tbuckley/cabot-search huggingface dataset:
Abstract 5224: Systemic microenvironment determines the disease outcome in murine models of breast cancer
Authors: Fulya Koksalar Alkan, Ahmet Burak Caglayan, Hilmi Kaan Alkan, Cordarryl Jones, Adriana Langer Gramer, Roni Bollag, Eric Sebzda, Kristen S. Purrington, Max Wicha, Huidong Shi, Hasan Korkaya
Journal: Cancer Research (2025)

Abstract The systemic immune microenvironment plays a critical role in determining disease outcomes in breast cancer, yet its molecular and functional characteristics remain largely unknown. Using single-cell RNA sequencing (scRNAseq), CyTOF, and functional assays, we investigated immune dynamics in metastatic (4T1) and non-invasive (EMT6) murine models of triple negative breast cancer (TNBC). While primary tumors in both models exhibited similar infiltration by macrophages and myeloid-derived suppressor cells (MDSCs), profoundly distinct immune profiles in target tissues of metastatic mice. In the metastatic 4T1 model, metastatic tissues showed an expansion of neutrophil progenitors and immature neutrophils (CD11b+CD33+Ly6G+CD115-Ly6Clow) at the expense of natural killer (NK) cells, T cells, and B cells. These immature neutrophils mediated systemic immune suppression, contributing to the establishment of pre-metastatic niches where they regulate cancer stem cell (CSC) proliferation. Recombinant S100A8/A9 (calprotectin) proteins induced a similar expansion of these immunosuppressive neutrophils in EMT6 models, driving metastasis and immune evasion. In contrast, S100A9 knockout mice showed reduced metastatic burden and enhanced anti-tumor immune responses. Depletion of Ly6G+ immature neutrophils using anti-Ly6G antibody significantly restored systemic anti-tumor immunity and eliminated metastasis, while having no effect on primary tumor growth. Conversely, depletion of CD115+ macrophages selectively inhibited EMT6 tumor growth without altering systemic immune profiles. Our findings highlight the critical influence of systemic immune dynamics in shaping metastatic progression and therapeutic resistance. The identification of neutrophil progenitors and inflammatory S100A8/A9 proteins as key mediators of immune suppression offers novel insights into the interplay between systemic immunity and tumor biology. Targeting these components may provide a promising approach to mitigating metastasis and improving therapeutic outcomes in aggressive breast cancer subtypes. Citation Format: Fulya Koksalar Alkan, Ahmet Burak Caglayan, Hilmi Kaan Alkan, Cordarryl Jones, Adriana Langer Gramer, Roni Bollag, Eric Sebzda, Kristen S. Purrington, Max Wicha, Huidong Shi, Hasan Korkaya. Systemic microenvironment determines the disease outcome in murine models of 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 5224.
Abstract 5299: <i>BZW2</i>: a novel therapeutic target for liver metastasis in lung cancer
Authors: Kuan-Li Wu, Ying-Ming Tsai, Ya-Ling Hsu
Journal: Cancer Research (2025)

Abstract Introduction: Liver metastasis (LM) occurs in approximately 13% of patients with lung cancer at the time of diagnosis and is associated with poor prognosis. Currently, there are no effective preventive or therapeutic strategies specifically targeting LM. Investigating the LM microenvironment can not only elucidate the mechanisms underlying its development but also provide opportunities to identify novel therapeutic targets. Methods: An LM-prone mouse model was established by repeatedly injecting and harvesting Lewis Lung Carcinoma (LLC) cells from LM lesions. The spatial transcriptomics (Visium, 10X Genomics) was applied to explore the microenvironment and intratumoral heterogeneity of LM. Validation was conducted using single-cell RNA sequencing and spatial proteomics (PhenoCycler System, Akoya Bioscience) on human and murine LM samples, respectively. Bioinformatics analyses, including Gene Set Enrichment Analysis (GSEA), were applied to infer gene function and associated behaviors. Gene set variation analysis (GSVA) was performed to evaluate lung cancer patient survival in relation to the expression of the BZW2-associated gene set. Functional validation of BZW2 was conducted in vitro by assessing cell migration using transwell and wound healing assays, and by examining epithelial-to-mesenchymal transition (EMT) markers via immunoblotting. Results: Bzw2 is the significantly upregulated differential expressed gene in LM, particularly at the invasive front, based on the murine spatial transcriptomic data. The finding was further validated in murine LM samples using spatial proteomics as well. In human single-cell RNA sequencing data, BZW2 exhibited high expression in LM subclusters characterized by aggressive phenotypes, including enhanced proliferation, hypoxia, mesenchymal traits, invasiveness, and cancer stemness. GSVA analysis demonstrated that elevated expression of the BZW2-associated gene set was associated with poorer patient survival and enrichment of EMT-related pathways using the TCGA LUAD dataset. Furthermore, in vitro functional assays showed that BZW2 inhibition suppressed cell migration and reduced the expression of EMT markers, as confirmed by immunoblotting. Conclusion: By integrating findings from spatial transcriptomics, proteomics, and single-cell RNA sequencing, this study elucidates the role of BZW2 in promoting the aggressiveness of LM in lung cancer through its influence on cell migration and metastasis. These results suggest that BZW2 could serve as a promising therapeutic target worthy of further advanced research for LM in lung cancer. Citation Format: Kuan-Li Wu, Ying-Ming Tsai, Ya-Ling Hsu. BZW2: a novel therapeutic target for liver metastasis in lung 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 5299.
Abstract 5235: Cancer associated fibroblasts-derived SULF1 facilitated carcinogenesis and metastasis of esophageal squamous cell carcinoma
Authors: Hongyu Zhou, Beilei Liu, Licheng Tan, Baifeng Zhang, Yingchen lyu, Xin-Yuan Guan
Journal: Cancer Research (2025)

Abstract Cancer-associated fibroblasts (CAFs) play a significant role in creating a supportive environment for tumor growth and progression. Esophageal squamous cell carcinoma (ESCC) ranks as the seventh leading cause of cancer-related deaths globally, characterized by poor clinical outcomes and limited treatment options. CAFs-based therapeutic strategies might benefit ESCC patients. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data from four integrated ESCC cohorts to identify a unique protein, SULF1, secreted by CAFs. Primary human CAFs were isolated from six clinical samples of ESCC and various functional assays, such as transwell migration/invasion and co-culture/co-injection experiments, were conducted to assess the oncogenic or pro-metastatic effects of SULF1-secreting CAFs. Neutralizing antibodies against SULF1 was proposedly used for treatment. Here, we revealed that CAFs exhibited the highest expression levels of SULF1 compared to other cell types based on scRNA-seq data. Immunohistochemistry and immunofluorescence staining confirmed the unique expression of SULF1 in CAFs, particularly in αSMA-rich CAFs within ESCC patient samples. Furthermore, extracellular secretion of SULF1 was elevated in primary human CAFs compared to tumor cells and normal fibroblasts. Co-culture or co-injection of SULF1-knockdown CAFs mixed with tumor cells significantly inhibited tumor growth and metastasis both in vivo and in vitro. Mechanistically, RNA-seq data suggested that CAF-derived SULF1 might activate the TGF-beta and PI3K-AKT signaling pathways, thereby mediating the aggressive behavior of tumor cells. Notably, blocking SULF1-secreted CAFs resulted in suppression of ESCC tumor growth and progression in vivo. Collectively, CAF-secreted SULF1 emerged as a critical mediator in educating the ESCC tumor microenvironment and promoting tumor aggressiveness. Targeting SULF1-expressing CAFs could be viewed as a potential therapeutic strategy for ESCC treatment. Citation Format: Hongyu Zhou, Beilei Liu, Licheng Tan, Baifeng Zhang, Yingchen lyu, Xin-Yuan Guan. Cancer associated fibroblasts-derived SULF1 facilitated carcinogenesis and metastasis of esophageal squamous cell carcinoma [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 5235.
Abstract 6437: Mutational patterns in normal tissue hold the key to understanding the cellular origins of cancer
Authors: Kirsten Kübler, Rosa Karlić, Mendy Miller, Chip Stewart, William D. Foulkes, Paz Polak, Peter F. Arndt, Gad Getz
Journal: Cancer Research (2025)

The processes that lead to cancer transformation, in particular the clonal evolution that precedes malignancy, remain incompletely understood. Somatic mutations accumulate throughout the life of a cell and are shaped by its epigenetic landscape. We hypothesize that integrating somatic mutational profiles with the epigenetic landscapes of normal cells can explain the distribution of mutations in cancer, provide insights into the relationships between normal and cancer cells, and thus shed light on the cellular origins of cancer. Our study integrates mutation data from more than 25 normal tissue types with epigenetic profiles from over 300 normal cell types. Using random forest regression, we show that mutational distributions in normal cells closely match the epigenetic landscapes of their corresponding cell types. For example, the mutational profile of normal breast tissue maps to the epigenomes of luminal progenitor cells, indicating that these mutations are predominantly acquired during the progenitor cell state. In contrast, mutations observed in ductal carcinoma in situ (DCIS) closely aligns with the epigenomes of mature luminal cells, reflecting a distinct pattern of mutation accumulation in the precancerous state compared to normal tissue. Building on this, we extended our analysis to cancer by comparing normal mutational profiles with data from 2,550 whole genomes spanning 32 cancer types. This reveals both close relationships and distinct origins of different cancer types and subtypes. For example, the different molecular subtypes of breast cancer are associated with specific cell types of the luminal cell lineage, with basal-like subtypes originating from luminal progenitors and all other subtypes (LumA, LumB, Her2) from luminal mature cells. Together, these findings demonstrate that both normal and cancer tissues retain a mutational profile ‘scar’ that reflects the ancestral cell state in which these mutations originally arose. This genomic ‘historical record’ of somatic mutations is a powerful tool for tracing the cellular origins of cancer and provides a framework for understanding how somatic evolution in normal tissues sets the stage for tumor initiation and subtype differentiation. With this approach, we are advancing our understanding of tumorigenesis and subtype differentiation, paving the way for more precise cancer diagnosis and tailored therapeutic strategies. Citation Format: Kirsten Kübler, Rosa Karlić, Mendy Miller, Chip Stewart, William D. Foulkes, Paz Polak, Peter F. Arndt, Gad Getz. Mutational patterns in normal tissue hold the key to understanding the cellular origins of 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 6437.
Abstract 4313: COPS5 inhibition synergizes the antitumor effect of trastuzumab by PTEN upregulation in HER2 amplified gastric cancer
Authors: Sung-Hyun Hwang, Ji-Won Kim, Kuijin Kim, Haseseong Park, Andrew Aguirre, Keun-Wook Lee
Journal: Cancer Research (2025)

Abstract COP9 Signalosome Subunit 5 (COPS5), a deubiquitinating enzyme, contributes to chemoresistance, and its expression is closely correlated with poor prognosis in patients with solid tumors. However, the role of COPS5 amplification in patients with gastric cancer (GC) and its inhibition in HER2-amplified GC models has never been elucidated. In the curated stomach adenocarcinoma cohort (n=294) from The Cancer Genome Atlas datasets, COPS5 amplification significantly co-occurred with HER2 amplification (10.5% vs. 2.7%, P=0.040) and was associated with worse disease-free survival (median 12.6 vs. 45.2 months, P=0.012) and overall survival (median 21.4 months vs. not reached, P=0.004) after surgery. In HER2-amplified GC cell lines, NCI-N87, SNU216, and OE19, COPS5 inhibition using CSN5i-3, a selective COPS5 inhibitor, synergistically enhanced the antiproliferative effect of trastuzumab. After CSN5i-3 treatment, COPS5 knock-out (KO) cell lines demonstrated a uniform increase in PTEN transcription and translation levels. This effect was mediated by SNAIL ubiquitination, suppressing the AKT downstream signaling pathway. However, in PTEN KO cell lines, the synergistic effect of CSN5i-3 and trastuzumab was not apparent. Similarly, reduced PTEN expression caused by SNAIL overexpression also decreased the responsiveness of CSN5i-3 treatment. Moreover, COPS5 KO cells exhibited increased sensitivity to the proliferative effect and downstream signaling inhibition of AKT inhibitors MK2206 and capivasertib compared to control cells. In a mouse xenograft model of NCI-N87 cells, CSN5i-3 treatment combined with trastuzumab yielded a synergistic anti-tumor effect compared to monotherapy without notable changes in body weight. This effect was accompanied by enhanced apoptosis and reduced SNAIL and AKT downstream signaling activity. In conclusion, the synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the AKT downstream inhibition. These findings highlight the potential of COPS5 as a therapeutic target in combination with trastuzumab for HER2-amplified GC, warranting further clinical studies. Citation Format: Sung-Hyun Hwang, Ji-Won Kim, Kuijin Kim, Haseseong Park, Andrew Aguirre, Keun-Wook Lee. COPS5 inhibition synergizes the antitumor effect of trastuzumab by PTEN upregulation in HER2 amplified gastric 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 4313.
Abstract 5432: Restoring mitochondrial quantity and quality to reverse Warburg effect and drive tumor differentiation
Authors: Haowen Jiang, Sarah Jane Tiche, Clifford JiaJun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela O. Emengo, Bo He, Yang Li, Albert M. Li, Anh T. Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J. Svensson, Daniel J. Cuthbertson, Florette K. Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye
Journal: Cancer Research (2025)

Abstract Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity. Citation Format: Haowen Jiang, Sarah Jane Tiche, Clifford JiaJun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela O. Emengo, Bo He, Yang Li, Albert M. Li, Anh T. Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J. Svensson, Daniel J. Cuthbertson, Florette K. Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye. Restoring mitochondrial quantity and quality to reverse Warburg effect and drive tumor differentiation [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 5432.
Abstract 3994: Comparing ATP-based and image-based viability readouts for assessing treatment responses in patient-derived organoids
Authors: Claudia Beaurivage, Tao Yang, Anna Schepers, Mayke Doorn, Sumeyra Mucuk, Merel Derksen, Sylvia F. Boj
Journal: Cancer Research (2025)

High-throughput viability determination often relies on quantifying intracellular Adenosine TriPhosphate (ATP) levels. While this offers a robust option for assessing the efficacy of various compounds, it poses significant challenges when assessing compounds that interfere with metabolic or differentiation pathways, which affect intracellular ATP levels. HUB Organoid Technology is built on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when embedded into an extracellular matrix. Patient-Derived Organoids (PDOs) are generated from normal and malignant tissues and stored as high-quality biobanks that yield highly reproducible results. HUB Organoids® recapitulate complex characteristics of the parental tissue, including molecular heterogeneity and morphological and functional traits. Notably, PDOs can differentiate when subjected to the right conditions. This study compared ATP-based and image-based viability readouts to determine the best fit for quantifying treatment response in a panel of PDOs exposed to drugs with different modes of action. Herein, we show that an ATP-based viability readout fails to detect a viability shift in organoids treated with compounds known to modulate differentiation and metabolism, which instead becomes apparent when using an image-based readout. On the other hand, both readouts are equally effective at detecting changes in organoid viability following treatment with Oxaliplatin and 5-FU, which affect DNA damage and replication, respectively. Our results reveal the importance of consulting an expert organoid service provider who has an in-depth understanding of organoid biology and who can tailor your study based on your compound's expected mode of action, thus increasing your program´s chance of success. Citation Format: Claudia Beaurivage, Tao Yang, Anna Schepers, Mayke Doorn, Sumeyra Mucuk, Merel Derksen, Sylvia F. Boj. Comparing ATP-based and image-based viability readouts for assessing treatment responses in patient-derived organoids [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 3994.
Abstract 5743: Design and synthesis of novel strifluoromethyl-thiazolidine analogs as anticancer agents
Authors: Mohamed A. Eltokhy, Eman A. Fayed, Moustafa S. Abusaif, Ahmed Rageb, Aya Thabet, Yousry A. Ammar, Sanjay K. Srivastava
Journal: Cancer Research (2025)

Abstract Cancer is a global health crisis, ranking as one of the leading causes of mortality worldwide. Its persistent increase in incidence is driven by the intricate nature of tumor biology, rapid mutations, drug resistance, and limited efficacy of many current treatment options. This underscores the urgent need for novel therapeutic approaches that offer greater efficacy and safety. Targeted therapies using small molecules are a promising strategy due to their ability to selectively inhibit cancer cells, minimizing damage to normal tissues. A library of derivatives (N3-N6 and V1-V8) containing the trifluoromethyl phenyl acetamide core was synthesized via a series of chemical reactions. The structural integrity of these compounds was verified through a combination of analytical techniques, including melting point determination, Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and Infrared (IR) spectroscopy. The trifluoromethyl phenyl acetamide scaffold is of particular interest in medicinal chemistry due to its favorable pharmacological properties, including enhanced stability, lipophilicity, and metabolic resistance. Our study aimed to synthesize and evaluate derivatives of trifluoromethyl phenyl acetamide for their cytotoxic potential against various cell lines, such as colorectal cancer (HT-29, MC38, CT26and COLO 205), hepatic (C3a and PLC/PRF), pancreatic (Suit-2, MiaPaca2, As-PC1 and Panc 02.03, CI66), breast (MDA-MB-468, MDA-MB-231, BT20, MCF7, 4T1, 4T1 paclitaxel resistant, JIMT-1, ZR-75-1, E0771, T47D, and HCC1806) and ovarian (OVCAR-5) cell lines. Normal breast epithelial cell line MCF10a was included to evaluate the toxicity of lead compounds. Based on the SRB assay the 12 compounds exhibited variable but significant cytotoxic effects in various cancer cell lines. Further experiments are in progress to validate the most effective compounds in selected cancer models. Citation Format: Mohamed A. Eltokhy, Eman A. Fayed, Moustafa S. Abusaif, Ahmed Rageb, Aya Thabet, Yousry A. Ammar, Sanjay K. Srivastava. Design and synthesis of novel strifluoromethyl-thiazolidine analogs as anticancer agents [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 5743.