tbuckley/cabot-search huggingface dataset:
Abstract LB059: Fructose transporter (SLC2A5)-dependent regulation of STAT3 expression in cancer cells metastasis
Authors: Jody Groenendyk, Myriam Pujol, Ning Dai, Izabela Quest, Ayshna Diya, Jingfeng Tang, Luis B. Agellon, Marek Michalak
Journal: Cancer Research (2025)

Abstract Endoplasmic reticulum (ER) stress plays an integral part during cancer progression and is utilized as an adaptive mechanism in stressful environments. During tumour formation, cancer cells experience a hostile microenvironment composed of a lack of oxygen, nutrients and lipids and an acidic pH and they undergo high metabolic demands, with increased protein production and cellular growth. Using an ER Stress reporter assay we discovered that silencing the fructose transporter SLC2A5 (GLUT5) gene and, consequently, reduced uptake of fructose resulted in inhibition of the IRE1/spXBP1 arm of the ER stress response. Furthermore, we showed that the loss of the fructose transporter inhibits cancer cell migration and proliferation in MIA-PaCa-2 pancreatic cancer cells. RPPA analysis of SLC2A5-deficient pancreatic cancer cells identified STAT3 playing an essential role in the response to reduced fructose uptake. In the absence of SLC2A5, there was a significant decrease in the abundance of STAT3 mRNA and protein, as well as decreased STAT3 transcriptional activity. Transcriptional analysis revealed that the STAT3 gene is regulated by ER stress via the IRE1α/spXBP1 pathway and that it was responsible for reduced abundance of STAT3 in SLC2A5-deficient pancreatic cancer cells. STAT3 association with the mitochondria was also reduced in the absence of the fructose transporter. Membrane contact SPLICS analysis revealed the loss of the close mitochondrial-ER contacts in SLC2A5-deficient MIA-PaCa-2 cells. Furthermore, flow cytometry analysis of calcium fluxes indicated a disruption in the calcium transfer between the ER and the mitochondria. Reduced calcium transfer to mitochondria in SLC2A5-deficient MIA-PaCa-2 cells was accompanied by increased amount of reactive oxygen species (ROS). Taken together, these findings indicated that a deficiency in the fructose transporter SLC2A5 in MIA-PaCa-2 pancreatic cancer cells resulted in reduced STAT3 expression and activity, a reduction of mitochondria-ER contact sites, reduced calcium transfer to the mitochondria and increased ROS production in the mitochondria, all contributing to disrupted mitochondrial architecture and function. Citation Format: Jody Groenendyk, Myriam Pujol, Ning Dai, Izabela Quest, Ayshna Diya, Jingfeng Tang, Luis B. Agellon, Marek Michalak. Fructose transporter (SLC2A5)-dependent regulation of STAT3 expression in cancer cells metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB059.
Abstract LB132: C8orf76 promotes colorectal tumorigenesis by promoting an immunosuppressive microenvironment and is a therapeutic target for boosting anti-PD-1 efficacy
Authors: Hongyan Gou, Shang Guo, Xiaohong Wang, Xia Jiang, Chi Chun Wong, Huarong Chen, Chunxian Wei, Lingxue Shi, Zengren Zhao, Jun Yu
Journal: Cancer Research (2025)

Abstract Immune checkpoint blockade (ICB) therapy demonstrated limited efficacy in colorectal cancer (CRC), and identification of intrinsic factors modulating immune suppression in CRC is an unmet need. Here, we revealed that Chromosome 8 open reading frame 76 (C8orf76) drives immunosuppression and is a molecular target to boost ICB therapy in CRC. C8orf76 is upregulated in primary CRCs compared to adjacent normal tissues in 2 independent CRC cohorts and its expression predicts poor patient survival. Intestine-specific C8orf76 knockin in mice exacerbated AOM/DSS-induced CRC, accompanied by increased intratumoral myeloid-derived suppressor cells (MDSCs) but reduced IFN-γ+ and granzyme B+ CD8+ T cells, inferring that C8orf76 promotes immunosuppression in CRC. Consistently, genetic depletion of C8orf76 augmented antitumour immunity in CT26 (MSS-CRC) and MC38 (MSI-H-CRC) allograft models. Integrated RNA-seq and ChIP-seq revealed that C8orf76 functions as a transcription factor to drive NDST1 expression, which activates the PI3K-Akt-NF-κB signaling cascade. Activated NF-κB in turn promotes the expression and secretion of CXCL1, a major chemoattractant for MDSCs. Consequently, C8orf76-induced CXCL1 mediates the recruitment of MDSCs via CXCR2 to antagonize functional CD8+ T cells in tumor immune microenvironment of CRC. Confirming this, targeting NDST1 or CXCR2 could reverse C8orf76 induced immunosuppression in vivo. Finally, we tested the translational value of C8orf76 using genetic ablation or vesicle-like nanoparticles (VNPs)-encapsulated C8orf76-siRNA. In line with our hypothesis, we demonstrated that targeting C8orf76 by genetic ablation or VNPs-encapsulated C8orf76-siRNA potentiated the anti-PD1 efficacy in both MSI-H and MSS CRC models. In summary, C8orf76 drives immunosuppression through a NDST1-CXCL1/CXCR2 axis, and targeting C8orf76 is a promising approach to boost ICB therapy efficacy in CRC. Citation Format: Hongyan Gou, Shang Guo, Xiaohong Wang, Xia Jiang, Chi Chun Wong, Huarong Chen, Chunxian Wei, Lingxue Shi, Zengren Zhao, Jun Yu. C8orf76 promotes colorectal tumorigenesis by promoting an immunosuppressive microenvironment and is a therapeutic target for boosting anti-PD-1 efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB132.
Abstract LB171: Drug response profiling of patient-derived tumoroids and immortalized cancer cell lines using a novel automation workflow and AI-assisted image analysis
Authors: Anthony Stephen Eritano, Dylan Bryda, Andreea Merloiu, Alissa Schutte, Gerri Ortiz, Barbara McIntosh, Seyoum Ayehunie, Evan Cromwell
Journal: Cancer Research (2025)

Abstract Three-dimensional in vitro cell models have gained popularity as they better recapitulated key aspects of human tissues and tumor microenvironments. Forming structures with patient-derived (PD) cancer cells show great promise for translational work. These 3D models are being used for drug discovery and development, but adoption has been limited in part due to challenges related to sample handling, assay development, and the need for optimized instrumentation. Here, we present a novel automated workflow for drug safety and efficacy studies using PD 3D tumor models and show utility for translational research. Individual tumoroids comprised of patient-derived colorectal cancer (CRC) cells or patient-derived breast cancer (BC) cells were isolated using the spheroONE into individual wells of the Pu·MA System flowchip. Isolated tumoroids were treated with varying concentrations of doxorubicin, oxaliplatin, Cetuximab and 5-Flourouricil using the integrated microfluidic architecture of the Pu·MA and iDOT systems. Treated tumoroids were incubated with compounds for 48 hours and stained with viability dyes. Tumoroids were imaged using widefield fluorescence microscopy and analyzed for viability using a custom AI-assisted analysis program. Patient-derived BCs, immortalized estrogen receptor positive breast cancer cells (MCF7) and triple negative breast cancer cells (MDA-MB-231) will be used to further validate the workflow we outlined. Viability of drug treated tumoroids showed a dose dependent increase in cell death, consistent with known cellular responses seen in humans. Furthermore, phenotypic differences and responses were observed between primary CRCs and spheroids generated from immortalized colorectal cells (HTC116). The mechanisms for these differences are being investigated. These data suggest that classical drug discovery using immortalized cell lines may not accurately reflect cellular behaviors seen in CRCs and potentially other patient-derived cancer cells. This novel automated workflow allows for the potential to use tumoroids from patients to be rapidly screened for drug effects, thus providing a promising platform for future clinical validation and personalized medicine. Citation Format: Anthony Stephen Eritano, Dylan Bryda, Andreea Merloiu, Alissa Schutte, Gerri Ortiz, Barbara McIntosh, Seyoum Ayehunie, Evan Cromwell. Drug response profiling of patient-derived tumoroids and immortalized cancer cell lines using a novel automation workflow and AI-assisted image analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB171.
Abstract LB407: Enhancing sensitivity and specificity of the CA15-3 (MUC1) breast cancer assay by detection of N-glycolylneuraminic acid (Neu5Gc) using the lectin SubB2M
Authors: Sara Nikseresht, Ramin Khanabdali, Lucy Shewell, Christopher Day, Amy McCart Reed, Michael Jennings, Haarika Haarika, Sunil Sunil, Peter Simpson, Romina Nabiee, Mathew Moore, Leearne Hinch, Gregory Rice
Journal: Cancer Research (2025)

Abstract Introduction: The aim of this study was to test the hypothesis that the diagnostic performance (as defined by the classification accuracy, sensitivity and specificity) of CA15-3 to detect breast cancer is increased by detection of the cancer-associated Neu5Gc sialic acids on the mucin MUC1 using the novel lectin, SubB2M. Methods A genetically engineered lectin (SubB2M) that binds Neu5Gc was used as a detection reagent in a sandwich ELISA format CA15-3 assay. In a case : control cohort equivalence study the classification accuracy for the SubB2M-based CA15-3 assay (neuCA15-3) was determined and compared to an FDA-approved CA15-3 IVD test (Elecsys CA15-3 II, Roche Diagnostics). Results Classification accuracy and AUC for neuCA15-3 were 81% and 0.886 ± 0.015 (standard error, n=567) and for Elecsys Ca15-3 II, 55% and 0.642 ± 0.023 (n=558), respectively. At a threshold cut-off serum concentration of 23.6 Units/ml, overall breast cancer classification accuracy of the neuCA15-3 was 81% (compared to 55% for the comparator assay, p &amp;lt; 0.001). At 95% specificity, the sensitivity of the NeuCA15-3 assay was 69.5%, significantly greater than the competitor assay (11.9%, p&amp;lt;0.001). NeuCA15-3 concentrations did not vary significantly with breast cancer receptor subtype. Conclusions The diagnostic performance of the neuCA15-3 assay was substantially improved over the classical CA15-3 sandwich assay that detects all forms of MUC1. The reporter signal generated for the neuCA15-3 assay depends on capture of the MUC1 protein and the presence of the aberrant Neu5Gc sialic acid residues on the MUC1 protein, thus increasing the assay specificity. The presence of multiple Neu5Gc lectin binding sites per glycoprotein molecule increases signal generation and assay sensitivity. The inclusion of additional cancer biomarkers in a multivariate index assay format may further increase diagnostic performance for breast cancer. Citation Format: Sara Nikseresht, Ramin Khanabdali, Lucy Shewell, Christopher Day, Amy McCart Reed, Michael Jennings, Haarika Haarika, Sunil Sunil, Peter Simpson, Romina Nabiee, Mathew Moore, Leearne Hinch, Gregory Rice. Enhancing sensitivity and specificity of the CA15-3 (MUC1) breast cancer assay by detection of N-glycolylneuraminic acid (Neu5Gc) using the lectin SubB2M [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB407.
Abstract LB071: Modulating TREM1 to boost NK cell activity and overcome MDSC-induced immunosuppression in neuroblastoma
Authors: Hae Soo Choo, Timothy Pham, Brent Kern, Jaya Lakshmi Thangaraj, Tina Yu, Mrunal Desai, Anusha Preethi Ganesan, Pablo Tamayo, Dan S. Kaufman, Shweta Joshi
Journal: Cancer Research (2025)

Abstract Neuroblastoma (NB) accounts for approximately 15% of pediatric cancer deaths, posing a significant challenge for high-risk patients. Although anti-GD2 immunotherapy has improved the 5-year survival rate, many patients still experience disease progression. The efficacy of anti-GD2 monoclonal antibodies depends on natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), but tumor and stromal cells employ immunosuppressive mechanisms that limit NK cell activity. Notably, the accumulation of myeloid-derived suppressor cells (MDSCs), particularly polymorphonuclear (PMN)-MDSCs, hampers both T cell and NK cell functions. Our studies reveal that PMN-MDSCs accumulate in both murine and human NB, and PMN-MDSCs impair NK cells by downregulating NKG2D and NKp46 expression. Furthermore, we identify triggering receptor expressed on myeloid cells (TREM1) as a key regulator of NK cell dysfunction, with PMN-MDSCs from both murine and human NB blood showing high TREM1 expression. Inhibition of TREM1 signaling reprograms MDSCs, restores NK cell function, and reduces tumor growth in mouse models of NB. These findings highlight the pivotal role of TREM1+ PMN-MDSCs in modulating NK cell activity and propose the therapeutic targeting of TREM1 in combination with anti-GD2 monoclonal antibodies to enhance NK cell function in neuroblastoma. Citation Format: Hae Soo Choo, Timothy Pham, Brent Kern, Jaya Lakshmi Thangaraj, Tina Yu, Mrunal Desai, Anusha Preethi Ganesan, Pablo Tamayo, Dan S. Kaufman, Shweta Joshi. Modulating TREM1 to boost NK cell activity and overcome MDSC-induced immunosuppression in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB071.
Abstract LB162: Clinically relevant humanized mouse models of metastatic prostate cancer facilitate therapeutic evaluation
Authors: Raymond J. Kostlan, John T. Phoenix, Audris Budreika, Marina G. Ferrari, Neetika Khurana, Jae Eun Choi, Kristin Juckette, Somnath Mahapatra, Brooke L. McCollum, Russell Moskal, Rahul Mannan, Yuanyuan Qiao, Donald J. Vander Griend, Arul M. Chinnaiyan, Steven Kregel
Journal: Cancer Research (2025)

Abstract There is tremendous need for improved prostate cancer models. Anatomically and developmentally, the mouse prostate differs from the human prostate and does not form tumors spontaneously. Genetically engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts are an alternative but must rely on an immunocompromised host. Therefore, we generated prostate cancer murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic prostate cancer and the impact of androgen receptor-targeted and immunotherapies. These mice maintain multiple human immune cell lineages, including functional human T-cells and myeloid cells. Implications: To the best of our knowledge, results illustrate the first model of human prostate cancer that has an intact human immune system, metastasizes to clinically relevant locations, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment. Citation Format: Raymond J. Kostlan, John T. Phoenix, Audris Budreika, Marina G. Ferrari, Neetika Khurana, Jae Eun Choi, Kristin Juckette, Somnath Mahapatra, Brooke L. McCollum, Russell Moskal, Rahul Mannan, Yuanyuan Qiao, Donald J. Vander Griend, Arul M. Chinnaiyan, Steven Kregel. Clinically relevant humanized mouse models of metastatic prostate cancer facilitate therapeutic evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB162.
Abstract LB052: HIF1α-driven glycolysis in hypoxic T cells modulates cytokine production and immunotherapy responses
Authors: Vivian Y. Shi, Hongxing Shen
Journal: Cancer Research (2025)

Abstract Other than the few T cells residing in the upper airways, most T cells live in hypoxia that shapes their survival and functions. Although it has long been known that HIF1α is the primary regulator of cellular adaptive responses to hypoxia, whether and how HIF1α regulates cell survival and effector functions (i.e., cytokine production) in hypoxic T cells have been poorly defined. Combining genetic mouse models, metabolic flux using 13C-labeled glucose tracer, and measurement of cellular metabolic function by Seahorse analyzer, we show that the HIF1α-dependent glycolysis drives IFN-γ but suppresses IL-2 production in T cells under hypoxia, cytokines associated with late and early stages of T cell activation, respectively. Specifically, HIF1α deletion in T cells (Hif1α -/-) and glycolytic inhibition with 2-DG suppresses IFN-γ but promotes IL-2 production. In contrast, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl -/-) increases IFN-γ but reduces IL-2. Hypoxic Hif1α -/- T cells and T cells treated with 2-DG survive better. Despite this, Hif1α -/- T cells are less able to kill tumor cells in vitro, and Hif1α -/- mice bearing established tumors are not responsive to immune checkpoint blockers (ICB) (combined anti-CTLA-4 and anti-PD-1) in vivo, in line with their drastically reduced production of IFN-γ. Mechanistically, HIF1α deficiency diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA. Restoration of intracellular acetyl-CoA by acetate supplementation rescues IFN-γ production in hypoxic Hif1α -/- T cells and re-sensitizes Hif1α -/- tumor-bearing mice to ICB. Taken together, HIF1α-dependent glycolysis reciprocally regulates the production of early (IL-2) and late effector cytokines (IFN-γ) as well as survival of hypoxic T cells, representing a key T cell-intrinsic metabolic checkpoint of ICB responses. Citation Format: Vivian Y. Shi, Hongxing Shen. HIF1α-driven glycolysis in hypoxic T cells modulates cytokine production and immunotherapy responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB052.
Abstract LB073: Characterizing the ovarian cancer immune microenvironment in a syngeneic murine model
Authors: Alexandra N. McMellen, Benjamin G. Bitler, Michael S. Leibowitz
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OvCa) is the deadliest gynecologic malignancy and, unfortunately, there are no effective salvage therapies for patients with refractory or resistant (r/r) disease. This is due in part to a limited understanding of the tumor microenvironment (TME), the marked differences between tumors established in different metastatic niches, and how the TME may change in the context of therapy resistance. OvCa uniquely metastasizes through peritoneal spread, resulting in various tumor niches with distinct tumor mutational burdens within the same patient. These niches have not been well characterized in murine models of OvCa and contribute to continued ineffective therapeutic interventions for r/r OvCa. To better define the ovarian cancer TME, we are utilizing orthotopic syngeneic murine models sensitive and resistant to the FDA approved PARP inhibitor (PARPi), Olaparib, ID8 and ID8-OR respectively. This model has both a TP53 and BRCA2 deletion, recapitulating the mutational status of OvCa patients likely to receive a PARPi. After tumor establishment, ascites as well as solid tumors at distinct tumor sites were collected and dissociated for further analysis. Using flow cytometric assays, we characterized the T cell infiltrate within the TME at distinct niches and surface marker expression on the tumor cells. These data confirm the presence of tumor infiltrating T cells within the OvCa TME across different tumor niches. We observed that the tumor infiltrating T cell percentage as well as their phenotype varies across the different metastatic niches of this disease. We observe a greater percentage of T cells present in the ascites as compared to the other metastatic sites including the omentum, the ovaries, and the bowel wall. Additionally, we observe a greater percentage of T-regulatory cells in PARPi-resistant omental tumors. Interestingly, while we do observe CD4+ and CD8+ T cells in the collected tumors, we do not see consistent expression of markers associated with either activation or exhaustion. Further studies are required to better characterize the functionality of the tumor infiltrating T cells. The data generated from these studies will inform the development of successful salvage immunotherapies for relapsed and refractory patients with ovarian cancer. Citation Format: Alexandra N. McMellen, Benjamin G. Bitler, Michael S. Leibowitz. Characterizing the ovarian cancer immune microenvironment in a syngeneic murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB073.
Abstract LB470: Caveolin-1 as a modulator of chemotherapeutic response and metastasis in triple negative breast cancer
Authors: Shreya Pokharel, Naveen Chintalaramulu, Dhirendra Pratap Singh, Abhishek Pathak, Biplov Sapkota, Shilpa Thota, Rizwana Begum, Joseph Francis
Journal: Cancer Research (2025)

Abstract Caveolin-1 (Cav-1) is a lipid raft protein with a dual role as an oncogene and a tumorsuppressor depending on the cellular context and breast cancer (BC) subtype. We havepreviously shown that Cav-1 knockout (KO) mitigated BC metastasis to lungs in a 4T1-syngeneic mouse model of TNBC. In this study, we examined the eHect of Cav-1 KO on thechemosensitivity to doxorubicin (Dox) both in vitro and in vivo. Our in vitro data showedenhanced chemosensitivity of Cav-1 KO cells to Dox as compared to the corresponding4T1.WT control. This eHect was mediated via the regulation of ABCG2 transporter. Inagreement with our previous study, Dox treatment further inhibited lung metastasis inBalb/c mice injected with Cav-1 KO cells as compared to the 4T1.WT group. Interestingly,Dox treatment of Cav-1 KO resulted in G2/M phase arrest of cell cycle when compared tothe WT control. Collectively, our study suggests a putative role of Cav-1 KO inchemosensitivity of 4T1 cells to Dox treatment both in vitro and in vivo. Currently, RNA-seqexperiments are underway to investigate the relationship between Cav-1 KO and Doxsensitivity in these cells and tissues. Citation Format: Shreya Pokharel, Naveen Chintalaramulu, Dhirendra Pratap Singh, Abhishek Pathak, Biplov Sapkota, Shilpa Thota, Rizwana Begum, Joseph Francis. Caveolin-1 as a modulator of chemotherapeutic response and metastasis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB470.