslinks. Loss of NER activity, however, can markedly increase tumor cell death from cisplatin-induced DNA damage, if the cell cycle checkpoint kinase MK2 is co-targeted, indicating an augmented synthetic lethal relationship between XPA, MK2, and mutant p53 in the presence of DNA crosslinks. A second targeted CRISPRi screen implicated several known and novel RNA-binding proteins (RBPs) as potent sensitizers of HGSOC to both platinum agents and taxanes, including the RNA-modifying enzyme ADAR1. Together, these findings indicate that (1) platinum-induced interstrand DNA crosslinks, which require repair by FA and HR, rather than intrastrand crosslinks repaired by NER, are the primary determinants of tumor cell survival following treatment, (2) loss of NER function alone, which only modestly sensitizes cells to platinum-induced DNA crosslinks, results in a markedly enhanced dependence of the DNA-damaged tumor cells on sustained cell cycle checkpoint arrest mediated by MK2 for tumor cell survival, and that (3) a small subset of RBPs control the sensitivity of ovarian cancer cells to both platinum-based agents and anti-microtubule drugs that form the current clinical standard of care for HGSOC. Citation Format: Yi Wen Kong, Erika D. Handly, Robin A. Lu, Molly A. Bird, Hannah-Lou Schilling, Samkyu P. Yaffe, Michael B. Yaffe, David H. Koch. Genome-wide CRISPRi screening reveals determinants of platinum sensitivity and resistance in high-grade serous ovarian cancer [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 A035.
Abstract B015: RNA N6-methyladenosine (m6A) as a therapeutic target in Diffuse Midline Glioma (DMG)
Authors: Samuel E. Ross, Holly Holliday, Maria Tsoli, David S. Ziegler, Marcel E. Dinger
Journal: Cancer Research (2024)

Abstract Diffuse Midline Glioma (DMG) is an incurable pediatric brain tumor thought to originate from oligodendrocyte precursor cells in midline brain structures. The RNA modification N6-methyladenosine (m6A) plays an important role in RNA stability and is critical to neuronal stem-cell self-renewal and differentiation. We therefore sought to investigate m6A as a therapeutic target in DMG. Moreover, targeting the epitranscriptome has shown promise in the treatment of other cancers, and several small-molecule inhibitors of m6A writers and erasers have been recently developed. To that end, we tested the sensitivity of a panel of patient-derived DMG cell lines to FB23-2, an inhibitor of the m6A eraser FTO, and STM2457, an inhibitor of the mRNA m6A writer METTL3. In order to interrogate the therapeutic mechanisms and identify predictive biomarkers for response, we then performed RNA-seq to measure gene expression changes, and native RNA-seq to measure RNA m6A levels. We found that DMG cell lines were more sensitive to FB23-2 (IC50 ~10μM) than STM2457 (IC50 ~100μM), indicating that m6A gain rather than loss may be a potential therapeutic strategy. Furthermore, we observed variation in FB23-2 sensitivity between cell lines with RNA-sequencing identifying marked changes in the expression of cell cycle, cell stress response, and differentiation associated genes in the cell lines which responded best to FB23-2. Additionally, these analyses also identified several potential biomarkers for response to FB23-2. Finally, we generated the first m6A transcriptome maps for DMG using native RNA sequencing and demonstrated that m6A is abundant in DMG cell lines and is particularly enriched on cell cycle, cell stress response, and metabolic pathway transcripts. Overall, our work identified the FTO m6A demethylase as a potential therapeutic target in DMG, whereby its inhibition with FB23-2 increases m6A abundance, altering the stability of critical transcripts and pathways. Citation Format: Samuel E. Ross, Holly Holliday, Maria Tsoli, David S. Ziegler, Marcel E. Dinger. RNA N6-methyladenosine (m6A) as a therapeutic target in Diffuse Midline Glioma (DMG) [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B015.
Abstract PR-007: H3.3K27M diffuse midline gliomas are sensitive to SWI/SNF chromatin remodeler degradation
Authors: Mateus Mota, Stefan Sweha, Matt Pun, Siva Kumar Natarajan, Yujie Ding, Chan Chung, Debra Hawes, Fusheng Yang, Alexander Judkins, Susanta Samajdar, Xuhong Cao, Lanbo Xiao, Abhijit Parolia, Arul Chinnaiyan, Sriram Venneti
Journal: Cancer Research (2024)

Abstract Diffuse Midline Gliomas (DMG) including Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. The lysine 27 (K27)-to-methionine (M) point mutation in histone H3.1 or H3.3 (H3.1K27M or H3.3K27M, respectively) affects about 80% of patients establishing H3K27M mutation as a tumor hallmark. Mutated H3 histones inhibit the function of Polycomb repressive complex 2 resulting in global reduction of repressive H3K27me3. In addition, increased acetylation of H3K27 is observed, further contributing to an aberrant chromatin state. Considering the impact of epigenetic alterations in DIPG, we investigated the role of Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelers in shaping the oncogenic chromatin state in DIPG cells. DIPG cells harboring H3.3K27M mutation were sensitive to combined SMARCA4/SMARCA2/PBRM1 degradation by the proteolysis targeting chimera (PROTAC) AU-15330 degrader. Our premise is based on the SWI/SNF complex altering chromatin states of tumor cells to regulate the tumor immune microenvironment. We hypothesized that the SWI/SNF complex in tumor cells modulates immune responses in DIPG. Cytokine profiler arrays in AU-15330 versus vehicle treated H3.3K27M cells showed a marked decrease of Intercellular Cell Adhesion Molecule-1 (ICAM-1) glycoprotein levels. In addition to its well-known role in leukocyte endothelial transmigration, ICAM-1 contributes to malignant potential of tumor cells. We validated downregulation of ICAM-1 mRNA and protein levels by AU-15330 by immunoblotting, proteomics, and transcriptomics, suggesting an epigenetic regulation of ICAM-1 gene transcription by the SWI/SNF complex. Moreover, silencing of mutant H3.3-encoding gene decreased ICAM-1 protein levels, suggesting ICAM-1 expression is promoted by H3.3K27M mutation-induced SWI/SNF chromatin remodeling in DIPG. In conclusion, our work suggests the H3.3K27M mutation renders DIPG cells dependent on chromatin remodeling by SWI/SNF complexes that can in turn alters the expression of immune system-associated components, such as ICAM-1. Our future work is geared to understanding the role of the SWI/SNF complex in regulating the immune tumor microenvironment in H3K27M DMGs. Citation Format: Mateus Mota, Stefan Sweha, Matt Pun, Siva Kumar Natarajan, Yujie Ding, Chan Chung, Debra Hawes, Fusheng Yang, Alexander Judkins, Susanta Samajdar, Xuhong Cao, Lanbo Xiao, Abhijit Parolia, Arul Chinnaiyan, Sriram Venneti. H3.3K27M diffuse midline gliomas are sensitive to SWI/SNF chromatin remodeler degradation [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-007.
Treatment‐free remission in <scp>CML</scp> patients with additional chromosome abnormalities in the Philadelphia‐positive clone or variant Philadelphia translocations
Authors: Simone Claudiani, Lynette Chee, Fiona Fernando, Loretta Brown, Udayakumar M. Achandira, Afzal Khan, Kate Rothwell, Chloe Hayden, Ioannis Koutsavlis, Guy Hannah, Andrew Innes, Jane F. Apperley, Dragana Milojkovic
Journal: American Journal of Hematology (2024)

Probability of treatment-free remission (TFR) in CML patients with additional chromosomal abnormalities (ACA) in the Philadelphia-positive clone or variant Philadelphia translocations (ACA/Var-Ph group, blue panel), in those with no cytogenetic abnormality other than the classical Philadelphia translocation (c-Ph group, green panel) and in the subgroups of CML patients with high-risk ACA (HR-ACA, yellow panel) and Var-Ph (red panel).
Toward Heart-Healthy and Sustainable Cities: A Policy Statement From the American Heart Association
Authors: Sanjay Rajagopalan, Anu Ramaswami, Aruni Bhatnagar, Robert D. Brook, Mark Fenton, Christopher Gardner, Roni Neff, Armistead G. Russell, Karen C. Seto, Laurie P. Whitsel
Journal: Circulation (2024)

Nearly 56% of the global population lives in cities, with this number expected to increase to 6.6 billion or >70% of the world's population by 2050. Given that cardiometabolic diseases are the leading causes of morbidity and mortality in people living in urban areas, transforming cities and urban provisioning systems (or urban systems) toward health, equity, and economic productivity can enable the dual attainment of climate and health goals. Seven urban provisioning systems that provide food, energy, mobility-connectivity, housing, green infrastructure, water management, and waste management lie at the core of human health, well-being, and sustainability. These provisioning systems transcend city boundaries (eg, demand for food, water, or energy is met by transboundary supply); thus, transforming the entire system is a larger construct than local urban environments. Poorly designed urban provisioning systems are starkly evident worldwide, resulting in unprecedented exposures to adverse cardiometabolic risk factors, including limited physical activity, lack of access to heart-healthy diets, and reduced access to greenery and beneficial social interactions. Transforming urban systems with a cardiometabolic health-first approach could be accomplished through integrated spatial planning, along with addressing current gaps in key urban provisioning systems. Such an approach will help mitigate undesirable environmental exposures and improve cardiovascular and metabolic health while improving planetary health. The purposes of this American Heart Association policy statement are to present a conceptual framework, summarize the evidence base, and outline policy principles for transforming key urban provisioning systems to heart-health and sustainability outcomes.
Abstract B039: Identification of sex-specific molecular features in glioma transcriptome
Authors: Yingbo Huang, Yuting Shan, Weijie Zhang, Christina Printzis, Lorenzo Pesce, Barbara Elaine Stranger, R. Stephanie Huang
Journal: Cancer Research (2024)

Abstract Glioma is a lethal disease with limited treatment options available. Sex differences in glioma are well-documented in clinical settings, with males having twice the risk of developing the disease and increased mortality compared to female counterparts. To investigate the molecular basis of sex differences in glioma, we analyzed transcriptomic sex differences in a collection of three independent glioma datasets and validated them in additional independent studies. The impact of differentially expressed genes were assessed through Gene Set Enrichment Analysis (GSEA) on approximately 5000 gene sets to interpret their biological relevance. Given the well-recognized heterogeneity of glioma, we also integrated three single-cell RNA (scRNA) sequencing datasets to decipher the sex differences in cellular composition and cell-type specific differential gene expression between male and female tumors. The effects of sex on gene expression are modest and primarily driven by the X chromosome (14 out of 16 differentially expressed genes were on the X chromosome). These genes are associated with escape from X-chromosome inactivation (e.g., KDM5C, KDM6A) and are also sex-differentially expressed (DE) in the healthy human brain according to Genotype-Tissue Expression (GTEx) data. GSEA results suggest increased activity in cell proliferation and neuronal signaling in male GBM samples, whereas females show enrichment in glycoprotein/lipid metabolism. By deconvoluting the cell-type composition, we identified a higher percentage of pericytes in the male glioma tumor microenvironment compared to those in females, which is consistent with recent spatial-omic discoveries in glioma. By integrating scRNA sequencing data, we found that both differentially expressed genes and pathways show cell-type-specific enrichment. For example, the female-biased gene GBGT1 is exclusively expressed in the myeloid lineage, while male-biased neuronal pathways are enriched in cancer stem cells. Integrating with the inference of cell trajectories, we observed that male tumors harbor more unconnected, invasive malignant cells than females, which might explain the poor prognosis in male glioma patients. In summary, our results provide a comprehensive multi-level characterization of sex differences in glioma tumors, and these findings will provide novel insights into glioma disease progression and development of new therapy. Citation Format: Yingbo Huang, Yuting Shan, Weijie Zhang, Christina Printzis, Lorenzo Pesce, Barbara Elaine Stranger, R. Stephanie Huang. Identification of sex-specific molecular features in glioma transcriptome [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B039.
Phosphatidic Acid Promoting the Generation of <scp>Interleukin‐17A</scp> Producing <scp>Double‐Negative</scp> T Cells by Enhancing <scp>mTORC1</scp> Signaling in Lupus
Authors: Wenjing Li, Xiaojun Tang, Yuanyuan Zheng, Xuefeng Xu, Nan Zhao, Betty P. Tsao, Xuebing Feng, Lingyun Sun
Journal: Arthritis & Rheumatology (2024)

Objective The goal was to investigate the role and intracellular regulatory mechanisms of double‐negative T (DNT) cells in the pathogenesis of systemic lupus erythematosus (SLE). Methods DNT cells were assessed in murine models, patients with SLE, and controls using flow cytometry (FCM). DNT cells from either resiquimod (R848) or vehicle‐treated C57BL/6 (B6) mice were cultured with B cells from R848‐treated mice to explore functions. Differential mechanistic target of rapamycin (mTOR) pathway signaling in DNT cells measured using FCM and quantitative polymerase chain reaction was validated by rapamycin inhibition. Candidate lipid metabolites detected using liquid chromatography with electrospray ionization mass spectrometry/mass spectrometry were functionally assessed in DNT cell cultures. Results DNT cells were markedly increased in both spontaneous and induced mouse lupus models and in patients with SLE. Expanded DNT cells from R848‐treated B6 mice produced elevated interleukin (IL)‐17A and IgG with increased germinal center B (GCB) cells. Expansion of DNT cells associated with activation of mTORC1 pathway that both IL‐17A levels and the number of DNT cells exhibited dose‐dependent reduction with rapamycin treatment. Lipidomics studies revealed differential patterns of lipid metabolites in T cells of R848‐treated mice. Among candidate metabolites, elevated phosphatidic acid (PA) that was partially controlled by phospholipase D2 increased the expression of the mTORC1 downstream target p‐S6 and positively expanded IL‐17A–producing DNT cells. Similarly, elevated proportions of circulating DNT cells in patients with SLE correlated with disease activity and proteinuria, and IL‐17A secretion was elevated after in vitro PA stimulation. Conclusion The accumulation of PA in T cells could activate the mTORC1 pathway, promoting DNT cell expansion and IL‐17A secretion, resulting in GCB cell abnormalities in lupus. image