tbuckley/cabot-search huggingface dataset:
Abstract 136: Discerning the role of the extracellular matrix on epithelial-to-mesenchymal transition and invasiveness of glioblastoma multiforme using a xeno-free 3D hydrogel system
Authors: Alejandra Ferrer Díaz, John Huang
Journal: Cancer Research (2025)

Abstract The invasive nature of cancer, driven by epithelial-to-mesenchymal transition (EMT), is a critical process influenced by external cues from the tumor microenvironment, such as extracellular matrix (ECM) composition. The ECM primes cells for EMT and metastasis, making it a key topic in understanding disease progression. For example, in glioblastoma multiforme (GBM), a grade IV astrocytoma and the most aggressive brain malignancy, EMT contributes to the highly invasive behavior of tumor cells, limiting patient survival to less than five years. Thus, developing in vitro models that can accurately examine how the ECM contributes to GBM invasiveness and survival is vital. Currently, most in vitro studies evaluating cell invasion and EMT are conducted in two-dimensions (2D), disregarding the microenvironment's complexity and the ECM role in such processes. The limited case studies on three-dimensional (3D) cancer invasion and EMT models heavily rely on animal-based ECM, such as Matrigel or collagen. These matrices, due to their inherent instability, introduce variability, compromise experimental consistency, and make it challenging to draw robust conclusions. In this study, we use the synthetic and biofunctional VitroGel® system to evaluate cell invasion and EMT in 3D GBM models. The fully characterized VitroGel system allow us to study the effect of the mechanical strength and biochemical composition of the ECM on cell invasion and EMT. In this study, GBM spheroids were formed in an ultra-low attachment plate, and hydrogels functionalized with ligands such as RGD peptides, matrix metalloproteinases, collagen-mimetic peptides, and others were gently added to the cultures to evaluate their role in cell invasion and EMT. The findings showed that the functional ligands stimulate spheroid invasion and promote EMT, evidenced by the rapid proliferation of the spheroid and engulfment of the matrix, resulting in the formation of tumoroid-like structures. Furthermore, we evaluated whether the mechanical strength of the ECM affects spheroid invasion and EMT by adjusting the stiffness of the matrix. Indeed, we showed that less stiff matrices propel spheroid invasion and EMT, indicating that the physical properties of the ECM influence migration. Overall, this study demonstrated that using the xeno-free 3D hydrogel system is an excellent approach to evaluate cancer invasiveness and EMT, and a promising tool for drug-screening applications. Citation Format: Alejandra Ferrer Díaz, John Huang. Discerning the role of the extracellular matrix on epithelial-to-mesenchymal transition and invasiveness of glioblastoma multiforme using a xeno-free 3D hydrogel system [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 136.
Abstract 286: Metabolic alterations in skeletal muscle and serum of tumor-bearing cachectic mice
Authors: Kuo-Chu Lai
Journal: Cancer Research (2025)

Abstract Cancer cachexia, a multifactorial syndrome characterized by systemic inflammation, high energy expenditure, and progressive skeletal muscle loss, poses a significant challenge in cancer management due to limited therapeutic options. Understanding the metabolic shifts associated with cachexia-related muscle wasting could provide critical insights into identifying potential biomarkers and therapeutic targets. In this study, we conducted targeted metabolomics to investigate metabolic alterations in the skeletal muscle and serum of tumor-bearing cachectic mice. To facilitate a comprehensive analysis, skeletal muscle samples from non-cachectic tumor-bearing mice were included to explore metabolic changes associated with tumor growth and its progression to cachexia. We found that tumor-bearing, non-cachectic muscles exhibited significantly higher levels of glucose-6-phosphate (G6P), fructose-6-phosphate with glucose-1-phosphate (F6P + G1P), glyceraldehyde-3-phosphate (G3P), glycerol-3-phosphate (Glycerol-3P), and phosphoenolpyruvate (PEP) compared to control muscles. However, no significant differences were observed between non-cachectic muscles and cachectic muscles. These findings indicate that increased glycolysis is more critical for tumor growth than for the progression to cachexia. Amino acids such as asparagine, alanine, and serine were significantly increased in cachectic muscle. Compared to non-cachectic muscle, levels of 2-hydroxyglutarate (2-HG) and CoA were decreased in cachectic skeletal muscle. Notably, alterations in 2-HG and CoA were consistent between muscle and serum, highlighting their potential as systemic biomarkers. These results reveal key metabolic alterations in skeletal muscle and serum associated with cancer cachexia, offering novel insights into the pathogenesis of muscle wasting and providing potential avenues for biomarker discovery and therapeutic intervention. Citation Format: Kuo-Chu Lai. Metabolic alterations in skeletal muscle and serum of tumor-bearing cachectic mice [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 286.
Abstract 297: Targeting splicing factor SF3B4 induces cancer cell senescence by elevating p21 mRNA levels
Authors: Donghee Kang, Hyun Jung Hwang, Min-Ji Kim, Jae-Seon Le
Journal: Cancer Research (2025)

Abstract SF3B4, a component of U2 snRNP complex, is amplified in various cancers and contributes to cancer cell proliferation, migration and invasion by regulating alternative gene splicing. Despite its potential significance, the mechanisms by which SF3B4 regulates nonsense-mediated mRNA decay (NMD) and cancer cell senescence remain poorly understood. In this study, we reveal a novel regulatory role of SF3B4 in the regulation of cancer cell senescence by targeting p21 mRNA. Depletion of SF3B4 leads to reduced cancer cell proliferation, increased SA-β-Gal positivity, and elevated p21 expression independent of p53, ultimately inducing cellular senescence. Mechanistically, SF3B4 directly binds to the 3’UTR of p21 mRNA, negatively regulating its stability. We demonstrate that SF3B4 plays a crucial role in recruiting key components of the NMD pathway, such as UPF1, MAGOH and RNPS1, to promote the degradation of p21 mRNA. Depletion of SF3B4 disrupted the association of NMD factors from the 3’UTR of p21 mRNA. Taken together, our results reveal a novel regulatory role in which SF3B4 collaborates with NMD factors to regulate p21 mRNA stability and cancer cell senescence. Citation Format: Donghee Kang, Hyun Jung Hwang, Min-Ji Kim, Jae-Seon Lee. Targeting splicing factor SF3B4 induces cancer cell senescence by elevating p21 mRNA levels [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 297.
Abstract 922: Mutant KRAS enhances immune evasion via epitranscriptomic regulation of NT5E in colon cancer
Authors: Seungjae Shin, Yoojin Yang, Sung-yup Cho
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Mutation in KRAS occurred in approximately 40% of patients, and leading to resistance to FDA approved anti-EGFR agents. Also, CRC patients harboring KRAS mutations do not respond well to immune checkpoint blockades. Therefore, additional therapeutic strategies to overcome KRAS mutations are strongly required. In recent years, N6-methyladenosine (m6A) modification on mRNA has been recognized for its significance in various cancer phenotype. This modification plays a crucial role not only in cancer cell behavior but also in shaping the tumor microenvironment (TME). Many studies about m6A in cancer focus on the direct roles and effects of m6A regulators. These regulators include writers, which attach m6A to RNA; erasers, which remove it; and readers, which bind to m6A to regulate the fate of mRNA. However, how oncogenic mutations affect the landscape of m6A deposition remains poorly understood. To explore the impact of KRAS mutations on m6A modifications, we performed MeRIP-seq and discovered significant changes, particularly in NT5E/CD73, a molecule known for its immune suppressive role in the TME. Our result suggest the potential for developing novel therapies by modulating the KRAS-m6A-NT5E axis in KRAS-mutated colorectal cancer. Citation Format: Seungjae Shin, Yoojin Yang, Sung-yup Cho. Mutant KRAS enhances immune evasion via epitranscriptomic regulation of NT5E in colon 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 922.
Abstract 116: CD73+cancer-associated fibroblasts augment cancer stemness and drug resistance in hepatocellular carcinoma through adenosine accumulation
Authors: Hui Hai Yang, Carmen Oi Ning Leung, Terence Kin-Wah Lee
Journal: Cancer Research (2025)

Abstract Background: Hepatocellular carcinoma (HCC) exhibits significant therapeutic resistance due to its high cancer stemness, which is strongly influenced by the tumor microenvironment (TME). Extracellular adenosine (eAdo), a critical metabolic regulator within the TME, is primarily generated from extracellular ATP via the enzymatic activity of CD73 (NT5E), which is highly expressed in cancer-associated fibroblasts (CAFs). In our pilot study, we found that the CAF populations marked by CD73 were drastically induced in a lenvatinib-resistant immune-competent mouse HCC model. Based on this data, we hypothesize that CD73+ CAFs confer cancer stemness-driven drug resistance via eAdo accumulation in the TME. Methodology: Liquid chromatography-mass spectrometry (LC-MS) was used to quantify adenosine levels, whereas flow cytometry was used to assess stemness-related surface markers. Tumor-initiating frequencies were evaluated using a limiting dilution assay, and CRISPR-Cas9-mediated CD73 knockdown in CAFs, the precursors of CAFs, was employed to validate CD73’s functional role. Western blot analysis was conducted to investigate the pathway activation.Results: Our results showed that CD73 is a functional marker of CAFs, and its overexpression is significantly correlated with poor prognosis of HCC patients. LC-MS detected a significant amount of adenosine in CAFs when compared with HCC cells, while a notable reduction in adenosine levels was observed in the conditioned medium (CM) of CD73-knockout CAFs. Interestingly, ATP-supplemented CM of CAF augments the cancer stemness of HCC cells, while its effect is offset upon CD73 knockout in CAFs. Echoed to this finding, adenosine treatment (10 µM) exerted similar effects, confirming the critical role of CD73 in CAF-driven cancer stemness via adenosine accumulation. Mechanistic studies have demonstrated that adenosine promotes stemness through activation of the A2AR/AKT/mTOR signaling pathway in HCC cells. Conclusion: This study establishes that CD73+ CAFs drive HCC stemness and drug resistance by modulating the TME through eAdo accumulation. Targeting CD73 and its downstream signaling pathways represents a promising therapeutic strategy to overcome drug resistance which potentially opens a new therapeutic avenue for HCC treatment. Citation Format: Hui Hai Yang, Carmen Oi Ning Leung, Terence Kin-Wah Lee. CD73+cancer-associated fibroblasts augment cancer stemness and drug resistance in hepatocellular carcinoma through adenosine accumulation [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 116.
Abstract 573: Radioimmunotherapy using 64/67copper labelled trastuzumab in mice bearing HER2-positve xenografts as a model for breast cancer therapy
Authors: Stacey E. Rudd, Jessica Van Zuylekom, Benjamin Blyth, Matthew Harris, Paul S. Donnelly
Journal: Cancer Research (2025)

Abstract Background and Purpose: Human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers including breast cancer. In the treatment of HER2 positive breast cancer, patients have shown significant improvements with trastuzumab therapy. Radioimmunotherapy (RIT) utilizes an antibody targeted to a receptor overexpressed on tumors to deliver radiation to the target. RIT utilizing trastuzumab could provide an additional treatment option for HER2+ breast cancer patients. We have produced the theranostic pair [64Cu]Cu-MeCOSar-trastuzumab, for PET imaging, and [67Cu]Cu-MeCOSar-trastuzumab, for therapy via beta emission, to evaluate this Targeted Copper Theranostic (TCT) approach as an effective radioimmunotherapy. Methods: The MeCOSar chelator was conjugated to trastuzumab and subsequently radiolabeled with either copper-64 (Cu-64) or copper-67 (Cu-67). Proof of concept studies were performed using SKOV-3 tumor bearing mice, injected with one dose of [64Cu]Cu-MeCOSar-trastuzumab or [67Cu]Cu-MeCOSar-trastuzumab to compare biodistribution of the theranostic pair. Tumor uptake was assessed using PET/CT imaging and/or ex vivo biodistribution studies. In therapy studies, a single dose of saline, MeCOSar-trastuzumab, or [67Cu]Cu-MeCOSar-trastuzumab was administered and endpoints assessed. Results: [64Cu]Cu-MeCOSar-trastuzumab and [67Cu]Cu-MeCOSar-trastuzumab showed comparable high tumor-specific uptake in biodistribution studies, with tumor uptake at 48 hours of 61 ± 6 % IA/g for [64Cu]Cu-MeCOSar-trastuzumab and 59 ± 7 % IA/g for [67Cu]Cu-MeCOSar-trastuzumab. Mice treated with [67Cu]Cu-MeCOSar-trastuzumab tolerated the treatment well with limited side effects or AEs. Treated mice also showed significant tumor growth inhibition and extended survival in a dose dependent manner compared with the control groups. The median survival was 32 days in the control groups and 102 days in the 9 MBq group. Conclusion: These results show high tumor uptake for [64Cu]Cu-MeCOSar-trastuzumab and [67Cu]Cu-MeCOSar-trastuzumab with very similar biodistribution profiles at 48 hours in SKOV-3 xenograft model. [67Cu]Cu-MeCOSar-trastuzumab demonstrated significant tumor growth inhibition compared to the control groups and effectively increased the survival of the treated group. This study demonstrates the potential of [67Cu]Cu-MeCOSar-trastuzumab for clinical translation. Citation Format: Stacey E. Rudd, Jessica Van Zuylekom, Benjamin Blyth, Matthew Harris, Paul S. Donnelly. Radioimmunotherapy using 64/67copper labelled trastuzumab in mice bearing HER2-positve xenografts as a model for breast cancer therapy [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 573.
Abstract 269: TRPM8 as a testosterone receptor: Exploring its role in prostate cancer and male behavior
Authors: Erick Benjamin Saldes, Alexandra Erdmier, Jai Velpula, Benny Tom, Timothy E. Koeltzow, Don Vander Griend, Swapna Asuthkar
Journal: Cancer Research (2025)

Abstract The transient receptor potential melastatin 8 (TRPM8) channel has emerged as a critical mediator of testosterone signaling in prostate cancer (PC), influencing both tumor progression and sexually dimorphic behaviors. Our research expands upon TRPM8's role as a testosterone receptor, facilitating calcium influx that modulates cell proliferation and apoptosis in PC cells. Notably, TRPM8 mRNA is overexpressed in androgen-dependent benign PC tumors, but exhibits decreased expression in metastatic tumors, indicating a potential tumor-suppressive function in early-stage PC. This suggests that TRPM8 may serve as a biomarker for disease progression and a therapeutic target in androgen-regulated PC. Moreover, our findings suggest that TRPM8 is involved in sexually dimorphic behavioral responses, particularly in the context of age-dependent testosterone’s effects on male physiology. The absence of TRPM8 has been shown to result in significant alterations in male-specific behaviors, highlighting its role in mediating testosterone's influence on male reproductive and territorial behaviors. The male TRPM8 knock out (TRPM8 KO) mice showed increased serum testosterone when compared to wild type. Together, increased testosterone in the male TRPM8 KO mice is associated with aberrant anxiety and depression-like behavioral responses. This data position TRPM8 as a promising therapeutic target in PC and a key player in the regulation of male-specific behaviors. Further studies are warranted to elucidate the mechanisms by which TRPM8 influences both cancer progression and sexually dimorphic behaviors, particularly in the context of androgen signaling. Citation Format: Erick Benjamin Saldes, Alexandra Erdmier, Jai Velpula, Benny Tom, Timothy E. Koeltzow, Don Vander Griend, Swapna Asuthkar. TRPM8 as a testosterone receptor: Exploring its role in prostate cancer and male behavior [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 269.
Abstract 267: ECD co-operates with ERBB2 to promote tumorigenesis through upregulation of unfolded protein response and glycolysis
Authors: Benjamin B. Kennedy, Mohsin Raza, Sameer Mirza, Asher Rajkumar Rajan, Farshid Oruji, Matthew M. Storck, Subodh M. Lele, Timothy E. Reznicek, Lusheng Li, M. Jordan Rowley, Shibiao Wan, Bhopal C. Mohapatra, Hamid Band, Vimla Band
Journal: Cancer Research (2025)

Abstract Introduction: The mammalian ortholog of the Drosophila ecdysoneless (ECD) protein regulates cell cycle progression and cell survival. ECD levels are overexpressed in breast cancer (BC), and its overexpression correlates with poor prognosis and short patient survival, particularly in ERBB2-positive BC. This study explores the cooperative oncogenic mechanisms of ECD and ERBB2 to enhance cancer progression. Methods: We generated immortal human mammary immortalized epithelial cell lines (hMECs) overexpressing ECD, ERBB2, or both. Additionally, we developed transgenic mice overexpressing ECD and/or ERBB2 (huHER2) in mammary epithelium under the control of the MMTV promoter (ECD; HER2Tg) to elucidate the co-oncogenic role and mechanisms underlying this cooperation. Results: hMECs co-expressing ECD and ERBB2 demonstrated a significant increase in in vitro oncogenic traits as compared to cells expressing either ECD or ERBB2. Similarly, while huHER2Tg mice developed more homogenous solid nodular carcinomas, double transgenic mice (ECD; huHER2Tg) developed heterogenous and histologically aggressive mammary tumors with basal-like phenotype and epithelial mesenchymal transition (EMT) features, resembling tumors seen in ECDTg mice. RNA sequencing revealed significant upregulation of two major oncogenic pathways, unfolded protein response (UPR) and glycolysis in ECD+ERBB2 expressing cells as compared to ECD or ERBB2 overexpressing hMECs. Consistently, transcriptomic profile of ECD; huHER2Tg tumors also demonstrated upregulation of glycolysis and UPR pathways. RNA immunoprecipitation assays showed ECD associates to mRNAs of three key glycolytic enzymes (LDHA, PKM2, and HK2) and the major UPR-regulated gene GRP78. This association resulted in increased mRNA stability, leading to higher expression of these genes in ECD+ERBB2-expressing cells. Consequently, ECD+ERBB2-overexpressing cells exhibited higher glucose uptake, and a higher glycolytic rate compared to cells overexpressing either ECD or ERBB2 alone. Conclusions: Our findings support a co-oncogenic role of ECD and ERBB2 in ERBB2-driven BC oncogenesis by enhancing two major oncogenic pathways, UPR and glycolysis. Citation Format: Benjamin B. Kennedy, Mohsin Raza, Sameer Mirza, Asher Rajkumar Rajan, Farshid Oruji, Matthew M. Storck, Subodh M. Lele, Timothy E. Reznicek, Lusheng Li, M. Jordan Rowley, Shibiao Wan, Bhopal C. Mohapatra, Hamid Band, Vimla Band. ECD co-operates with ERBB2 to promote tumorigenesis through upregulation of unfolded protein response and glycolysis [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 267.
Abstract 1841: NanoGhost - A drug targeting system for treatment of solid tumors
Authors: Haim Tsubery, Ziv Azoulay, Shir Weber, Michal Lulu, Limor Matzrafi, Yonatan Malca, Marcell Machluf, Osnat Bohana-Kashtan
Journal: Cancer Research (2025)

Introduction: NanoGhosts (NGs) are nanovesicles derived from the cell membrane of human bone marrow mesenchymal stem cells (hBM-MSCs). NGs preserve MSCs cell membrane architecture and characteristics, thus harnessing MSCs’ innate targeting capability towards tumors. SN38 (a topoisomerase 1 inhibitor) is a highly potent anti-cancer drug with poor water solubility, low plasmatic stability, high systemic toxicity, and low bioavailability. SN38 is approved for colorectal cancer (CRC), and pancreatic cancer as the prodrug Irinotecan or as liposomal Irinotecan, respectively. It is also approved as the antibody drug conjugate sacituzumab govitecan-hziy for triple negative and HR+HER2- breast cancer and metastatic urothelial cancer. We aim to target SN38 to various solid tumors by utilizing the inherent tumor targeting capability of MSCs derived NGs while minimizing SN38 systemic exposure. Methods: MSCs derived NGs were loaded with SN38 using an NHS ester-activated linker. NGs bearing SN38 were tested for anti-cancer activity in vitro and in-vivo. Results: SN38-NHS linker reacted in excess of 20 equivalents to protein content in NGs suspension resulted in average loading of ∼0.08 µg SN38 per 1 µg NGs lipid. SN38 loaded NGs demonstrated relatively low leakage (of up to 34%) after up to 6 hr at 37°C in mouse serum. In vitro, SN38 loaded NGs inhibited proliferation of H460 lung cancer cells (IC50 of 1.6 µg/mL after 6 hr exposure). In vivo, IV administration of SN38 loaded NGs at a dose level of 5 mg/kg NGs lipid (∼0.4 mg/kg SN38), resulted in tumor growth inhibition of HCT116 CRC in mice, similar to the positive control given at a dose level that was ∼25 fold higher. Biodistribution analysis showed concentration of Cy7 labeled SN38-NGs at the tumor site while minimal-no retention in infiltrating organs. Maximal tolerated dose of SN38 loaded NGs was not yet achieved following administrating of up to 10 mg/kg, supporting use of higher levels in follow on studies. Summary: Our data support the use of NGs for targeting highly potent and toxic drugs with draggability barriers (such as SN38) to tumors. Citation Format: Haim Tsubery, Ziv Azoulay, Shir Weber, Michal Lulu, Limor Matzrafi, Yonatan Malca, Marcell Machluf, Osnat Bohana-Kashtan. NanoGhost - A drug targeting system for treatment of solid tumors [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 1841.