tbuckley/cabot-search huggingface dataset:
Abstract 5129: Molecular markers in brain metastases: Role of PI3K/mTOR pathway in epithelial-to-mesenchymal transition
Authors: Monica C. Mureb, Sabrina L. Zeller, Eris Spirollari, Simon Hanft, Chirag D. Gandhi, Meena Jhanwar-Uniyal
Journal: Cancer Research (2025)

Abstract Brain metastasis (BM) is a devastating disease that causes significant morbidity and reduced overall survival; however, the underlying mechanisms of metastatic dissemination to the brain remain to be elucidated. The metastatic cascade involves orderly cellular reprogramming processes, termed epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), facilitating tumor cells to acquire a stem cell-like phenotype and migrate, colonize, and grow at secondary sites. The mechanistic target of rapamycin (mTOR) pathway controls cellular functions and stem cell regulation. Thus, we hypothesize that the mTOR pathway plays an important role in BM, perhaps via EMT/MET. Immunohistochemical analysis of markers for EMT and MET (Snail, TWIST, STAT3, Vimentin, NF-kB) and stem cells (CD44) were performed. In addition, the expression of Akt/mTOR and its components (Rictor and Raptor) were also examined immunohistochemically. Functional analyses of proliferation, migration, and S-phase entry were performed in BM breast cancer cells (MDA-MB-231). Epithelial (E-cadherin) and mesenchymal (Vimentin) expression were analyzed following inhibition of the mTOR pathway using mTOR complex 1 (mTORC1) inhibitor (rapamycin), combined mTORC1/2 inhibitor (PP242), or with SiRNAs targeting mTOR, Raptor and Rictor. Results demonstrated: 1) Higher levels of phosphorylated AktSer473(93%) with significant overlap with STAT3 (87%); 2) Enhanced expression of mTOR/Raptor/Rictor (50%). EMT and CD44 were expressed in 80% of tumors; 3) Gene expression analysis showed high presence of transcriptional factors associated with differentiation and reprogramming; 4) Migration and proliferation were enhanced in astrocytic media and inhibited by rapamycin or PP242; 5) EdU-pulsing showed enhanced S-phase entry in astrocytic media, which was inhibited by rapamycin; 6) Inhibition of mTOR forced translocation of E-cadherin to the nucleus and enhanced Vimentin expression. These results provide evidence that the mTOR pathway is involved in metastatic brain tumors, suggesting its critical role in achieving a metastatic potential to the brain. Furthermore, these findings point to its role in diagnosis, prognosis, and clinical management in patients with metastatic brain tumors. Citation Format: Monica C. Mureb, Sabrina L. Zeller, Eris Spirollari, Simon Hanft, Chirag D. Gandhi, Meena Jhanwar-Uniyal. Molecular markers in brain metastases: Role of PI3K/mTOR pathway in epithelial-to-mesenchymal transition [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 5129.
Abstract 4932: Modeling uncertainty in personalised breast cancer risk prediction
Authors: Bethan L. White, Lorenzo Ficorella, Xin Yang, Douglas F. Easton, Antonis C. Antoniou
Journal: Cancer Research (2025)

Abstract Breast cancer risk prediction models use a range of predictors to estimate an individual’s chance of developing breast cancer in a given timeframe. These can facilitate risk stratification, to identify individuals who would benefit most from screening or preventive options. The BOADICEA breast cancer risk model, implemented in the CanRisk tool (www.canrisk.org), uses genetic, lifestyle, hormonal, family history and anthropometric data to estimate an individual’s risk. When implementing risk prediction models, risk predictor data are often incomplete. Point-estimates calculated when some risk factor data are missing can hide considerable uncertainty. We developed a methodological approach for quantifying uncertainty and the probability of risk-reclassification in the presence of missing data. We employed Monte-Carlo simulation methods to estimate the distribution of breast cancer risk for individuals with missing data. Multiple imputation by chained equations (MICE) with UK Biobank as a reference dataset was used to sample missing covariates. We developed a framework for estimating uncertainty, that can be applied to any given individual with missing risk factor data. We used exemplar cases to assess the probability that collecting missing data would result in a change in risk categorisation, on the basis of the 10-year predicted risk from age 40, using the UK National Institute for Health and Care Excellence (NICE) guidelines. For example, a woman known to have a pathogenic variant in CHEK2, but with all other information unmeasured, will be categorised as at “moderate risk” by the BOADICEA model. Measuring lifestyle and hormonal risk factors would result in reclassification to either the “population-” or “high-risk” group in around 24% of cases (respectively 23% and 1%). Measuring only a polygenic score (PGS) would reclassify the individual about 43% of the time into either the “population-” or “high risk” group (respectively 34% and 9%); measuring a PGS and lifestyle and hormonal risk factors would reclassify the individual to the “population-” or “high-risk” group in around 51% of cases (respectively 43% and 8%). The results demonstrate that there may be a considerable likelihood of reclassification into a different risk category after collecting missing data. The methodology presented here can identify situations where it would be most beneficial to collect additional patient information, and enable better informed clinical decision making. Citation Format: Bethan L. White, Lorenzo Ficorella, Xin Yang, Douglas F. Easton, Antonis C. Antoniou. Modeling uncertainty in personalised breast cancer risk prediction [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 4932.
Abstract 5119: Serine proteases modulate neutrophil survival and contribute to immunosuppression
Authors: Reegan Sturgeon, Sumanas Maram, Ainsley Meyerson, Ridhi Bhola, Esther Johnson, Rakesh K. Singh
Journal: Cancer Research (2025)

Abstract Tumor-promoting inflammation is a hallmark of cancer, contributing to malignant cells’ survival and proliferation. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation. We have previously shown that increased infiltrating neutrophils are associated with pancreatic ductal adenocarcinoma (PDAC) disease progression, which correlates with increased inflammation and neutrophil accumulation. Prolonged neutrophil accumulation has been linked to chronic inflammation, which in turn is thought to contribute to tumor progression, therapy resistance, and metastasis. In the present study, we examined how neutrophil-PDAC interaction enhances the survival of neutrophils dependent on serine proteases and their inhibitors. Previous reports suggest that serine proteases, such as cathepsin G, can contribute to inflammation and induce caspase-independent neutrophil apoptosis. We examined the role of serine proteases and their inhibitors on neutrophil survival using defined cellular models. We observed an association between increased serine protease and neutrophil survival. Moreover, this survival was modulated by cellular aggressiveness and therapy resistance. In addition, we observed increased survival of neutrophils associated with inhibition of serine proteases and increased expression of serpins to proteases in neutrophils upon PDAC cancer cell conditioned media treatment. In summary, these studies point to neutrophil serine proteases and their inhibitors as versatile mediators that modulate neutrophil survival, leading to an immunosuppressive microenvironment and identifying them as potential targets for therapeutic interventions. Citation Format: Reegan Sturgeon, Sumanas Maram, Ainsley Meyerson, Ridhi Bhola, Esther Johnson, Rakesh K. Singh. Serine proteases modulate neutrophil survival and contribute to immunosuppression [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 5119.
Abstract 3089: Silencing the stress oncoprotein LEDGF/p75 reveals potentially novel roles in lymphocyte function and inflammation
Authors: Pedro Toscano Ochoa, Evelyn S. Sanchez-Hernandez, Kai Wen Cheng, Zhong Chen, Isaac Kremsky, Charles Wang, Carlos A. Casiano
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortality for men in the U.S. Although the five-year survival rate for localized PCa is nearly 100%, once the disease progresses to later stages patients ultimately develop therapy resistance and the survival rate drops to roughly 30%. Understanding the mechanisms underlying PCa therapy resistance is crucial for developing new treatment options. Our recent studies have implicated the glucocorticoid receptor (GR)-lens epithelium derived growth factor p75 (LEDGF/p75) axis in PCa resistance to docetaxel (DTX). We demonstrated that GR upregulates and interacts with LEDGF/p75 in DTX-resistant PCa cells and that both proteins contribute to chemoresistance by regulating gene pathways associated with stress survival. LEDGF/p75 is a cellular survival protein that is upregulated in cancer cells exposed to environmental stressors, including cytotoxic drugs, and plays an important role in cellular protection against stress-induced cell death. This study was designed to gain mechanistic insights into the biological functions of LEDGF/p75 in DTX-resistant PCa cells. We silenced LEDGF/p75 expression in chemoresistant PCa cells via RNA interference, followed by RNA-sequencing (RNA-seq) analysis. Robust LEDGF/p75 silencing, confirmed by Western blotting, led to the identification of 970 differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) revealed a role for this protein in the regulation of gene pathways that are normally associated with B cell and T cell responses and inflammatory responses. For instance, LEDGF/p75 knockdown led to upregulation of the inflammatory cytokines IL7R and IL18, as well as several MHC class I genes, implicating this protein in suppressing inflammatory responses. Using publicly available RNA-seq data for various immune cells we also found evidence for LEDGF/p75 promoting CD4 and CD8 T cell activation. In addition, using public scRNA-seq data, we observed that LEDGF/p75 is found in T cell clusters for various cancer types, further suggesting immune functions in a broad array of tissues. Thus, understanding the novel roles of LEDGF/p75 in immunity may provide new insights into its biological and tumorigenic functions, and its potential role in modulating responses to immunotherapy. Citation Format: Pedro Toscano Ochoa,Evelyn S. Sanchez-Hernandez,Kai Wen Cheng,Zhong Chen,Isaac Kremsky,Charles Wang,Carlos A. Casiano. Silencing the stress oncoprotein LEDGF/p75 reveals potentially novel roles in lymphocyte function and inflammation [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 3089.
Abstract 2810: Investigating the oncogenic function of the long noncoding RNA KCNQ1OT1 in rhabdomyosarcoma
Authors: Ara Jo, Alex Kovach, Christian Stackhouse, Samantha Weitzel, Brian Masters, Justina McEvoy, Wenyue Sun, Frederic G. Barr, Mauro Calabrese, Xiang Chen, Corinne M. Linardic
Journal: Cancer Research (2025)

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, with survival for high-risk cases stagnant at less than 30%. Contemporary molecular classification of RMS is into fusion-positive (FP) and fusion-negative (FN) groups, based on expression of fusion oncogenes. Although the majority of FN-RMS tumors exhibit mutations in protein coding genes, especially in the RAS pathway, about 25% instead show only copy number alterations and LOH at chromosome 11p15.5, which harbors tumor suppressor genes (TSGs) CDKN1C, PHLDA2, and SLC22A18. The 90kb long noncoding RNA KCNQ1OT1 (OT1) is a known cis silencer of this locus. We hypothesize that OT1 is upregulated in RMS, contributes to RMS tumorigenesis by repressing critical TSGs, and that targeting OT1 could provide a novel therapeutic approach. Using qPCR and epigenomic interrogation of available RMS tissue, we find OT1 highly expressed in FN-RMS cell lines and banked tumor samples. Complementary genomic methylome data of RMS tumors shows silencing and activation of the CDKN1C and OT1 promoters, respectively. Suppression of OT1 using shRNA against various sites along the transcript, or a dual excision CRISPR knockout (DECKO) of the promoter, inhibits RMS cell proliferation, induces apoptosis, and recovers TSG expression. In a candidate approach, using both gain and loss of function approaches, the Hippo pathway YAP1 transcriptional co-activator was found to modulate OT1 expression. Unbiased genomic screens are planned. Finally, using in silico binding prediction models, we designed OT1-directed anti-sense oligonucleotides (ASOs), demonstrating they can be delivered to RMS cell lines. These ASOs, designed to degrade or inhibit OT1 function, will be tested in RMS cell-based and xenograft models to determine their efficacy and specificity. To generate additional information about regions of OT1 that might be therapeutically tractable, antisense DNA capture probes will be applied to OT1 in RMS cells to generate higher nucleotide resolution maps of OT1 structure and protein binding. This study not only deepens our understanding of OT1's role in RMS but also advances the development of innovative RNA-based treatments, addressing a critical need for effective therapies in this aggressive childhood cancer. Citation Format: Ara Jo, Alex Kovach, Christian Stackhouse, Samantha Weitzel, Brian Masters, Justina McEvoy, Wenyue Sun, Frederic G. Barr, Mauro Calabrese, Xiang Chen, Corinne M. Linardic. Investigating the oncogenic function of the long noncoding RNA KCNQ1OT1 in rhabdomyosarcoma [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 2810.
Abstract 6056: Aging accelerates breast tumorigenesis though cancer immunosuppression
Authors: Shanshan Yin, Kay Yeung, Jing Yang, Peter D. Adams
Journal: Cancer Research (2025)

Abstract Age is a major risk factor for breast cancer. However, the mechanisms by which age affects breast cancer initiation and progression is not fully understood. Unfortunately, there is a paucity of mouse with which to study the role of aging in cancer, especially the impact of aging on the epithelial tumor cells-of-origin. To address this for breast cancer, we established a mouse model in which breast cancer was induced de novo in young and old wildtype mice through intraductal injection of a lentivirus carrying the breast cancer oncogene HER2/neu. Consistent with human data, breast tumors in the old mice grew more rapidly than in young mice. Old mice exhibited more aggressive, invasive and higher grade breast tumor lesions. GeoMx whole-transcriptome spatial transcriptomics revealed that old tumor cells upregulated genes associated with invasion, epithelial-to-mesenchymal transition, cell migration, blood vessel development, and extracellular matrix formation, while downregulating genes related to immune response, interferon gamma response, and antigen presentation. Specifically, several chemokines were downregulated in old tumor cells, with Cxcl9 and Cxcl10 (hereafter Cxcl9/10) being the most prominent, an observation confirmed by RNAscope and immunostaining. Expression of Cxcl9/10 is known to attract Cd8+ and Cd4+ T cells through binding to the T cell Cxcr3 receptor, thereby facilitating anti-tumor T cell infiltration into tumors. We observed fewer tumor infiltrating Cd4+ and Cd8+ T cells in old tumors. Simultaneous depletion of Cd4 and Cd8 T cells significantly accelerated tumor growth in young mice but not in old mice. Blocking Cxcr3 in young mice accelerated tumor growth and reduced T cell infiltration, while enhancing Cxcl9/10 expression slowed down the tumor growth in old mice. These results suggest that age-associated downregulation of Cxcl9/10 in tumor cells is responsible for an impaired anti-tumor immune response in aged tissue. Furthermore, scATACseq revealed that Cxcl9/10 gene regions were less accessible in old tumor tissues. Taken together, these results suggest that age-associated downregulation of Cxcl9/10 in tumor cells is responsible for an impaired anti-tumor immune response in aged tissue, with epigenetic rewiring playing a critical role in this process. Citation Format: Shanshan Yin, Kay Yeung, Jing Yang, Peter D. Adams. Aging accelerates breast tumorigenesis though cancer immunosuppression [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 6056.
Abstract 5304: Profiling the tumor- immune landscape with a same-section multiomics assay
Authors: Anushka Dikshit, Cansaran Saygili Demir, Rose Delvillar, Emerald Doolittle, Alice Comberlato, Arec Manoukian, Maria-Giuseppina Procopio, Pino Bordignon, Saska Brajkovic, Maithreyan Srinivasan
Journal: Cancer Research (2025)

Abstract Checkpoint therapies and engineered immune cell therapies are increasingly becoming the mainstay when it comes to cancer treatments. Continued and improved success of these therapies relies on our deep understanding of the checkpoint marker and immune cell biology, cell-cell interaction in the tumor microenvironment (TME), and immune cell activation. Spatially visualizing the expression of soluble factors such as cytokines and chemokines along with immune cell markers can provide information about the immune cell composition and enable a comprehensive understanding of mechanisms underlying immune cell recruitment, infiltration and exclusion. To address this, we have developed a fully automated spatial multiomics protocol on the COMET™ platform that enables RNA detection using the RNAscope™ HiPlex Pro assay combined with protein detection using sequential immunofluorescence (seqIF™, (Rivest et al, 2023) ) to integrate same-section sequential detection of up to 12 RNAs followed by up to 24 proteins. This workflow allows the detection of any RNA and protein target of interest by utilizing existing RNAscope probes or generating a custom design for any RNA target and use standard, non-conjugated primary antibodies for protein detection. We used Lunaphore’s HORIZON™ software to analyze this multiomics dataset. Here, we have demonstrated the precise spatial profiling of FFPE solid tumors through the detection of key cytokines indicative of activated T cells and macrophages by using cytokine RNA probes targeting IFNG, IL-1B, TNFA, TGFB1, IL-4, IL-6, IL-8, IL-10 among others in combination with cell marker antibodies detecting CD3, CD8, CD4, FOXP3 and CD68.In addition, we were also able to visualize T cell recruiting chemokines and receptors such as CXCL10, CXCL9, CXCL13, CXCL12 and CXCR3, and spatially map tumor-infiltrating T cells within tissue context and with subcellular resolution. To that end, we successfully demonstrated same-slide RNA-protein detection for profiling the TME. Using single-cell spatial multiomics we were able to identify unique phenotypes within the tumors that might directly correlate to immunosuppressive or immunostimulatory microenvironments. Detailed mapping of the cellular components of the TME has the potential to better predict therapeutic response for checkpoint and immune-based therapies. Citation Format: Anushka Dikshit, Cansaran Saygili Demir, Rose Delvillar, Emerald Doolittle, Alice Comberlato, Arec Manoukian, Maria-Giuseppina Procopio, Pino Bordignon, Saska Brajkovic, Maithreyan Srinivasan. Profiling the tumor- immune landscape with a same-section multiomics assay [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 5304.
Abstract 4544: Immunotherapy with chemotherapy provides superb pathologic complete response rate in chemotherapy-resistant metaplastic carcinoma of breast
Authors: I-Chun Chen, Shang-Hsuan Peng, Tsung-Che Wu, Ching-Hung Lin, Diana Hui-Min Lin, Li-Wen Huang, Chi-Han Cheng, Yen-Shen Lu
Journal: Cancer Research (2025)

Abstract Background: Metaplastic carcinoma of breast (MCB) is a rare subtype of breast cancer (BC) accounting for &amp;lt;1% of newly diagnosed BC. It is composed of co-existing sarcomatous and carcinomatous components. Because of its sarcomatous components, the response rate of chemotherapy in MCB is low both in early BC and advanced BC. The pathologic complete response rate (pCR%) after neoadjuvant chemotherapy in MCB is as low as 10%. Neoadjuvant immunotherapy plus chemotherapy is a new standard of care for early triple-negative BC providing improved pCR%, event-free survival, and overall survival. Pembrolizumab was also approved by the FDA in 2021 for neoadjuvant treatment in TNBC. We aim to examine the modern pCR% of immunotherapy and chemotherapy in MCB patients. Methods: MCB patients and treatment regimens, including neoadjuvant immunotherapy, were retrospectively selected from Flatiron Health, a nationwide electronic health record database. Demographic data and neoadjuvant regimens were collected. pCR% was calculated for patients treated with neoadjuvant chemotherapy versus neoadjuvant immunotherapy plus chemotherapy. Results: A total of 87 early stage MCB patients diagnosed between January. 2011 and May 2024 were included from the Flatiron Health. 20 and 5 of the MCB patients received neoadjuvant chemotherapy alone and neoadjuvant immunotherapy plus chemotherapy, respectively. 2 in the neoadjuvant chemotherapy group (pCR%=10%) and 3 in the neoadjuvant immunotherapy/ chemotherapy group (pCR%=60%) achieved pCR. The pCR% of neoadjuvant chemotherapy is as low as previously reported in MCB patients. Conclusion: Neoadjuvant immunotherapy and chemotherapy provide comparably high pCR% in MCB patients as compared to other TNBC patients. We are validating the findings from additional cohorts from Taiwan. The high pCR% makes immunotherapy and chemotherapy an attractive strategy that worth further investigation in MCB patients. Citation Format: I-Chun Chen, Shang-Hsuan Peng, Tsung-Che Wu, Ching-Hung Lin, Diana Hui-Min Lin, Li-Wen Huang, Chi-Han Cheng, Yen-Shen Lu. Immunotherapy with chemotherapy provides superb pathologic complete response rate in chemotherapy-resistant metaplastic carcinoma of breast [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 4544.