tbuckley/cabot-search huggingface dataset:
Abstract 4146: USP36 associates with the rixosome complex and promotes ribosome biogenesis
Authors: Yanping Li, Xiao-Xin Sun, Mushui Dai
Journal: Cancer Research (2025)

Abstract Eukaryotic ribosome biogenesis is a highly regulated multistep process to generate the ribosome, including transcription of pre-ribosomal RNA (pre-rRNA), rRNA processing, ribosome subunit assembly and export. Dysregulation of ribosome biogenesis has been associated with development of various diseases, including ribosomopathies and cancer. Therefore, it is crucial to understand how ribosome biogenesis is regulated during normal cell homeostasis and how it is deregulated in human diseases. We previously reported that the ubiquitin-specific protease USP36 acts as a SUMO ligase to promote nucleolar protein SUMOylation. Using affinity purification, we found that USP36 associates with a number of nucleolar and ribosome biogenesis-related proteins, including the rixosome complex that consists of Las1L, Nol9, MDN1, Pelp1, WDR36, Tex10 and SENP3 and plays a critical function in ribosome maturation. We confirmed that that USP36 interacts with all the components of the rixosome complex. We further showed that USP36 promotes the SUMOylation of Las1L, Nol9 and Pelp1, suggesting that USP36 promotes rixosome protein group SUMOylation. As USP36 is a ubiquitin specific protease, we also test whether the stability of these rixosome proteins is regulated by USP36. We found that the levels of MDN1 and Las1L, Nol9 are reduced upon USP36 knockdown. Abolishing Las1L SUMOylation impaired rRNA processing and inhibited cell growth. Together, these results suggest that USP36 plays an important role in regulating ribosome biogenesis by post-translationally regulating the function of rixosome complex. Citation Format: Yanping Li, Xiao-Xin Sun, Mushui Dai. USP36 associates with the rixosome complex and promotes ribosome biogenesis [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 4146.
Abstract 5581: Melatonin and 17β-estradiol treatment modulating TIMP’s family gene expression profile in IDCC
Authors: Kelly P. Ferreira, Bruna C. Almeida, Katia C. Carvalho
Journal: Cancer Research (2025)

Introduction: Tissue Inhibitor of Metalloproteinases (TIMPs) are genes that encodes four (TIMP1-4) proteins that act as endogenous protease inhibitors. They regulate directly the matrix metalloproteinases (MMPs) known to be associated with growth and invasiveness of sundry cancer types, including breast cancer cells. Several evidences have shown that melatonin can present both anti-proliferative and invasiveness role in cancer, while estrogen seems to have the opposite function. Thus, our goal was to evaluate the expression of TIMPs’ family compounds in invasive ductal carcinoma cells (IDCC) of breast cancer after treatment with 17β-estradiol (malignancy inducer), melatonin (malignancy inhibitor), isolated and associated with each other. Methods: IDCC [T47D (ER+/PR+), MCF7 (ER+), and MDA-MB231 (triple-negative)] were cultured as recommended by ATCC. All three cell lines were plated (5X105 in 6 wells plate) and treated with 17β-estradiol (E2 - 100 nM), Metatonin (Mel - 3000 μM) or both (Mel + E2). After treatment the RNA was extracted using mirVana miRNA Isolation Kit (Ambion, CA, USA) and then, purity and concentration of total RNA were accessed. The Reverse transcription synthesis was performed using High-Capacity cDNA Reverse Transcription Kit and RT-PCR was accessed for TIMP 1 - 4 using TaqMan assay system. The beta2-microglobulin (B2M) was established as a housekeeping gene and the relative quantification was determined by 2-DDCT method. Results: All members of the TIMPs’ family were expressed in IDCC tested with significant differences in their expression when compared to control cells. Mel treatment led to TIMP1, -3 and -4 mRNA upregulation, while E2 upregulated TIMP1 but downregulated TIMP2 in T47D cells. Otherwise, TIMP1 and -3 were downregulated and -2 and -4 were upregulated in MCF7 cells treated with Mel, while an increase of TIMP1, -2 and -4 were observed for E2. In comparison with control group, E2 treatment of MDA-MB231 cells led to upregulation of TIMPs -1, -3 and -4, and Mel upregulated all, except TIMP4 that was downregulated. Conclusion: Melatonin and 17β-estradiol treatments seems to modulate negative or positively the gene expression profile of all the assessed members of TIMPs’ family in IDCC cells. Citation Format: Kelly P. Ferreira, Bruna C. Almeida, Katia C. Carvalho. Melatonin and 17β-estradiol treatment modulating TIMP’s family gene expression profile in IDCC [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 5581.
Abstract 5548: Single-cell transcriptome analysis reveals the role of myofibroblastic cancer-associated fibroblasts in chemotherapy resistance in pancreatic cancer
Authors: Jiahao Guo, Samuele Cancellieri, Liangru Fei, Tero Aittokallio, Biswajyoti Sahu
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types often diagnosed late due to lack of specific biomarkers and its high capacity to metastasize early. In PDAC, tumor microenvironment (TME) is particularly complex, representing up to 80% of the tumor mass. Thus, better understanding of the cellular states and their controlling transcriptional networks within both malignant and stromal cells is pertinent to improve the survival of PDAC patients. The goal of this project is to elucidate the dynamic non-genetic regulatory mechanisms that contribute to PDAC progression and development of chemoresistance. We have performed in-silico analysis of single-cell RNA-sequencing data from &amp;gt;200,000 cells derived from pancreatic cancer patients with and without neoadjuvant treatment. Based on their gene expression profiles, we identified 12 distinct cell types including three major fibroblast subtypes: regular cancer-associated fibroblasts (CAF), inflammatory CAFs (iCAF), and myofibroblastic CAFs (myCAF). We found that tumors from patients with poor treatment response as well as from untreated patients exhibited a higher proportion of myCAFs compared to treatment-responsive patients. Using specific markers derived from each fibroblast subtype, we applied these signatures to the PAAD cohort from TCGA and found a significant association between the myCAF signature and worse prognosis as well as advanced TNM staging. Functional analyses further demonstrated elevated levels of Wnt/β-Catenin and Notch signaling pathways in the untreated and poor-response groups. Second, we utilized state-of-the-art machine learning methods to model robust relations between transcription factors (TF) and gene regulatory networks from treatment-naïve and neoadjuvant-treated PDAC patients. Our analysis revealed both well-known and new TFs related to pancreatic cell identity and PDAC progression. In-silico perturbation of these TFs was performed to study their effect on gene expression and cell state dynamics. The predictions reported a strong activity from both well-known and newly predicted TFs regarding the cell state transitions and their regulatory role. Currently, we are further characterizing the identified cell states and associated transcriptional programs, and the findings will be presented in the meeting. Citation Format: Jiahao Guo, Samuele Cancellieri, Liangru Fei, Tero Aittokallio, Biswajyoti Sahu. Single-cell transcriptome analysis reveals the role of myofibroblastic cancer-associated fibroblasts in chemotherapy resistance in pancreatic 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 5548.
Abstract 4157: Prodrug development of Cyclo-Creatine: Enhancing permeability and reducing toxicity for HER2+ breast cancer treatment
Authors: Ya Li, Yetong Huang, Puja Dey, Sadae Hitosugi, Sarah A. Buhrow, Joel M. Reid, Taro Hitosugi
Journal: Cancer Research (2025)

Abstract HER2+ breast cancer is an aggressive subtype of cancer that often develops resistance to the current first-line therapy, Trastuzumab. In our previous work, we demonstrated that HER2 signaling activates mitochondrial creatine kinase 1 (MtCK1), which enhances mitochondrial energy metabolism for rapid proliferation of breast cancer cells. However, pharmacological blockage of MtCK1 with a creatine analog, Cyclo-Creatine (CCr), requires millimolar concentration to inhibit breast cancer cell proliferation and is associated with brain toxicity, limiting its clinical application. This brain toxicity may result from the inhibition of the creatine transporter SLC6A8 by CCr, which decreases to transport creatine into brain. In this study, we took a prodrug development approach to identify and optimize protection groups for CCr, designed to bypass the SLC6A8 transporter, enhancing bioavailability and reducing toxicity. Liquid chromatography-mass spectrometry (LC-MS) was utilized to analyze drug uptake and creatine metabolites in cells treated with the prodrugs. Prodrug C, which is our lead prodrug candidate, demonstrated a seven-fold increase in cellular uptake and more than a hundred-fold improvement in cell-killing effects as compared to CCr in an MtCK1 specific manner in breast cancer cells. This approach offers a promising therapeutic strategy to inhibit HER2+ breast cancer cell by disrupting mitochondrial energy metabolism. Future investigations will focus on validating this prodrug’s pharmacokinetics (PK) and pharmacodynamics (PD) through further preclinical studies. Citation Format: Ya Li, Yetong Huang, Puja Dey, Sadae Hitosugi, Sarah A. Buhrow, Joel M. Reid, Taro Hitosugi. Prodrug development of Cyclo-Creatine: Enhancing permeability and reducing toxicity for HER2+ breast cancer treatment [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 4157.
Abstract 3849: Pygo2 deletion stimulates tertiary lymphoid structure formation and forms the cornerstone for a quadruple combination immunotherapy of prostate cancer
Authors: Yan Liu, Ziyu Zeng, Yini Zhu, Xin Lu
Journal: Cancer Research (2025)

Abstract Introduction: Advanced prostate cancer (PCa) shows overwhelming de novo resistance to immune checkpoint blockade (ICB). We previously identified Pygopus 2 (Pygo2) as a critical epigenetic regulator in PCa to orchestrate the Pygo2/p53/Sp1/Kit/Ido1 pathway to foster a microenvironment hostile to cytotoxic T lymphocytes (CTLs), and inhibiting Pygo2 genetically or pharmacologically sensitized PCa mouse models to ICB and adoptive CTL transfer therapy (Sci Immunol. 2023; PMID: 36897957). Here, we continued this line of research and examined the effect of Pygo2 targeting on castration (androgen deprivation therapy), anti-MDSC therapy and ICB in genetically engineered mouse models. Methods: We crossed Pygo2 conditional null allele to the PB-Cre/Pten/Smad4 (DKO) mice and generated PB-Cre/Pten/Smad4/Pygo2 (TKO) PCa mouse model. Using this model, we performed a series of combination treatments including ICB, surgical castration, and anti-MDSC therapy SX682 (Cxcr1/2 inhibitor). Various immune-phenotyping techniques (single-cell RNA-seq, bulk RNA-seq, flow cytometry and immunohistochemical staining) were performed on treated tumors. Results: The best tumor protection phenotype came from the combination of Pygo2 deletion, castration, ICB and SX682 treatment. This quadruple combination regimen led to nearly curative outcome, rendering the mouse tumors extensively necrotic. scRNA-seq and IHC revealed that Pygo2 deletion promoted the formation of tertiary lymphoid structures (TLS) within the tumor microenvironment. The quadruple combination demonstrated the highest level of infiltration of B cells and CTLs. Emerging data suggest that Pygo2 loss instigates cancer-cell-intrinsic signaling distinct from the previously identified Kit/Ido1-dependent pathway and connects an antiviral mimicry state of the cancer cells to adaptive tumor immunity that culminates in TLS formation and maturation. Conclusions: Our study further consolidates Pygo2 as a valid and promising therapeutic target in combination immunotherapy of prostate cancer. The quadruple combination immunotherapy composed of Pygo2 inhibition, androgen deprivation therapy, SX682 and ICB demonstrates superior preclinical efficacy and should be further investigated for its clinical implications. Citation Format: Yan Liu, Ziyu Zeng, Yini Zhu, Xin Lu. Pygo2 deletion stimulates tertiary lymphoid structure formation and forms the cornerstone for a quadruple combination immunotherapy of 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 3849.
Abstract 3837: Defining the mechanism of semaphorin4D tumorigenesis in prostate cancer models
Authors: Kavin Velur Ganesan, Maolake Aerken, Renyuan Zhang, Kent L. Nastiuk
Journal: Cancer Research (2025)

Background: Advanced and recurrent prostate cancer exhibits a “cold” immune phenotype characterized by an influx of immunosuppressive cells and fewer tumor-infiltrating lymphocytes (TILs), limiting the efficacy of checkpoint inhibitors. Semaphorin4D (SEMA4D/CD100), via the PlexinB receptors, regulates cell-cell interactions and migration in the nervous system, also responsible for cancer metastasis. Further, SEMA4D affects angiogenesis and immune regulation in other cancers. We hypothesize that SEMA4D promotes the recruitment of immunosuppressive cells via tumor blood vessels, further impairing TIL activity and anti-tumor immunity. Loss of SEMA4D function could disrupt vascularization, creating hypoxia that induces tumor cell apoptosis. Methods: Two mouse models—subcutaneous Myc-CaP allografts in immunocompetent mice and Hi-Myc prostate cancer GEMM were treated with a SEMA4D blocking mAb (pepinemab) to inhibit SEMA4D signaling. Tumor volume changes, vascularity, and oxygen saturation were assessed during treatment using high-frequency ultrasound, Power doppler, and photoacoustic imaging followed by FACS and IHC analyses on tumor tissues to evaluate immune cell phenotypes, hypoxia, apoptosis, and microvascular damage. To further elucidate genotypic changes in the tumor immune microenvironment, RNA sequencing gene expression changes associated with SEMA4D inhibition, including signaling pathways and Immune cell constituents. Results: Blocking SEMA4D significantly arrested tumor growth and reduced vasculature in Hi-Myc mice, with no prominent changes in immune phenotype by FACS after 4 weeks pepinemab treatment. IHC will test for changes in hypoxia, apoptosis, and microvascular damage. Allografts of prostate tumor cells similarly demonstrated tumor growth arrest. Effects on vasculature and microvascular integrity, leading to hypoxia and apoptosis, in this more tractable imaging environment, are anticipated. Transcriptomically, gene ontology and enrichment analyses may reveal pathways related to vessel formation, immune regulation, and metastasis. Conclusion: Our findings suggest that SEMA4D inhibition effectively arrests tumor growth by disrupting angiogenesis and potentially regulating immune activity, alongside inducing hypoxia and apoptosis. Ongoing transcriptomic analyses will further explore molecular mechanisms, including pathways involved in angiogenesis and immune regulation. Citation Format: Kavin Velur Ganesan, Maolake Aerken, Renyuan Zhang, Kent L. Nastiuk. Defining the mechanism of semaphorin4D tumorigenesis in prostate cancer models [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 3837.
Abstract 3628: Associations between per and polyfluoroalkyl substances (PFAS) and inflammatory markers in a racially diverse cohort of breast cancer patients
Authors: Alicia Arredondo Eve, Ashlie Santaliz Casiano, Haihley Connors, Oana Danciu, Garth Rauscher, Natalie Pulliam, Elona Liko-Hazizi, Sarah Friedewald, Seema Khan, Julie Kim, William Gradishar, Kent Hoskins, Zeynep Madak-Erdogan
Journal: Cancer Research (2025)

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants known for their resistance to degradation and their potential to accumulate in biological systems. These compounds have been associated with various adverse health effects, including promoting cancer progression. Aim: This study aimed to examine the associations between plasma PFAS levels and inflammation-related proteins identified through targeted proteomics in a racially diverse cohort of menopausal women and breast cancer patients. Methods: Three PFAS compounds—perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorobutane sulfonic acid (PFBS)—were quantified in plasma samples from both cancer-free individuals and breast cancer patients using targeted liquid chromatography-mass spectrometry (LC-MS). Results: We found higher levels of PFBS in African American patients with breast cancer compared to Non-Hispanic White patients. Analysis of variance (ANOVA) revealed marginal differences in PFAS levels between racial groups for PFBS (p=0.056p) with no significant differences for PFOA or PFOS (p&amp;gt;0.05). Logistic regression models showed no significant associations between normalized PFAS levels (PFOA, PFOS, and PFBS) and health outcomes (tumor grade or status) in the overall cohort or within racial subgroups. Lastly, Among African American patients, PFBS levels were strongly associated with inflammatory and cancer-related markers including CASP8, CCL3, MMP10 and TRANCE, which are implicated in immune regulation tissue remodeling and cancer progression. These findings highlight the potential role of PFAS in contributing to inflammation and cancer progression, particularly among African American breast cancer patients, emphasizing the need for further research on PFAS exposure and its impact on cancer disparities. Citation Format: Alicia Arredondo Eve, Ashlie Santaliz Casiano, Haihley Connors, Oana Danciu, Garth Rauscher, Natalie Pulliam, Elona Liko-Hazizi, Sarah Friedewald, Seema Khan, Julie Kim, William Gradishar, Kent Hoskins, Zeynep Madak-Erdogan. Associations between per and polyfluoroalkyl substances (PFAS) and inflammatory markers in a racially diverse cohort of breast cancer patients [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 3628.
Abstract 3481: Transarterial embolization for HCC: how embolic agents shape tumor immunity and systemic responses
Authors: Andrea C. Cortes, Simone Anfossi, Kiyoyuki Minamiguchi, Rony Avritscher
Journal: Cancer Research (2025)

Abstract Transarterial embolization (TAE) is an effective therapy for hepatocellular carcinoma (HCC). Effects of the treatment on tumor immune microenvironment are poorly understood. Different TAE agents induce varying degrees of tumor and peritumoral hypoxia and nutrient-depletion. The purpose of this study is to investigate the immunological effects of the most commonly used embolic agents. Using a preclinical rat HCC model, tumors treated with oil or microspheres were compared to untreated controls. Tumor and serum samples collected at 7 and 14 days post-treatment were analyzed by flow cytometry, cytokine assays, and gene expression profiling using nanoString CodeSet. Ethiodized oil significantly altered the TME, reducing exhausted CD8+Tcells and PD-1+regulatory T cells while increasing CD45+CD3+immune cell infiltration (P≤0.05). Microsphere-treated tumors showed less pronounced effects. Serum cytokine analysis revealed a shift from Th2- to Th1-dominated immunity in the Ethiodized oil group, with elevated Th1 cytokines (IL-12,IL-18,IFNγ) and reduced Th2 cytokines (IL-4,IL-5,IL-10) at 14 days (P≤0.05). Both embolic agents reduced pro-inflammatory cytokines (IL-1α,IL-1β, TNFα,G-CSF), indicating a dampened systemic inflammatory response. Gene expression analysis showed significant downregulation of Th2-associated pathways, in tumors treated with Ethiodized oil. This treatment promoted a Th1-dominant immune response, contrasting with the Th2-skewed signaling seen in microsphere-treated tumors. Pathway analyses further demonstrated a reduced activity of Th2-associated chemokine receptors and cytokine pathways in Ethiodized oil-treated tumors compared to microspheres, highlighting distinct immunological modulations driven by embolic agent choice. The findings demonstrate how embolic agents impact the tumor microenvironment and systemic immunity. Ethiodized oil exhibits superior immunomodulatory effects, promoting a Th1 phenotype and reducing pro-tumoral factors. This information is critical for devising new combinatorial immunotherapy strategies in HCC that consider the distinct effects of different embolic agents. Citation Format: Andrea C. Cortes, Simone Anfossi, Kiyoyuki Minamiguchi, Rony Avritscher. Transarterial embolization for HCC: how embolic agents shape tumor immunity and systemic responses [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 3481.