tbuckley/cabot-search huggingface dataset:
Abstract 4172: Carnitine metabolism regulates ovarian cancer metastasis
Authors: Medine Tasdemir, Shree Bose, Jason Locasale, Ernst Lengyel, Abir Mukherjee
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OvCa), the most lethal gynecological malignancy, is often detected late when the cancer cells have metastasized throughout the peritoneal cavity. OvCa cells are readily shed into the abdominal cavity from the ovary or the fallopian tube and are disseminated throughout the peritoneal cavity via the peritoneal or ascetic fluid. Therefore, ascites function as a liquid tumor microenvironment intermediary between primary tumor and metastasis. It is unclear if the ascites is a mere vehicle for disseminating cancer cells or if it alters the metabolic machinery of OvCa cells to increase their metastatic capacity. Here, we performed systematic multi-site metabolomic analyses to characterize the metabolic milieu of ascites and identified the mechanisms that augment the metastatic capacity of OvCa cells. We analyzed patient-matched samples (comprised of primary, metastatic omental tumors, ascites, and plasma) collected from a cohort of 25 high-grade serous ovarian cancer patients using liquid chromatography-mass spectrometry. By performing multidimensional scaling, we show that each sample site has a characteristic metabolic profile. The metabolome of the ascites is unique, and a higher abundance of acylcarnitines distinguishes its metabolome from patient-matched tumor and plasma. Conjugation of fatty acids to carnitine (generating acylcarnitines) aids in transfer of fatty acids across the mitochondrial membrane for their oxidation and subsequent ATP generation. We found that ascites-driven growth of OvCa cells correlates with methionine uptake and accumulation of N6-trimethyl-L-lysine (a key metabolite in the biosynthesis of carnitine). We also observed increased levels of acylcarnitines in metastatic tumors from the omentum compared to primary ovarian/fallopian tube tumors. Therefore, increased carnitine synthesis is a metabolic phenotype of OvCa cells growing in ascites and is associated with progression through the metastatic cascade. Gamma-butyrobetaine hydroxylase 1 and 2 (BBOX1 and BBOX2), are enzymes that regulate the rate-limiting steps of carnitine synthesis. Stable knockdown of BBOX1 and BBOX2 reduced the growth rate, and migratory and invasive capacities of OvCa cells in vitro. Colonization of the omentum (a visceral adipose tissue covering the bowel) marks an essential step in OvCa progression. We and others have shown that heightened fatty acid oxidation capacity in cancer cells aids in omental metastasis. We now show that increased carnitine biosynthesis in the OvCa cells precedes omental colonization and is a potential metabolic vulnerability. Citation Format: Medine Tasdemir, Shree Bose, Jason Locasale, Ernst Lengyel, Abir Mukherjee. Carnitine metabolism regulates ovarian cancer metastasis [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 4172.
Abstract 2411: Identification of loss of heterozygosity-associated genes linked to loss of function in Korean population through in-silico analysis
Authors: Sun-Woo Lee, Jae-Yoon Kim, Hyojin Heo, Seung-Woo Baek, Jee-Woo Seo, Jong-Lyul Park, Seon-Young Kim
Journal: Cancer Research (2025)

Abstract Loss of heterozygosity (LOH) is a common event in cancer development, disrupting gene and protein translation and resulting in loss of function (LOF). In terms of additional vulnerability, recent studies have suggested that investigating LOF due to LOH can be beneficial for cancer treatment. Additionally, genetic regions, including single nucleotide polymorphisms (SNP) linked to LOF caused by LOH, vary across cancer types. From this perspective, we conducted an in-silico analysis of Korean genomic data, cancer cell line data, and public genomic databases to identify genes associated with SNPs leading to LOF due to LOH. We analyzed a total of 10 million SNPs from a large cohort of 1, 496 Koreans using whole genome sequencing (WGS) data, as well as up to 9 million SNPs from 1, 007 cancer cell lines (including 129 lung, 21 stomach, and 28 colon samples) based on whole exome sequencing (WES). After filtering out rare variants, we identified 453 functional SNPs affecting protein translation in both Korean and cancer cell line data. Of these, 194 SNPs with heterozygous genotype frequencies between 0.1 and 0.9 were selected. Using copy number loss regions from the COSMIC database, we identified 39 genes associated with potential LOH-related SNPs. Finally, through the analysis of gene expression data from The Human Protein Atlas and previous studies, six LOH-associated genes linked to LOF in Koreans were identified: ADAMTS1, ANXA2, IL17RB, LPL, TUBA8, and ZNF117. Based on these six genes, we propose a list of drugs that, when used in combination, enhance the efficacy of conventional anticancer treatments. We plan to validate the effectiveness of these drugs in addressing additional vulnerabilities through in vitro experiments. While experimental validation is ongoing, we anticipate that our study will serve as a valuable resource for researchers aiming to identify population-specific LOH-associated genes using in-silico approaches. Citation Format: Sun-Woo Lee, Jae-Yoon Kim, Hyojin Heo, Seung-Woo Baek, Jee-Woo Seo, Jong-Lyul Park, Seon-Young Kim. Identification of loss of heterozygosity-associated genes linked to loss of function in Korean population through in-silico analysis [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 2411.
Abstract 4613: Differential TROP2 immunohistochemical expression between pleomorphic and classic invasive lobular carcinoma of the breast
Authors: Elizve Barrientos-Toro, Harsh Batra, Pandurengan Renganayaki, Yasmeen Qamar Rizvi, Jason Aboudi Mouabbi, Funda Funda Meric-Bersntam, Qingqing Ding, Aysegul Sahin, Maria Gabriela Raso
Journal: Cancer Research (2025)

Abstract Background: TROP2, a transmembrane glycoprotein implicated in tumor progression and metastasis, exhibits variable expression across breast cancer subtypes. The classic variant of invasive lobular carcinoma (ILC-C) and the pleomorphic variant (ILC-P) display distinct morphological and biological characteristics. This study aims to investigate differences in TROP2 expression between ILC-C and ILC-P, enhancing our understanding of its potential as a biomarker for aggressive subtypes. Methods: TROP2 protein expression was evaluated in 14 samples (8 ILC-C and 6 ILC-P) using immunohistochemistry (IHC) and quantified with digital image analysis software. Samples were annotated and classified into tumor and stroma components. The percentage of TROP2-positive cells was assessed, and staining intensity was categorized as weak, moderate, or strong. H-scores were calculated to assess overall TROP2 expression. Statistical analyses included descriptive statistics and the Wilcoxon test to compare expression levels between ILC-C and ILC-P groups. Results: TROP2 expression was significantly higher in ILC-P samples compared to ILC-C across multiple metrics. The percentage of positive cells was markedly elevated in ILC-P (mean: 73.04; median: 81.09; SD: 16.08) compared to ILC-C (mean: 17.97; median: 15.14; SD: 12.48). Similarly, H-scores were significantly higher in ILC-P (mean: 153.07; median: 146.79; SD: 54.31) than in ILC-C (mean: 24.97; median: 17.96; SD: 18.81). The Wilcoxon test for both parameters revealed statistical significance (p = 0.002). However, no significant difference was observed between molecular classification groups and TROP2 expression levels. Conclusion: Our findings demonstrate distinct TROP2 protein expression profiles in ILC, with ILC-P samples exhibiting significantly higher expression levels. This elevated TROP2 expression in the aggressive ILC-P variant highlights its potential as a biomarker for identifying high-risk lobular carcinoma subtypes. Further studies are warranted to explore the clinical implications of TROP2 in ILC-P, potentially guiding targeted therapeutic strategies. Citation Format: Elizve Barrientos-Toro, Harsh Batra, Pandurengan Renganayaki, Yasmeen Qamar Rizvi, Jason Aboudi Mouabbi, Funda Funda Meric-Bersntam, Qingqing Ding, Aysegul Sahin, Maria Gabriela Raso. Differential TROP2 immunohistochemical expression between pleomorphic and classic invasive lobular carcinoma of the 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 4613.
Abstract 4806: CAR binders affect CAR T cell tonic signaling, durability, and sensitivity to target
Authors: Divanshu Shukla, Khatuna Gabunia, Shannon E. McGettigan, Prachi R. Patel, Shannon Christensen, Ting Jia Fan, Decheng Song, Yanping Luo, Yanling Wang, Huaishan Wang, Regina M. Young, Carl H. June, John Scholler, James L. Riley
Journal: Cancer Research (2025)

Patients can develop human anti mouse immune responses against CD19- specific CAR T cells (CARTs) due to the use of a murine scFv to redirect T cells. To mitigate immunogenicity, a humanization process of the FMC63- based binder was undertaken that resulted in a CAR (119) that when introduced into T cells showed improved activity in a humanized mouse model. To further characterize how binding domains affect CART function, we screened a yeast display library to identify an array of fully human CD19 scFv binders. We saw significant differences in the ability of CARs employing these CD19 binders to be expressed on the cell surface, induce tonic signaling, redirect T cell function, mediate tumor killing, recognize lower levels of CD19 antigen, and maintain function upon continuous antigen exposure. From this in vitro analysis, CARTs using binders 42 and 52 were selected to be evaluated in a humanized mouse model. Here, we observed that CARTs using both 42 and 52 binders controlled the initial tumor burden and prevented tumor establishment upon rechallenge. We advanced a CAR construct using binder 42 for more advanced preclinical testing due to its greater similarity to FMC63 based binders and ability to robustly respond to tumors expressing lower levels of CD19. We found that this binder uniquely bound CD19 using distinct contact residues than FMC63 with ∼40-fold lower affinity. Combined with their potential for less immunogenicity and comparable in vivo activity, CARTs using the 119 or 42 binder should be considered for clinical use. Citation Format: Divanshu Shukla, Khatuna Gabunia, Shannon E. McGettigan, Prachi R. Patel, Shannon Christensen, Ting Jia Fan, Decheng Song, Yanping Luo, Yanling Wang, Huaishan Wang, Regina M. Young, Carl H. June, John Scholler, James L. Riley. CAR binders affect CAR T cell tonic signaling, durability, and sensitivity to target [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 4806.
Abstract 5561: Ankyrin repeat domain 1 confers resistance to tepotinib in MET-altered cancers
Authors: Ryunosuke Fujii, Tomoaki Higashihara, Ken Suzawa, Kousei Ishimura, Kazuya Hisamatsu, Ryota Fujiwara, Atsushi Matsuoka, Ryo Yoshichika, Naohiro Hayashi, Yuma Fukumoto, Kazuhiro Okada, Fumiaki Mukohara, Mao Yoshikawa, Kazuhiko Shien, Shinichi Toyooka
Journal: Cancer Research (2025)

Purpose: The mesenchymal epithelial transition factor receptor (MET) is a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In NSCLC, activation of the MET pathway occurs through diverse mechanisms, influencing cancer cell survival, growth, and invasiveness. These tumors exhibit oncogene addiction to MET and show remarkable responses to MET-Tyrosine Kinase Inhibitors (TKIs). However, the long-term effectiveness of MET-TKIs is usually limited due to acquired drug resistance. The mechanisms underlying primary and acquired resistance to MET-TKIs in NSCLC remain poorly understood. In this study, we investigated the mechanisms to tepotinib in MET-amplified and MET exon 14 skipping cancer cell lines. Experimental Design: Two MET-amplified lung cancer cell lines, EBC-1 and H1993, and one MET exon 14 skipping gastric cancer cell line, Hs746T, were used to establish models of acquired resistance to MET-TKI tepotinib. Resistance mechanisms were explored through functional analyses, comprehensive gene expression analysis using RNA sequencing, and the alterations hypothesized to confer resistance were validated. Results: Multiple mechanisms contributing to tepotinib resistance were identified. In EBC1 and Hs746T derived resistant cells, Ankyrin Repeat Domain 1 (ANKRD1) was highly expressed, and suppression of ANKRD1 using shRNA impaired resistance to tepotinib. Additionally, activation of the MAPK pathway was observed in EBC1 derived resistant cells, and inhibition of this pathway with MEK inhibitors had a synergistic effect with tepotinib. All 3 resistant cell lines used in this study showed epithelial-mesenchymal transition (EMT), which may further contribute to the resistance. Conclusions: In this study, we revealed the different mechanisms of acquired resistance to MET-TKI tepotinib with potential therapeutic application. Citation Format: Ryunosuke Fujii, Tomoaki Higashihara, Ken Suzawa, Kousei Ishimura, Kazuya Hisamatsu, Ryota Fujiwara, Atsushi Matsuoka, Ryo Yoshichika, Naohiro Hayashi, Yuma Fukumoto, Kazuhiro Okada, Fumiaki Mukohara, Mao Yoshikawa, Kazuhiko Shien, Shinichi Toyooka. Ankyrin repeat domain 1 confers resistance to tepotinib in MET-altered cancers [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 5561.
Abstract 3851: Vascular regulation of immune exclusion in melanoma
Authors: Ha-Ram Park, Nika Kozolv, Shawn Jaeha Kim, Eugene Son, Sungsoo Kim, Hee Won Yang, Minah Kim
Journal: Cancer Research (2025)

Abstract The infiltration of immune cells into the tumor is as crucial as their activity in determining the responses to immune checkpoint inhibitors (ICIs). Immune cell exclusion from tumors has been linked to poor responses to ICIs across various cancers, including melanoma; however, the underlying biological mechanisms remain poorly understood. Abnormal tumor vasculature, characterized by leakage and instability, represents a key barrier to immune cell infiltration, but the mechanisms underpinning these vascular changes and their impact on immune exclusion development remain poorly understood.To address this, we utilized a syngeneic mouse melanoma model to investigate the role of vascular changes in regulating immune cell positioning and exclusion during tumor progression. Spatial distribution of various immune cell populations and vascular integrity were assessed through multiplexed immunofluorescence staining across whole tumor cross-sections. While early-stage tumors exhibit well-infiltrated CD8+ T cells and neutrophils throughout the tumors, these immune cells became confined to the tumor periphery as tumors grew, leaving the core devoid of infiltration. This immune exclusion development correlated with vascular instability and leakage, particularly observed at the tumor periphery. Transcriptomic analysis of endothelial cells, sorted from the tumor periphery and core revealed increased gene expression of chemotaxis and immune migration in endothelial cells at the tumor periphery. Through multi-omics approaches including single-cell and spatial transcriptomic analysis, we aim to unravel the molecular mechanisms by which vascular abnormalities shape immune cell exclusion. These findings will guide us in building strategies to restore vascular integrity, enhance immune cell infiltration, and improve the efficacy of ICIs, addressing critical unmet needs for melanoma patients resistant to current immunotherapies. Citation Format: Ha-Ram Park, Nika Kozolv, Shawn Jaeha Kim, Eugene Son, Sungsoo Kim, Hee Won Yang, Minah Kim. Vascular regulation of immune exclusion in melanoma [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 3851.
Abstract 5381: Tumor nutrient stress regulates cancer-associated fibroblast heterogeneity
Authors: Marta Storl-Desmond, Kevin Muñoz Forti, Michał Nizio, Alexander Muir, Simon Schwörer
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type with a 5-year survival rate of only 13%. PDAC is unique in that up to 90% of the tumor bulk is comprised of a dense desmoplastic stroma. Enriched within PDAC’s extensive stroma are cancer-associated fibroblasts (CAFs). CAFs orchestrate tumor progression through the secretion of signaling molecules that impact cancer and immune cell function, and extracellular matrix proteins that remodel the surrounding stroma. CAFs are functionally and transcriptionally heterogeneous, with three distinct subtype classifications: myofibroblastic (myCAF), inflammatory (iCAF), and antigen-presenting (apCAF). In PDAC, an increased iCAF to myCAF ratio has been associated with worse clinical outcomes; however, efforts to selectively target CAF populations have been met with the challenge of CAF plasticity. A better understanding of the mechanisms underlying CAF state decisions is required before pro-tumor CAFs can be targeted. A key feature of PDAC is impaired perfusion, which leads to regions of hypoxia and altered nutrient availability; however, the significance of this unique metabolic environment to CAF state remains unknown. It has been reported that nutrient stress within the tumor microenvironment directly impacts cancer cell state leading to targetable metabolic adaptions, but how these same stresses affect the CAFs that share this microenvironment have been overlooked. To investigate how the altered nutrient availability of PDAC impacts CAFs, we acclimated pancreatic stellate cells (PSCs), a precursor CAF, to culture in tumor nutrient-relevant media. Characterization of these cells by high-dimensional flow cytometry and RNA-sequencing has revealed that the nutrient environment is sufficient to alter CAF state. CAFs in conditions of tumor nutrient stress are enriched for inflammatory signatures, along with higher expression and secretion of several potent cytokines and chemokines. Changes in CAF state induced by tumor nutrient stress are reversible, highlighting nutrient availability as a dynamic regulator of CAF plasticity. This work demonstrates the importance of the tumor nutrient environment to CAF state decisions. It further suggests that incorporating metabolic features of the PDAC TME increases the fidelity of existing model systems, which may allow uncovering novel regulators of CAF heterogeneity. Citation Format: Marta Storl-Desmond, Kevin Muñoz Forti, Michał Nizio, Alexander Muir, Simon Schwörer. Tumor nutrient stress regulates cancer-associated fibroblast heterogeneity [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 5381.
Abstract 258: RUNDC1 is required for p53-mediated tumor suppression
Authors: Atul Ranjan, Elizabeth Thoenen, Mrinalini Bhosale, Dipesh Thapa, Alejandro Parrales, Tomoo Iwakuma
Journal: Cancer Research (2025)

The tumor suppressor p53 is a transcription factor whose downstream target genes are involved in the regulation of the cell cycle and apoptosis, thus leading to tumor suppression. In many cancers, wild-type p53 activity is inhibited. Small molecule inhibitors of MDM2 (a negative regulator of p53), like Nutlin-3a which activates p53 by binding to MDM2, induce tumor suppression. Although p53-dependent tumor suppression is well studied, crucial factors required for the efficacy of p53-activating agents remain unknown. Toward this goal, we conducted a human whole-genome lentiviral shRNA screening in wild-type p53 carrying cells treated with Nutlin-3a. We identified RUNDC1 (Run domain containing 1) as one of crucial factors that were required for Nutlin-3a-mediated inhibition of colony formation in a p53-dependent manner. RUNDC1 is a poorly characterized protein, and its role in cancer is still unknown. Here, we demonstrated that downregulation of RUNDC1 attenuated p53-mediated cell cycle arrest. As a mechanism, RUNDC1 bound to p53 and enhanced p53’s binding to the p53-responsive elements in the promoter regions of p53 target genes. Our study, for the first time, reveals the biological function of RUNDC1, and its functional association with p53, suggesting the possibility that RUNDC1 contributes to p53-mediated tumor suppression. Citation Format: Atul Ranjan, Elizabeth Thoenen, Mrinalini Bhosale, Dipesh Thapa, Alejandro Parrales, Tomoo Iwakuma. RUNDC1 is required for p53-mediated tumor suppression [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 258.
Abstract 5932: Molecular determinants of 10-second diagnosis of brain cancer types with laser mass spectrometry
Authors: Alexa Fiorante, Michael Woolman, David Munoz, Lan Anna Ye, Taira Kiyota, Sunit Das, Ahmed Aman, Howard Ginsberg, Gelareh Zadeh, Arash Zarrine-Afsar
Journal: Cancer Research (2025)

Abstract Surveys of neurosurgical outcome data have suggested suitable extents (aggressiveness) of resection to improve survival for many brain cancer types. Here, personalization of the extent of resection relies on highly subjective intraoperative diagnoses wherein the depth of the diagnostic information depends on the level of experience of the pathologist. Picosecond InfraRed Laser Mass Spectrometry (PIRL-MS) uses picosecond bursts of mid- infrared laser radiation to extract, in a non-thermal manner, tissue lipids (1) present in cellular membranes, giving cells and nuclei their unique shapes (utilized in morphometric pathology with staining &amp; microscopy) and (2) altered in tumorigenesis due to cross-talk with cellular signalling in metabolism (potentially also revealing cancer molecular subtypes in 10 seconds as shown) for real-time profiling of molecular content unique to each tumour type. In our laboratory, close to 1, 300 frozen brain cancer specimens over 30 different classes of adult and pediatric cancers are being subjected PIRL-MS to build a comprehensive molecular signature library using various supervised and unsupervised dimensionality reduction and data analysis methods. The sensitivity and specificity of the integrated morphometric and molecular diagnosis for pediatric brain cancers with 10-second PIRL-MS was &amp;gt; 96%. This classification could use as little as only 18 tissue lipids whose identities were determined using chromatography and tandem mass spectrometry. Greater than 90% sensitivity and specificity have been obtained for adult brain cancer classifications with 10-second PIRL-MS analysis utilizing 40 lipids spanning fatty acids, phospholipids and ceramides. PIRL-MS can provide non-subjective differentiation between various brain cancer types with as little as 10 seconds of sampling and analysis time. Citation Format: Alexa Fiorante, Michael Woolman, David Munoz, Lan Anna Ye, Taira Kiyota, Sunit Das, Ahmed Aman, Howard Ginsberg, Gelareh Zadeh, Arash Zarrine-Afsar. Molecular determinants of 10-second diagnosis of brain cancer types with laser mass spectrometry [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 5932.