bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3623: Targetable cofactor landscape of transcription factors in human cancers
Authors: Thatikonda Venu , Lipp Jesse , Schlattl Andreas , Gerlach Daniel , Popa Alexandra 
Published: June 2022

Abstract
Transcription factors (TF) are proteins that bind to DNA to regulate target gene expression and play a crucial role in maintaining tumor initiating and maintenance programs. However, except for a small fraction, it is difficult to directly target TF proteins due to lack of defined pockets and inherent protein-DNA, protein-protein interactions. In many cases, TF activity is tuned via cofactors, which e.g. dimerize to bind DNA (MYC/MAX) or maintain active TF protein turnover (HIF1A/EGLN1, MYC/HDAC2). Identifying such targetable cofactors of TFs will open new opportunities to target oncogenic TFs in cancers. Genome-scale CRISPR knock-out screens have been proven to be a valuable resource for identifying targets and biomarkers in cancers. In this work, we developed a framework called CONTEXT (COfactor depeNdencies in high Transcription factor EXpression phenoType) utilizing functional genomic screens and matched TF expression data. In CONTEXT, we aim to identify cofactor dependencies associated with TF activities using 859 cell lines spanning 28 cancer types. We further utilized patient cancer gene expression data from the TCGA project, to prioritize clinically relevant TF-cofactor associations. In total, we identified 1,003 TF-cofactor associations which involve 196 and 503 unique TFs and cofactors, respectively. Our approach reliably identified previously known TF-cofactor associations e.g. HIF1A/EGLN1, HIF1A/VHL, TEAD1/JUN but also previously unknown associations such as TEAD1/RAC1 or TEAD1/PTK2. Our analysis and validations provide a framework for the identification of potential cofactors of TFs which are crucial for the development and progression of cancer. We anticipate the cofactor dependencies from this resource to guide early stage drug development and inform on potential combination therapies in resistant phenotypes.
Citation Format: Venu Thatikonda, Jesse Lipp, Andreas Schlattl, Daniel Gerlach, Alexandra Popa. Targetable cofactor landscape of transcription factors in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3623.
Abstract 3712: The C-terminal HSP90 inhibitor, a novel deguelin derivative, exerts anti-metastatic effects in triple-negative breast cancer by targeting cancer stem-like properties
Authors: Park Minsu , Cho Tae-Min , Park Soeun , Park Jung Min , Seo Juyeon , Ko Dongmi , Kim Seongjae , Seuk So Ra , Kang Yong Gu , Nam Kee Dal , Kim Yoon-Jae , Kim Ji Young , Seo Jae Hong 
Published: June 2022

Abstract
Purpose: Triple-negative breast cancer (TNBC) still relies on non-selective cytotoxic anticancer agents due to the absence of established molecular targets for the phenotype. The heat shock protein 90 (HSP90) is a promising therapeutic target because it affects the overall progression of cancer, including cell proliferation, angiogenesis and metastasis. A variety of N-terminal HSP90 inhibitors have been tried several times in clinical trials, but none have been approved for clinical use to date due to issues including heat shock response (HSR) induction, undesirable effects, and clinical toxicity. In this study, we sought to investigate whether a novel C-terminal HSP90 inhibitor SL-145 could resolve metastasis in TNBC through inhibition of cancer stem-like properties.
Experimental Design: The effects of SL-145 on TNBC cell lines in vitro were evaluated in terms of cell proliferation, apoptosis, caspase-3 activity, breast cancer stem cell (BCSC)-like properties and heat shock response. An orthotopic allograft model with 4T1 mammospheres was used to examine the effect of SL-145 on tumor growth and metastasis in vivo.
Results: SL-145 induces apoptosis without triggering the HSR and simultaneously inhibits several oncogenic signaling pathways including AKT, MEK/ERK and JAK2/STAT3. SL-145 effectively targets BCSC-like properties with significant reductions in CD44, CD49f and ALDH1 expression as well as impairment of mammosphere-forming ability. To confirm the physiological relevance of our in vitro observations, we investigated the effects of SL-145 on tumor growth, angiogenesis and metastasis in mammosphere-derived allograft tumors with self-renewal capacity. SL-145 administration reduced tumor burden and angiogenesis, which were enriched in BCSCs, and it resulted in significant reductions in lung and liver metastases. In addition, no toxic effects of inhibitors on markers of liver or renal function were observed.
Conclusion: Our findings suggest that SL-145 may represent an effective therapeutic approach for targeting cancer stem cells and simultaneous inhibition of the HSP90 client oncoprotein to treat TNBC with a heterogeneous and aggressive nature.
Citation Format: Minsu Park, Tae-Min Cho, Soeun Park, Jung Min Park, Juyeon Seo, Dongmi Ko, Seongjae Kim, So Ra Seuk, Yong Gu Kang, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. The C-terminal HSP90 inhibitor, a novel deguelin derivative, exerts anti-metastatic effects in triple-negative breast cancer by targeting cancer stem-like properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3712.
Abstract 3804: Interferon gamma induces NOS2 and COX2 expression in estrogen receptor negative breast cancer leading to immunosuppressive tumor microenvironment
Authors: Cheng Yuk Sing Robert , Ridnour Lisa , Somasundaram Veena , Bhattacharyya Dana , McGinity Christopher , McVicar Daniel , Anderson Stephen , Lockett Stephen , Wink David 
Published: June 2022

Abstract
Breast cancer is the second leading cause of cancer death among U.S. women although the mortality is on a steadily decreasing trend since early 90s. We previously demonstrated a strong correlation between elevated NOS2 and COX2 expressions suggesting these genes can serve as markers of poor prognosis in estrogen receptor negative (ER-) breast cancer. In other words, NOS2 and COX2 is generally associated with the immune response. Induction of NOS2 and COX2 has also been shown to orchestrate multiple pro-oncogenic pathways that may contribute to the immunosuppressive nature of cancer cells. To better understand the interactions between cytokines and breast cancer cells and develop effective therapeutics for breast cancer, we examined the effects of selected cytokines on MDA-MB-231, a human (ER-) breast adenocarcinoma cell line. We found that in combination with cytokines, such as IFNG plus TNF, IL1B, or IL17, significantly induced NOS2 and COX2. IFNG plus TNF or IL1B most strongly induced NOS2 and COX2 where IFNG or IL17 to a lesser extent. It indicates that expressions of NOS2 and COX2 required IFNG but at a low dose in presence of other cytokines. Single-cell RNAseq analysis shows that cells treated with IFNG plus TNF or IL1B clustered with those expressed NOS2 and COX2 as revealed in tSNE plots. Expression of other factors such as IL8 and IL6 (suggested markers for prognosis of breast cancer) or PDL1 and IDO1 (suggested cancer therapeutic targets) also co-clustered with NOS2 and COX2 expressions. In addition, we found increased IL1A and IL1B expressions provide fortification to NOS2 and COX2 expressions. Taken together, our current findings indicate the interactions between breast cancer cells and cytokines. We believe further spatial transcriptomic and proteomic studies may be beneficial for clarifying the complex networks of the immunosuppressive tumor microenvironment.
Citation Format: Yuk Sing Robert Cheng, Lisa Ridnour, Veena Somasundaram, Dana Bhattacharyya, Christopher McGinity, Daniel McVicar, Stephen Anderson, Stephen Lockett, David Wink. Interferon gamma induces NOS2 and COX2 expression in estrogen receptor negative breast cancer leading to immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3804.
Abstract 3848: Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow
Authors: Whiteley Andrew E. , Price Trevor T. , Simon Brennan G. , Xu Katie R. , Sipkins Dorothy A. 
Published: June 2022

Abstract
Breast cancer cell (BCC) metastasis to the leptomeninges (LM) is an increasingly common disease complication with a grim prognosis of weeks to months. There are currently few therapeutic options to prevent or treat leptomeningeal disease (LMD), in part due to our limited knowledge of the molecular pathways involved in tumor invasion and survival within this unique niche. Here we show that BCCs in mice can bypass the restrictive blood-brain barrier and invade the LM by migrating along the abluminal surface of emissary vessels that connect the vertebral/calvarial bone marrow and meninges. This is mediated by tumor cell integrin α6 engaging extracellular matrix laminin on the vascular basement membrane. Upon invasion of the LM, BCCs co-localize with CSF1R+ meningeal macrophages/microglia in the perivascular space. We demonstrate that ablation of these myeloid cells by CSF1R inhibition leads to prolonged disease-free survival due to decreased LMD burden. Importantly, we show that CSF1R+ cell depletion does not prevent tumor cell LM colonization, but instead limits disease expansion within the LM, highlighting the pro-tumor phenotype of these meningeal macrophages/microglia. Our data suggest that meningeal macrophages/microglia support BCC proliferation/survival by up-regulating glial cell line-derived neurotrophic factor (GDNF), a key neurotrophic factor released by macrophages/microglia in response to neuronal injury. In vitro, GDNF protects BCCs from cell death induced by glucose deprivation, suggesting that tumor cells may hijack a macrophage neuronal injury response program to thrive within the nutrient-poor LM niche. Unexpectedly, we found that integrin α6 deletion or antibody blockade eliminates the protective role of GDNF by modulating GDNF/NCAM receptor signaling in BCCs. Taken together, our data suggest that BCCs co-opt neuronal pathfinding mechanisms and resident macrophages/glia to efficiently invade and thrive within the LM niche. Integrin α6 appears to be a master regulator of this neuronal mimicry through its ability to promote abluminal vessel trafficking and mediate responsiveness to GDNF. Finally, a case-control study of bone-metastatic breast cancer patients reveals a significant correlation between integrin α6 expression and incidence of dural-based meningeal metastasis, suggesting the clinical relevance of this pathway and potential role of α6 integrin as a biomarker of LMD risk and therapeutic target.
Citation Format: Andrew E. Whiteley, Trevor T. Price, Brennan G. Simon, Katie R. Xu, Dorothy A. Sipkins. Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3848.
Abstract 387: Blood brain barrier (BBB) disruption by tumor treating fields (TTFields) in a human 3D in vitro model
Authors: Salvador Ellaine , Kessler Almuth F. , Köppl Theresa , Schönhärl Sebastian , Burek Malgorzata , Brami Catherine Tempel , Voloshin Tali , Giladi Moshe , Ernestus Ralf-Ingo , Löhr Mario , Förster Carola Y. , Hagemann Carsten 
Published: June 2022

Abstract
The clinical translatability of novel drug delivery systems begins with basic scientific breakthroughs. Our recent discovery of the ability of Tumor Treating Fields (TTFields) to potentially and transiently disrupt the blood brain barrier (BBB) using our murine in vitro and in vivo models, led us to validate our findings in a human 3D in vitro model established in our lab. The model consists of primary brain microvascular endothelial cells co-cultured with immortalized perciytes in a transwell system. TTFields are alternating electric fields of low intensity (1-3V/cm) and intermediate frequency (100-300kHz), which are effective and approved for the treatment of glioblastoma (GBM) using 200kHz frequency. Our murine data point out that TTFields could disrupt the BBB optimally at 100kHz. To investigate if TTFields exhibit similar effects in the human cell-based in vitro model, it was subjected to TTFields at various frequencies for 24-96h. Cells were afterwards made to recover for 24-96h. To assess BBB integrity and compromise, transendothelial electrical resistance (TEER) was measured before start of TTFields, immediately after end of TTFields, as well as 24-96h after TTFields. In addition, a permeability assay was performed. Finally, immunofluorescence (IF) staining visualized the effects of TTFields on tight junction protein claudin-5 localization. TTFields application of all investigated frequencies significantly decreased TEER. However, the strongest effects were observed with 100kHz after 72h. IF staining revealed delocalization of claudin-5 from the cell boundaries to the cytoplasm. Restoration of cell integrity was already evident as early as 24h, with complete recovery after 48h. Results using our human 3D in vitro model validated our previous observations from murine in vitro and in vivo models that TTFields could transiently disrupt the BBB. These findings provide fundamental pre-clinical data for translation from bench to bedside. Accordingly, TTFields demonstrate to be a promising novel approach in opening the BBB to facilitate drug delivery for improved treatment of central nervous system diseases including devastating brain tumors such as GBM.
Citation Format: Ellaine Salvador, Almuth F. Kessler, Theresa Köppl, Sebastian Schönhärl, Malgorzata Burek, Catherine Tempel Brami, Tali Voloshin, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Y. Förster, Carsten Hagemann. Blood brain barrier (BBB) disruption by tumor treating fields (TTFields) in a human 3D in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 387.
Abstract 391: Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids
Authors: Pappas Kyrie Jean , Karthaus Wouter , Laclair Justin , Russo Marco , Sawyers Charles 
Published: June 2022

Abstract
Cancers harboring bi-allelic loss of the breast cancer genes (BRCA1 and BRCA2) are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi), which are clinically approved in breast, ovarian, and more recently prostate cancer. Genetic alteration of BRCA2 is frequent in metastatic castration-resistant prostate cancer (mCRPC), and confers sensitivity to the PARPi olaparib; however, resistance is anticipated. mCRPC has a unique genetic landscape, and is likely to present different mechanisms of resistance compared to breast and ovarian cancer because loss of BRCA2 in prostate cancer occurs primarily through a large deletion of 13q that frequently includes Rb1; a setting in which reversion mutations of Brca2 are not possible.
We have developed Brca2-deficient olaparib-sensitive murine prostate organoid models in clinically relevant genetic backgrounds (Brca2∆/∆Trp53∆/∆Pten∆/∆, Brca2∆/∆Trp53∆/∆, and Brca2∆/∆ sgRb1), as well as cell lines and patient-derived xenografts (PDX) to identify molecular mechanisms of olaparib resistance. We employed a genome-wide sgRNA positive selection screen to identify gene drivers of olaparib resistance in Brca2-deficient murine prostate organoid models. Putative resistance drivers are involved in many relevant pathways including DNA replication and repair, PARP1 substrate NAD+ metabolism, and androgen receptor signaling. While some pathways are genotype-specific, some are driving resistance in a pan-genotype manner. We are currently using our olaparib-sensitive model systems to validate specific resistance drivers in vitro and in vivo, determine their specificity to the BRCA1 or BRCA2 loss settings, and unravel the precise molecular mechanisms behind these resistance drivers.
Citation Format: Kyrie Jean Pappas, Wouter Karthaus, Justin Laclair, Marco Russo, Charles Sawyers. Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 391.
Abstract 395: Characterizing the role of chaperone-mediated autophagy in prostate cancer treatment resistance
Authors: Nikesitch Nicholas , Beraldi Eliana , Zhang Fan , Adomat Hans , Bell Robert , Fazli Ladan , Wells Christopher , Pinette Nicholas , Wang Yuzhuo , Gleave Martin 
Published: June 2022

Abstract
Androgen deprivation therapy (ADT) and androgen receptor pathway inhibition (ARPI) remains the standard of care for advanced prostate cancer (PCa). As part of its canonical activities, the androgen receptor (AR) plays an important role in PCa metabolism. AR inhibition with ARPI subjects PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. The upregulation of ARPI-induced stress response mechanisms is essential adaptive mechanism for cell proliferation and survival. This process requires PCa cells undergoing rapid phenotypic changes to adapt to their environment and circumvent lethal outcomes. By profiling the proteomic pathway alterations associated with the ARPI stress response in LNCaP cells, we noted a significant upregulation of chaperone mediated autophagy (CMA), a stress response mechanism yet to be defined in PCa. CMA, a selective protein degradation pathway, specifically targets protein substrates via a CMA recognition motif and is an essential survival mechanism in cancer cells during energy depleted metabolic stress. Within in-vitro and in-vivo PCa models, ARPI induced CMA is reflected through the increased activity of CMA lysosomes and specifically by the increased expression of the CMA marker, lysosomal associated membrane protein 2a (L2A). L2A knockdown using shRNA not only elicited a strong anti-proliferative effect in PCa cells, but also compromised PCa metabolism with decreases in ATP levels and mTORC1 signaling. Proteomic analysis by mass spectrometry further identified that CMA promotes chromatin silencing, and the suppression of pathways associated with transcription. Conversely, L2A overexpression not only promoted PCa cell proliferation during Enza treatment, but upregulated of hallmark target genes of AR-indifferent PCa growth. The upregulation of CMA facilitated proteome remodeling during ARPI, leading to increased mTORC1 signaling and biosynthesis. In summary, our data illustrates the importance of CMA in mediating the ARPI stress response in PCa, providing novel insights into the mechanisms of ARPI treatment resistance.
Citation Format: Nicholas Nikesitch, Eliana Beraldi, Fan Zhang, Hans Adomat, Robert Bell, Ladan Fazli, Christopher Wells, Nicholas Pinette, Yuzhuo Wang, Martin Gleave. Characterizing the role of chaperone-mediated autophagy in prostate cancer treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 395.
Abstract 398: Tribbles 2 confers resistance to anti-androgenic therapy in prostate cancer via lineage switching
Authors: Monga Jitender , Adrianto Indra , Rogers Craig , Gadgeel Shirish , Chitale Dhananjay , Ghosh Jagadananda 
Published: June 2022

Abstract
Background: About 33,000 men will die due to prostate cancer in the US in the year 2021. Prostate cancer initially responds to androgen receptor (AR) targeted therapies (e.g., enzalutamide, darolutamide). However, therapy-resistant, aggressive, lethal malignancy invariably develops for which no effective, targeted treatment options are available. Though failures of AR-targeted therapies remain as major cause for mortality among prostate cancer patients, molecular mechanisms underlying the emergence of resistance are still to be fully characterized.
Methods: To understand the molecular basis of enzalutamide resistance, we developed a prostate cancer cell model to mimic the clinical conditions in enzalutamide-resistant disease. These cells were transcriptionally profiled for gene expression analysis by Illumina Hi-Seq whole genome gene-expression array. Hits were validated by RT-qPCR and Western blot. For clinical correlation, samples from enzalutamide treated prostate PDX models as well as surgical prostate tumors from patients were comprehensively analyzed. Role of new hits were determined by lentiviral shRNAs and analysis of cell viability, apoptosis, and downstream targets. Pro-cancer effects were analyzed by cell proliferation, invasion, and soft-agar colony formation.
Results: We identified that the Tribbles 2 (TRIB2) pseudokinase is overexpressed in enzalutamide resistant prostate cancer (ERPC) cells. Elevated level of TRIB2 was also observed in enzalutamide treated PDX tumors in mice, and in prostate tumors from patients who were treated with enzalutamide. We found that TRIB2 protein level is especially higher in prostate cancer cells where the AR activity is low, or absent due to genetic changes. Forced overexpression of TRIB2 results in aggressive prostate cancer cell growth and makes the cells resistant to enzalutamide. Conversely, inhibition of TRIB2 by shRNA or chemical inhibitor decreases viability and re-sensitizes ERPC cells back to enzalutamide, suggesting that TRIB2 plays an important role as a driver in the resistance mechanism. Interestingly, TRIB2 downregulates luminal markers, but upregulates neuroendocrine markers via the master neuronal transcription factor, BRN2, and the reprogramming factor, SOX2. Inhibition of either BRN2 or SOX2 also re-sensitizes ERPC cells to enzalutamide.
Conclusion: These findings suggest that TRIB2 confers resistance to enzalutamide therapy through lineage switching from luminal to neuroendocrine type, involving BRN2 and SOX2.
Citation Format: Jitender Monga, Indra Adrianto, Craig Rogers, Shirish Gadgeel, Dhananjay Chitale, Jagadananda Ghosh. Tribbles 2 confers resistance to anti-androgenic therapy in prostate cancer via lineage switching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 398.