tbuckley/cabot-search huggingface dataset:
Abstract 2634: IL34-induced Arg1 positive macrophage cells at the edge of invasion in cerebellum metastasis model of HER2-positive breast cancer
Authors: Xiaoqing (Cathy) Cheng, Khooshbu Kantibhai Patel, Yiwei Fu, Ryan Cleary, Brandon Zhou, Maureen Highkin, Jacob Hsia, Xiaohua Jin, Julie L. Prior, Megan Michie, Rui Sun, Ian S. Hagemann, Tristan Li, Vaibhav Jain, Simon Gregory, Albert Kim, Ron Bose
Journal: Cancer Research (2025)

Abstract Brain metastases occur in about 30% breast cancer patients. The cerebellum is a frequent location for metastases in HER2-positive breast cancer patients, but the mechanisms for this is unknown. We hypothesize that the cerebellar microenvironment plays a crucial role in promoting the growth of metastatic HER2+ breast cancer cells. To study the interaction between cerebellar cells and metastatic breast cancer, we developed a syngeneic, immunocompetent mouse model for breast cancer brain metastasis, by stereotactically injecting mouse breast cancer organoids with HER2V777L; PIK3CAH1047R activating mutations or HER2V777L; TP53fl/fl1 into the cerebellum. Growth of these cerebellar metastasis was monitored both by MRI and also with Herceptin imaging using a Near-Infrared fluorophore conjugated to Herceptin. We observed significant tumor growth in the cerebellum for up to 7 weeks post injection. We further investigated cellular interactions within the pro-tumorigenic microenvironment and HER2+ breast cancer cells using spatial transcriptomics. We identified inflammation-induced ARG1+ macrophage cells at the edge of the cerebellar metastasis. Further, the cytokine IL34 is upregulated in the brain metastasis. IL34, which is secreted by HER2+ breast cancer, induces Arg1 expression in both homeostatic microglial cells and bone marrow derived macrophages. These results suggest IL34 polarizes macrophages facilitating tumor invasion in the brain. These novel mouse models and findings elucidate the molecular mechanisms and the role of the tumor microenvironment that promotes cerebellar metastasis, and suggest a therapeutic approach to inhibit breast cancer invasion into the brain. Citation Format: Xiaoqing (Cathy) Cheng, Khooshbu Kantibhai Patel, Yiwei Fu, Ryan Cleary, Brandon Zhou, Maureen Highkin, Jacob Hsia, Xiaohua Jin, Julie L. Prior, Megan Michie, Rui Sun, Ian S. Hagemann, Tristan Li, Vaibhav Jain, Simon Gregory, Albert Kim, Ron Bose. IL34-induced Arg1 positive macrophage cells at the edge of invasion in cerebellum metastasis model of HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2634.
Abstract 3451: Exploring the impact of neoantigen expression on lung tumor development
Authors: Jennifer Loza, Ishan Bansal, Brian Hunt, Kelli Connolly, Srividhya Venkatesan, Advait Jeevanandam, Nikhil Joshi
Journal: Cancer Research (2025)

Abstract Lung adenocarcinoma (LUAD) stands as a formidable challenge in oncology, despite the emergence of immunotherapy as a promising treatment avenue. The dynamic interplay between the immune system and cancer plays a pivotal role in shaping cancer development and progression. Central to this process are neoantigens, tumor-specific antigens recognized by cytotoxic T cells, which trigger the elimination of tumor cells. It has been implicated that the presence of T cells also decreases tumor grade. However, the precise impact of neoantigen expression on LUAD development and progression remains poorly understood. Our lab previously developed a genetically engineered mouse model with the ability to induce expression of a fluorescent neoantigen in oncogenic KRAS, P53-null, tdTomato-expressing lung adenocarcinoma cells. Using this system, we track tumor initiation, progression, and advanced LUAD development across 20 weeks in both immune-deficient and -sufficient settings. Further, tumors initiated in this system give rise to heterogeneous (neoantigen+ and -) tumors, enabling the study of T cell-driven tumor selection. Through multiplexed immunofluorescence, we identified that neoantigen+ tumors experience increased T cell infiltration and reduced volume, ultimately leading to prolonged animal survival. Surprisingly, advanced lung tumors maintain neoantigen+ cells, indicating that endogenous lung T cells are ineffective at clearing neoantigen-expressing tumor cells. Yet, we detected that infiltrated tumors exhibit reduced p-ERK expression, suggesting that T cells may slow tumor progression through non-cytotoxic mechanisms. Transferring stimulated neoantigen-specific T cells to tumor-bearing mice largely eliminated neoantigen+ tumor cells. All these data together suggest complex mechanisms for the role of endogenous T cells in controlling lung tumors. Through molecular characterization of tumor progression and T cell-mediated tumor suppression, this study reveals specific pathways that LUAD cells undergo during the process of development and progression, providing valuable insights into the immune response against neoantigen-expressing tumors. Ultimately, by unraveling the intricate interplay between neoantigen expression, immune surveillance, and tumor progression, this project aims to contribute significantly to our understanding of how neoantigens shape the dynamics of tumor biology. Citation Format: Jennifer Loza, Ishan Bansal, Brian Hunt, Kelli Connolly, Srividhya Venkatesan, Advait Jeevanandam, Nikhil Joshi. Exploring the impact of neoantigen expression on lung tumor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3451.
Abstract 3077: Pharmacological inhibition of NUAK1 and NUAK2 synergizes with chemotherapy in pancreatic cancer models by abrogating drug resistance and suppressing fibrosis
Authors: Minji Seo, Jihye Yoon, Song-Eun Park, Jong-Won Lim, Sungho Park, Yuntae Kim, Taeyoung Yoon
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-resistance cancers with a 5-year survival rates of around 10%. Since most PDAC cases are diagnosed at an advanced stage, current treatment options are essentially limited to chemotherapy, which is unfortunately barely effective. Therefore, the development of new, innovative therapies is desperately needed. PDAC is characterized by its desmoplastic nature and exceptionally high recurrence rates, both of which are also known to be furthered by chemotherapy. It is hypothesized that therapy-induced cell death exacerbates fibrosis and paradoxically facilitates resistance development. Therefore, concurrent inhibition of these pathways alongside cytotoxic therapy may enhance treatment outcomes in PDAC patients. NUAK family kinase1 and 2 are members of AMP-related kinase family, known to be implicated in cancer progression, cell adhesion, cell proliferation and metastasis. Elevated NUAK1/2 expression correlates with poor prognosis and patient survival rate in many cancer types including pancreatic cancer. Recently, it was also shown that NUAK1 inhibition by genetic knockdown or a chemical inhibitor reduced organ fibrosis via Hippo pathway modulation in mouse models. In this study, we demonstrate anti-chemoresistance and anti-fibrotic activities of P4899, a potent and selective NUAK1/2 dual inhibitor, in pancreatic cancer. Treatment of pancreatic cell lines with chemotherapeutic agents such as gemcitabine and cisplatin initially causes massive cell death, but the surviving cells undergo hyperploidy that eventually leads to repopulation of para-diploid cells, mimicking chemoresistance and tumor recurrence. In the presence of P4899, however, the number of the transient hyperploid cells as well as ensuing repopulation was dramatically reduced. Furthermore, administration of the orally bioavailable NUAK1/2 inhibitor in combination with gemcitabine in a mouse orthotopic PDAC model resulted in significant inhibition of tumor growth as well as reduction of collagen deposition and expression levels of fibrotic genes in tumor tissue. These data suggest that NUAK1/2 inhibition can effectively ameliorate desmoplasia and impede the development of chemo-resistance in pancreatic tumors, which warrants further investigation in the clinical setting. Citation Format: Minji Seo, Jihye Yoon, Song-Eun Park, Jong-Won Lim, Sungho Park, Yuntae Kim, Taeyoung Yoon. Pharmacological inhibition of NUAK1 and NUAK2 synergizes with chemotherapy in pancreatic cancer models by abrogating drug resistance and suppressing fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3077.
Abstract 3075: Targeting endoplasmic reticulum stress pathways to combat enzalutamide resistance in prostate cancer
Authors: Amos Olalekan Akinyemi, Md Rakibul Alam, Mithu Howlader, Jianlin Wang, Lixiang Gu, Xiaoqi Liu, Zhiguo Li
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) is a significant public health issue, ranking as the second leading cause of cancer-related death in men in the United States, with projections for 2024 estimating 299,101 new cases and 35,250 deaths. A critical driver of PCa progression, the androgen receptor (AR) signaling pathway remains a major therapeutic target, particularly in castration-resistant prostate cancer (CRPC). Although AR-targeted therapies such as abiraterone and enzalutamide were developed to delay the need for chemotherapy, they provide only modest survival benefits of approximately five and two months, respectively, emphasizing the need for more effective strategies. This research investigates a resistance mechanism in CRPC mediated by a kinase-driven phosphorylation of GRP78, a key chaperone protein that aids in cellular survival independent of conventional AR signaling pathways. In this study, we examine how this phosphorylation of GRP78 triggers post-translational modifications that support CRPC cell survival under AR-targeted therapy. Using both in vitro and in vivo approaches, we characterize this adaptive resistance pathway. In vitro assays using CRPC cell lines include RNA sequencing (RNA-Seq) for transcriptomic profiling, cell viability assays, proteasome activity measurements, and Western blot analysis to evaluate protein expression changes. Confocal microscopy and flow cytometry are employed to assess cellular responses, while kinase assays and mass spectrometry elucidate specific GRP78 modifications. Chromatin immunoprecipitation sequencing (ChIP-Seq) further investigates the impact of GRP78 modification on AR’s genomic binding. In vivo, CRPC xenograft models are treated with enzalutamide, allowing us to assess tumor progression and validate cellular findings via immunohistochemistry (IHC) and RNA-Seq analysis. Preliminary data indicate that phosphorylation-induced modifications of GRP78 enhance CRPC cell resilience under AR inhibition, supporting a proteostasis mechanism that counters therapeutic pressure. Targeting this adaptive response pathway may offer a novel strategy to disrupt resistance and improve the effectiveness of AR-directed therapies in advanced CRPC. By advancing insights into the cellular reprogramming associated with AR resistance, this work contributes to identifying new therapeutic targets for enhanced PCa management. Citation Format: Amos Olalekan Akinyemi, Md Rakibul Alam, Mithu Howlader, Jianlin Wang, Lixiang Gu, Xiaoqi Liu, Zhiguo Li. Targeting endoplasmic reticulum stress pathways to combat enzalutamide resistance in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3075.
Abstract 1510: Glutathione-oxidation of ovarian tumor deubiquitinase-1 promotes lung adenocarcinoma survival through stabilizing system xc-
Authors: Reem Aboushousha, Jos van der Velden, Nicholas Hamilton, Cuixia Erickson, David J. Seward, Jianing Li, Yvonne M. Janssen-Heininger
Journal: Cancer Research (2025)

Abstract The small thiol antioxidant glutathione (GSH) is critical in maintaining redox homeostasis that is essential in combating oxidative stress. We and others have reported increases of GSH in KRAS-mutant lung adenocarcinoma (LUAD). However, little is known about GSH-dependent protein oxidation (S-glutathionylation- PSSG) in LUAD development and progression. We recently discovered that glutaredoxin (GLRX), the enzyme that reverses PSSG, is decreased in human LUAD, and that KrasG12D-induced lung tumorigenesis is enhanced in mice lacking Glrx. To elucidate the link between PSSG and GSH levels we conducted a redox proteomics screen and identified ovarian tumor deubiquitinase-1 (OTUB1) as a glutathionylation target. We determined that OTUB1 glutathionylation at Cys23 and Cys204 is a regulator of GSH in LUAD cell lines and organoids. Mechanistically, glutathionylation of OTUB1, specifically at Cys23, promoted interaction with the E2-conjugating enzyme UBCH5A, leading to diminished ubiquitination and proteasomal degradation of the active subunit of system xC−, SLC7A11, thereby augmenting GSH. The cystine-glutamate antiporter, System xC−, has been linked to aggressive tumors with worse survival. The use of a specific inhibitor of OTUB1-SSG, led to decreased SLC7A11 and GSH levels in LUAD cell lines. These findings provide an intricate link between S-glutathionylation of OTUB1, GSH and system xC− and provide a mechanism by which LUAD cells combat oxidative stress. Avenues to interfere with OTUB1-SSG may provide a promising therapeutic approach to overcome LUAD progression and resistance. Funded by: R01 CA273238 Citation Format: Reem Aboushousha, Jos van der Velden, Nicholas Hamilton, Cuixia Erickson, David J. Seward, Jianing Li, Yvonne M. Janssen-Heininger. Glutathione-oxidation of ovarian tumor deubiquitinase-1 promotes lung adenocarcinoma survival through stabilizing system xc- [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1510.
Abstract 2635: E3 ubiquitin ligase ARIH1 mechanism and regulation in triple-negative breast cancer
Authors: Casey B. Staby, Vanessa Zapata, Sean Cruz, Kelly Anderson, Abigail Quesnelle, Breege Howley, Philip Howe
Journal: Cancer Research (2025)

Abstract We have recently identified a novel role for the ubiquitin E3 ligase ARIH1 in Epithelial-to-Mesenchymal transition (EMT) induction, tumor initiation, and metastatic progression of triple-negative breast cancer (TNBC). In TNBC cells, ARIH1 knockdown (KD) leads to a reduction in cell invasion and mammosphere formation, and loss of tumor initiation and metastasis. In this current study, we aim to define the underlying mechanisms controlling ARIH1 expression and contributing to ARIH1 function in TNBC. Quantitative proteomic analysis of control and ARIH1 silenced TNBC cells revealed an enrichment of mitochondrial proteins consistent with ARIH1’s role in mitophagy. Additionally, a striking deregulation of proteins involved in oxidative stress response was observed. This analysis revealed that ARIH1 increases in response to various oxidative stressors, as detected by qPCR and immunoblot. The ARIH1 promotor contains conserved motifs for transcription factors (TFs), including CREB1 and HIF1α sites, linked to oxidative stress. Of note, CREB1 is positively correlated with ARIH1 transcript in breast cancer patient tumors. These findings support the transcriptional upregulation of ARIH1 in response to oxidative stress and may explain why we see an upregulation of this protein during breast cancer progression.As ARIH1 plays a role in both mitochondrial dynamics and EMT, we tested ARIH1 silencing in response to Doxorubicin (Dox), a DNA-damaging agent that induces oxidative stress, and saw improved sensitivity compared to WT MDA-MB-231 cells. Next, we assessed ARIH1 expression in the Dox-resistant cell line of our model, showing ARIH1 is upregulated in these cells at the transcript level, supporting the oxidative stress model. To further understand the crucial players impacting chemoresistance mechanisms in relation to this protein, we will test the contribution of downstream targets in response to chemotherapy. We hypothesize ARIH1’s upregulation in response to oxidative stress and DNA-damaging treatment promotes cancer cell survival and enhances chemoresistance. This study expands on our novel discovery of ARIH1’s role in EMT and cancer progression. The significance of ARIH1 in TNBC is highlighted in patient data, where high ARIH1 expression is correlated with worse patient survival. Citation Format: Casey B. Staby, Vanessa Zapata, Sean Cruz, Kelly Anderson, Abigail Quesnelle, Breege Howley, Philip Howe. E3 ubiquitin ligase ARIH1 mechanism and regulation in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2635.
Abstract 2613: The role of the RNA methyltransferase RNAMT1 as a tumorigenic driver and therapeutic target in neuroblastoma
Authors: Kian Chung Chok, Kenny Ip, Jing Wu, Satyanarayana Gadde, Sujanna Mondal, Justin Wong, Belamy Cheung, Tao Liu
Journal: Cancer Research (2025)

Abstract Neuroblastoma is the most common extracranial solid tumor in children worldwide. We have found that high expression of the RNAMT1 gene in tumor tissues is associated with poor prognosis in both MYCN-amplified [Overall survival (OS): p = 0.0409 and event-free survival (EFS): p = 0.0061] and MYCN non-amplified neuroblastoma patients (OS: p &amp;lt; 0.0001 and EFS: p &amp;lt; 0.0001). Multivariable Cox regression analysis for neuroblastoma patient prognosis of RNAMT1 gene expression [OS: hazard ratio (HR) = 1.92, p = 0.003 and EFS: HR = 1.72, p = 0.0001] is independent from current prognostic markers: MYCN amplification (OS: HR = 3.39, p = 5.1E-8 and EFS: HR = 1.77, p = 0.0001), age older than 18 months (OS: HR = 2.73, p = 2.9E-5 and EFS: HR = 1.59, p = 0.01), and International Neuroblastoma Staging System stages 3&amp;4 (OS: HR = 5.68, p = 5.00E-6 and EFS: HR = 3.00, p = 6.83E-8). Doxycycline (DOX)-inducible RNAMT1 knockdown in MYCN-amplified and MYCN non-amplified neuroblastoma cells decreased cell viability and colony formation capability, and induced apoptosis in vitro. DOX-inducible RNAMT1 knockdown delayed tumor growth and improved survival in mice bearing SK-N-BE(2)-C shRNA1 (OS: p = 0.0034) and SK-N-AS shRNA2 (OS: p &amp;lt; 0.0001). RNAMT1 regulates protein translation based on previous literatures, we demonstrated that RNAMT1 did not affect global mRNA translation alteration via puromycin incorporation assay and slightly affected polysome profile. The subset of mRNA transcripts after RNAMT1 knockdown and RNAMT1 inhibitor treatment will be analyzed with translating ribosome affinity purification sequencing (TRAP-Seq). RNAMT1 inhibitor was discovered by AlphaScreen of 2952 small molecule compounds provided by National Cancer Institute (NCI). Unravelling the molecular mechanisms of RNAMT1 in neuroblastoma tumorigenesis and mechanism of actions of RNAMT1 inhibitor, may provide novel insights to develop a more effective treatment for neuroblastoma patients. Citation Format: Kian Chung Chok, Kenny Ip, Jing Wu, Satyanarayana Gadde, Sujanna Mondal, Justin Wong, Belamy Cheung, Tao Liu. The role of the RNA methyltransferase RNAMT1 as a tumorigenic driver and therapeutic target in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2613.
Abstract 1179: Epigenetic subtypes and cellular plasticity are driven by an interplay between RUNX2 and FOSL1 in osteosarcoma
Authors: Eunice Lopez Fuentes, Andrew S. Clugston, Alex Lee, Leanne Sayles, Alejandro Sweet-Cordero
Journal: Cancer Research (2025)

Abstract Chromatin accessibility is a crucial driver of cellular plasticity, priming gene expression and defining distinct cellular states. Variability in chromatin accessibility is a significant determinant of epigenetic transcriptional regulation and can reveal clinically relevant subtypes and biomarkers of therapy response. In osteosarcoma (OS), we identified two epigenetic subtypes, EC1 and EC2, using ATAC-seq analysis. These subtypes are defined by differential chromatin accessibility and transcriptional circuitry, with EC1 characterized by developmental transcription factors such as RUNX2, MEF2C, and homeobox proteins, while EC2 is dominated by AP1 transcription factors, including FOSL1 and FOSL2. Our findings reveal intricate regulatory mechanisms underpinning these states. RUNX2 in EC1 is tightly controlled by superenhancers that promote osteogenic transcriptional programs, while in EC2, chromatin remodeling supports FOSL1-driven activation of stress-response and proliferation pathways. CUT&amp;RUN assays demonstrated that distinct enhancer landscapes marked by H3K27ac regulate these subtypes. By integrating ATAC-seq and superenhancer mapping using the ROSE algorithm, we identified core regulatory circuits (CRC) unique to each subtype, demarcating transcription factor binding regions and refining cis-regulatory site predictions. OS cells can transition between EC1 and EC2 states driven by CRC members, causing alterations in chromatin accessibility. This plasticity is accompanied by RUNX2 and FOSL1 activity shifts, with transitions regulated by feedback loops in their respective CRCs. Therapeutic screening of the PDX-derived cell line panel revealed distinct vulnerabilities between subtypes. EC2, marked by AP1 upregulation and ERK activation, was highly responsive to MEK inhibitors, while EC1 demonstrated sensitivity to AURKB inhibitors. Single-cell RNA-seq analysis further suggested that these subtypes may coexist within a single tumor, highlighting intratumoral heterogeneity. In summary, our study uncovers two epigenetically distinct subtypes of OS, defined by intricate regulation of RUNX2 and FOSL1, and highlights their capacity for state transitions. These findings offer a framework for subclassifying OS and identifying targeted therapies, paving the way for precision medicine approaches in this aggressive disease. Citation Format: Eunice Lopez Fuentes, Andrew S. Clugston, Alex Lee, Leanne Sayles, Alejandro Sweet-Cordero. Epigenetic subtypes and cellular plasticity are driven by an interplay between RUNX2 and FOSL1 in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1179.