tbuckley/cabot-search huggingface dataset:
Abstract 1831: Development and characterization of a radiation resistant GBM cell line from PDX for the screening of novel treatment modalities
Authors: Sigrid Cold, Jérémy Ariey-Bonnet, Monica Brandt, Rikke Nørgaard Bøge, Emma Papin, Ida Thorøe Michler, Lotte Kellemann Kristensen, Jacob Hald, Michael Wick, Andreas Kjær, Krister Wennerberg, Carsten Hagen Nielsen, Sebastian Gnosa
Journal: Cancer Research (2025)

Glioblastoma (GBM) remains one of the most lethal brain tumors, with standard-of-care therapies such as radiation and temozolomide offering limited survival benefit. Patient-derived xenograft (PDX) models have become critical tools for studying treatment resistance and identifying novel therapeutic strategies. Here, we report the establishment and characterization of a novel GBM cell line, ST146c, derived from a radiation-resistant PDX model (ST146). This cell line retains the therapy-resistant phenotype observed in the patient, making it a valuable resource for preclinical studies. To uncover vulnerabilities, ST146c was subjected to a mid-throughput drug screen, identifying SIK as a promising target. Subsequent in vitro studies confirmed that SIK inhibition significantly impairs ST146c cell proliferation and survival. To validate these findings, we conducted in vivo experiments using the parental PDX model. SIK inhibition demonstrated robust anti-tumor activity, corroborating the in vitro results and underscoring its potential as a therapeutic target in radiation-resistant GBM. Building upon these findings, we performed a focused synergy screen, testing 40 handpicked drugs in combination with radiation. Among these, SIK3 inhibition emerged as a top candidate, showing evidence of synergistic effects with radiation in vitro. We are now extending these investigations to in vivo models to further evaluate the potential for SIK3 inhibitors to enhance the efficacy of radiation therapy. This study highlights the translational potential of the ST146c model for identifying and validating novel therapies targeting radiation-resistant GBM. The discovery of SIK3 as both a monotherapy target and a radiation-sensitizing agent opens new avenues for overcoming resistance in this challenging disease. Citation Format: Sigrid Cold, Jérémy Ariey-Bonnet, Monica Brandt, Rikke Nørgaard Bøge, Emma Papin, Ida Thorøe Michler, Lotte Kellemann Kristensen, Jacob Hald, Michael Wick, Andreas Kjær, Krister Wennerberg, Carsten Hagen Nielsen, Sebastian Gnosa. Development and characterization of a radiation resistant GBM cell line from PDX for the screening of novel treatment modalities [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 1831.
Abstract 6416: Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis
Authors: David Falvo, Adrien Grimont, Rohit Chandwani
Journal: Cancer Research (2025)

Abstract Inflammation in the context of pancreatic injury drives acinar-to-ductal metaplasia (ADM), a cell state that can be hijacked by mutant Kras to drive the formation of pancreatic cancer. ADM has been described alternatively to bear progenitor features, but the extent to which lineage reversion is a broad feature of the response to injury and early tumorigenesis - particularlyacross the different mutant Kras alleles - remains poorly understood. Herein we implement novel Ptf1a-tdTomato mice to characterize early and late pancreatic progenitors to serve as benchmarks that define cell fate decisions in the context of inflammatory injury and initiation. In so doing, we define ADM as a mixed-lineage transcriptomic and epigenetic state, harboring ductal features but also featuring a lineage reversion to a late progenitor program. By contrast, while inducible mutant Kras alone is able to induce oncogenic gene expression, it does little to alter chromatin in the absence of injury. The most frequent Kras mutant alleles - G12D, G12V, and G12R - display differential cooptation of the injury-induced mixed-lineage state, with mutant KrasG12D able to form ADM and PanIN more robustly than either KrasG12V or KrasG12R. In particular, KrasG12R fails to promote phenotypic transformation on its own or even in concert with inflammatory injury. Whereas KrasG12Dand injury induce enhancer reprogramming at AP-1 chromatin and a lineage reversion to resemble early progenitors, KrasG12Rcan initiate but not sustain the key cell-intrinsic transcriptional and epigenetic programs characteristic of neoplasia. In KrasG12R we identify a decrease in Rac1 signaling, not AKT activation, as the key molecular defect. Together, these data demonstrate that the PDAC-associated Kras variants are not functionally equivalent and distinctly drive lineage reversion and epigenetic reprogramming, such that allele-specific approaches will be essential to therapeutic targeting in pancreatic cancer. Citation Format: David Falvo, Adrien Grimont, Rohit Chandwani. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis [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 6416.
Abstract 1609: Targeting the oncogenic MAP4K4 regulatory axis in pancreatic cancer tumor microenvironment
Authors: Sunil Singh, Sandeep Kumar, Saket Jha, Harsh Vyas, Piush Srivastava, Rakesh S. Nair, Basabi Rana, Ajay Rana
Journal: Cancer Research (2025)

Pancreatic Ductal Adenocarcinoma (PDAC) remains remarkably lethal, with a 5-year survival rate of less than 12%. Due to its widespread resistance to conventional therapy, PDAC is expected to be the second most common cause of cancer-related death in the United States by 2030. One of the major impediments to therapeutic failure in PDAC is the presence of an immunosuppressive tumor microenvironment (TME). We examined the function of Mitogen-activated protein kinases (MAPKs) upstream member, MAP4K4, in the PDAC-TME and tested the efficacies of MAP4K4 inhibitor and immunotherapy to overcome PDAC tumor burden. The role of MAP4K4 in regulating innate and adaptive components of PDAC-TME was determined in vivo using a preclinical immunocompetent murine model (i.e., in KPC) of PADC. The genes related to T cell dysfunctions were determined by the RT2 PCR array. Flow cytometry analyses were performed to determine the immune checkpoint proteins and cytotoxic cytokines in T cells. The therapeutic efficacy of MAP4K4 inhibitor and agonists of 4-1BB and OX40 was determined in the murine model of PDAC. The IHC analyses showed that overexpression of MAP4K4 increases tumor infiltration of macrophages and neutrophils and decreases T cells in the murine model of PDAC. Furthermore, treating PDAC mice with MAP4K4 pharmacological inhibitor GNE-495 decreased tumor-infiltrating macrophages and neutrophils and increased T cell counts. However, the GNE-495 treatment increased tumor-infiltrating T cells and was not associated with increased cytotoxicity of T cells. The RT2 PCR array analysis showed that treatment of GNE-495 decreased 4-1BB gene expression in peripheral and tumor-infiltrating T cells. The combined therapy of GNE-495 and 4-1BB agonistic mAb showed noticeable tumor regression and increased survival in the preclinical model of PDAC. Our study suggests that MAP4K4 regulates innate and adaptive immune cells in pancreatic-TME, and pharmacological inhibition of MAP4K4 decreases tumor macrophages and neutrophil counts. Moreover, the rationalized approach of combining a MAP4K4 inhibitor and a 4-1BB agonist mAb induced a T cell-mediated antitumor response, and this combination could serve as a viable treatment for PDAC. Citation Format: Sunil Singh, Sandeep Kumar, Saket Jha, Harsh Vyas, Piush Srivastava, Rakesh S. Nair, Basabi Rana, Ajay Rana. Targeting the oncogenic MAP4K4 regulatory axis in pancreatic cancer tumor microenvironment [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 1609.
Abstract 2802: Circular RNA variants of the<i>NUMB</i> gene modulate the oncogenicity of oral squamous cell carcinoma
Authors: Chung-Hsien Chou, Pin-Yu Chen, Shu-Chun Lin, Kuo-Wei Chang
Journal: Cancer Research (2025)

Abstract NUMB adaptor protein confers pleiotropic biological and pathological functions by binding with ubiquitin ligases to break down targeted molecules and other activities. Our previous studies have identified that NUMB protein suppresses oral squamous cell carcinoma (OSCC) oncogenicity, and it binds monocarboxylate transporters to elicit the degradation and the associated metabolic disruption. Besides, several oncogenic miRNAs co-target NUMB to abrogate its activity. However, in the TCGA head and neck squamous cell carcinoma (HNSCC) dataset and our OSCC cohort, NUMB expression is slightly unregulated. Despite several isoforms of NUMB owing to alternative slicing, our studies have disclosed the resemblance in oncogenic potential from different NUMB isoforms. Circular RNAs deriving from exons' back-splicing are new RNA entities mediating versatile biological functions. This study identifies several uncharacterized circular RNA variants of the NUMB gene (circNUMBs) in OSCC cell lines and tissues. Following the induction of NUMB promoter activity using the Crispr SAM activation system, the endogenous linear and circular NUMBs are upregulated similarly. The NUMB-null cell subclones, devoid of linear and circular NUMB transcripts, exhibit decreased oncogenicity. However, circNUMBs expression increases the oncogenicity of parental OSCC cells, and it profoundly reverses oncogenic phenotypes of cell subclones as being repressed by NUMB deletion. Analysis using transcriptomic algorithms reveals that circNUMBs modulate cancer, cell development, cell injury, and cell movement genes. The MYC and WNT/β-catenin are the leading signals affected by circNUMBs. This study concludes that circNUMBs mediate oncogenic functions opposite to linear NUMB transcript. Illuminating the interplay of linear NUMB, circNUMB, and their effectors would enable mechanistic insight into HNSCC/OSCC pathogenesis associated with NUMB expression. Citation Format: Chung-Hsien Chou, Pin-Yu Chen, Shu-Chun Lin, Kuo-Wei Chang. Circular RNA variants of theNUMB gene modulate the oncogenicity of oral 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 2802.
Abstract 3635: Racial-ethnic comparisons in surgical treatment and outcomes of non-metastatic renal cell cancer in an equal access system
Authors: Yvonne L. Eaglehouse, Sarah Darmon, Craig D. Shriver, Kangmin Zhu
Journal: Cancer Research (2025)

Background: Access to care has been implicated in racial-ethnic disparities in surgical treatment and survival for patients with renal cell carcinoma (RCC) in the United States. We assessed whether there were racial-ethnic disparities in surgery receipt and clinical outcomes of RCC in the U.S. Military Health System (MHS), which provides equal access to care for beneficiaries. Materials and Methods: We used the MilCanEpi database to study a cohort of patients aged 18 and older who were diagnosed with stage I-III RCC between 1998 and 2014. Treatment with nephrectomy was evaluated in logistic regression models expressed as adjusted odds ratios (AORs) with 95% confidence intervals (CIs). Risk of recurrence and all-cause death were estimated using multivariable Cox regression models. Results: The study included 1,371 non-Hispanic White, 362 non-Hispanic Black, and 177 Hispanic patients. Black patients were less likely to receive nephrectomy as non-Hispanic White patients overall (AOR=0.69, 95% CI=0.47, 1.00) and in strata for stage I (AOR=0.62, 95% CI=0.41, 0.95) or clear cell subtype (AOR=0.46, 95% CI=0.22, 0.96). Hispanic patients were as likely to receive nephrectomy as non-Hispanic White patients overall (AOR=1.13, 95% CI=0.49, 2.62) and in strata by stage or histologic subtype. There were no statistically significant differences in risk of recurrence or all-cause death for Black or Hispanic patients compared to non-Hispanic White patients in multivariable models. Conclusion: In the equal access MHS, nephrectomy receipt was similar for Hispanic patients compared to non-Hispanic White patients while Black patients, especially with stage I or clear cell RCC, were less likely to receive nephrectomy. Nevertheless, there were no differences in recurrence or survival for non-Hispanic Black or Hispanic patients compared to non-Hispanic White patients with non-metastatic RCC. Further research on factors other than access to care that may explain the lower likelihood of receiving nephrectomy for Black patients is needed. Citation Format: Yvonne L. Eaglehouse, Sarah Darmon, Craig D. Shriver, Kangmin Zhu. Racial-ethnic comparisons in surgical treatment and outcomes of non-metastatic renal cell cancer in an equal access 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 3635.
Abstract 2780: Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes
Authors: Jüri Reimand, Christian A. Lee, Robin H. Oh, Zoe P. Klein, Nina Adler, Sana Akhtar Alvi, Ellen Langille, Elisa Pasini, Kevin C. Cheng, Diala Abd-Rabbo, Huayun Hou, Ricky Tsai, Mamatha Bhat, Daniel Schramek, Michael D. Wilson, Liis Uusküla-Reimand
Journal: Cancer Research (2025)

Abstract Type-II topoisomerases resolve topological stress in DNA through controlled double-strand breaks. While TOP2A is a chemotherapy target in proliferating cells, the ubiquitously expressed TOP2B is a potential off-target. Here we explore roles of TOP2B in mutagenesis by generating DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analyzing these maps for driver mutations and mutational processes in 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants (SVs), especially at evolutionary conserved sites displaying high transcription and long-range chromatin interactions. TOP2B binding underlies SVs and hotspot mutations in cancer-driving genes such as TP53, MYC, FOXA1, and VHL, and many cis-regulatory elements. We show that the TOP2B-bound mutational hotspot at RMRP drives tumor initiation and growth in vivo. These data highlight TOP2B as a protector of the genome from topological challenges whose aberrant activity promotes driver and passenger mutations in cancer genomes. Citation Format: Jüri Reimand, 1 Christian A. Lee, 1 Robin H. Oh, 2 Zoe P. Klein, 1 Nina Adler, 1 Sana Akhtar Alvi, 3 Ellen Langille, 2 Elisa Pasini, 4 Kevin C. Cheng, 1 Diala Abd-Rabbo, 1 Huayun Hou, 3 Ricky Tsai, 2 Mamatha Bhat, 1 Daniel Schramek, 2 Michael D. Wilson, 3 Liis Uusküla-Reimand3. Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes [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 2780.
Abstract 1503: Elucidating the role of transcription coregulator MED15 in cancer cell oxidative stress response and proliferation
Authors: Chiaki Shuzenji, Xuanjin Cheng, Stefan Taubert
Journal: Cancer Research (2025)

Abstract Hyperproliferation is a hallmark of cancer that leads to increased ROS levels, leading to oxidative stress, which causes DNA damage and reinforces cell proliferation. To grow in these conditions, cancer cells activate cellular pathways to rewire the transcriptome to promote oxidative stress resistance. Mapping these response pathways can lead to potential new drugs. Mediator complex subunit MED15 is upregulated in many cancer types and confers oxidative stress resistance in lower animals. To test if MED15 promotes oxidative stress resistance in cancer, we generated three MED15 knockout A549 lung adenocarcinoma cells. Transcriptome, real-time quantitative PCR, and Western Blot analysis showed that MED15 loss downregulates oxidative stress response genes, both at baselines and after stress-inducing compounds. Furthermore, the MED15 knockouts were observed to proliferate slower, so I performed cell cycle analysis using flow cytometry which showed that MED15 knockouts arrest cell cycle more after serum starvation compared to their wild-type counterparts. In sum, our data indicate that MED15 is required for normal cancer cell stress resistance and growth. This has clinical potential, as MED15 can be targeted by small molecules, making it a promising drug target. Citation Format: Chiaki Shuzenji, Xuanjin Cheng, Stefan Taubert. Elucidating the role of transcription coregulator MED15 in cancer cell oxidative stress response and proliferation [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 1503.
Abstract 5123: Up-regulation of KRT14 promotes EMT in basal muscle-invasive bladder cancer through IGF2BP1/FTO dependence on methyladenosine-modified SNAI1
Authors: Chuanshu Huang
Journal: Cancer Research (2025)

Abstract Basal muscle-invasive bladder cancer (BMIBC) is considered one of the subtypes of BC with the highest metastatic rate and the poorest prognosis. Therefore, elucidating the mechanisms underlying BMIBC metastasis and identifying novel precision therapeutic targets are current research hotspots and challenges to the cancer researchers. Through a series of in vitro and in vivo functional experiments, we have identified the crucial role of KRT14 in the high invasiveness and adverse prognosis of BMIBC. We found that the K294 site within the IGF2BP1-KH2 domain is responsible for reading the conserved genetic information carried by D226/E227 in the KRT14 nuclear export signal (NES). Activation of the KRT14-IGF2BP1 signaling axis is essential for IGF2BP1-mediated stabilization of SNAI1 mRNA through FTO modification. Additionally, IGF2BP1 forms a positive feedback loop by stabilizing its own mRNA, thereby accelerating the invasion and metastasis of BMIBC. Collectively, our study identifies the KRT14/IGF2BP1/FTO/Snail signaling axis as an essential regulatory mechanism associated with poor prognosis in BMIBC, providing a theoretical basis for KRT14 and its downstream regulated molecules as therapeutic targets for BMIBC and the development of corresponding targeted therapies. Keywords: Basal muscle invasive bladder cancer; KRT14; IGF2BP1; m6A methylation; Nuclear translocation Citation Format: Chuanshu Huang. Up-regulation of KRT14 promotes EMT in basal muscle-invasive bladder cancer through IGF2BP1/FTO dependence on methyladenosine-modified SNAI1 [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 5123.
Abstract 4694: (R)evolutionary approach to predicting individual response to radiation therapy in breast cancer
Authors: Naheel Khatri, Raafat Chalar, Saiful Samad, Alexander Stessin, Mehdi Damaghi
Journal: Cancer Research (2025)

Abstract Despite increasing incorporation of gene panel testing into radiotherapeutic decision-making, there is no established method to tailor prescribed radiation regimens to individual tumor radiosensitivity. We propose a novel approach to assessing evolutionary determinants of radioresistance from patient-derived tumor samples. We hypothesized that pre-existing resistance to oxidative damage in tumor microenvironment (TME) can define a cell's evolutionary trajectory and its radiosensitivity. In contrast with the current genetic panels, we use a panel catered toward heterogeneity within the tumor and the TME niches, which may harbor radioresistant populations from collateral TME mechanisms of resistance. The aim is to develop an AI-based algorithm using these eco-evolutionary results to individualize radiation dose in patients, thus minimizing the percentage of non-responders. 3D spheroids of several breast cancer cell lines were grown and collected at multiple time points after 10 Gy of radiation. MALDI data was acquired in negative and positive ionization mode for spatial lipidomics and metabolomics analysis. Additionally, spatial single cell multiplexed immunofluorescence was performed on the sequential cut to MALDI using markers associated with hypoxia, acidosis, ROS, and epithelial-to-mesenchymal transition. Then we grew patient derived organoids (PDO) of breast cancer and irradiated them and analyzed them as described above. Based on a previously validated oxygen diffusion model, spheroids were categorized according to size, with those &amp;lt;240 micrometers in diameter designated as O-spheroids (oxygenated) and those ≥ 240 microns designated as H-spheroids (hypoxic core). While the irradiated O-spheroid growth curves plateaued upon irradiation, H-spheroids grew at the same rate as the non-irradiated controls. To investigate this phenomenon, habitats and cell phenotypes were defined using spatial multi-omics data from MALDI and multiplexed-IF, respectively. We found differential distributions of habitats in radiated spheroids as determined by the cluster size and abundance spatio-temporally. We discovered a switch in the sphingolipid metabolism pathway. Using principles of ecology and evolution, we have developed a novel approach to identifying radiosensitivity markers. Detecting these cell states and ecological niches in patients’ pre-treatment biopsies can inform a more individualized approach to radiotherapy. Citation Format: Naheel Khatri, Raafat Chalar, Saiful Samad, Alexander Stessin, Mehdi Damaghi. (R)evolutionary approach to predicting individual response to radiation therapy in 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 4694.