tbuckley/cabot-search huggingface dataset:
Abstract 4080: A novel integrated target capture and rapid sequencing workflow for myeloid malignancy mutation detection within 12 hours
Authors: Kyle S. Metcalfe, Benjamin J. Krajacich, Xiaodong Qi, Kelly Wiseman, Marina McCowin, Shawn Levy, Junhua Zhao
Journal: Cancer Research (2025)

Abstract Hybrid capture technology is a powerful and cost-effective tool in precision oncology research to detect somatic mutations in hematologic malignancies. While target capture is important for efficient mutation detection, obtaining rapid sequencing results is critical for research in this field. Traditional hybrid capture workflows involve several time-consuming steps prior to sequencing, including post-hybridization capture, washes, and amplification, which can delay results. Here, we combine Trinity™ hybrid capture and a rapid AVITI™ sequencing protocol to deliver targeted sequencing results within 12 hours. We applied this rapid Trinity™ workflow together with a custom myeloid panel based on a design used by Genomics Medicine Sweden to detect mutations in reference DNA and patient blood/bone marrow/fresh frozen tissue. This custom panel builds on an earlier design, targeting genes included in contemporary guidelines and those with strong or potential clinical impact as well as genes reported in the literature but with less established clinical relevance. The final 7,901-probe panel spans a target region of 0.73 kb and provides uniform coverage across all targets, including challenging GC-rich regions. We were able to detect myeloid malignancy mutations between 0.5%-70% VAF in Horizon’s Mimix™ Myeloid DNA Reference Standard, including internal tandem duplications observed in some patients with acute myeloid leukemia (AML). In sum, the Trinity™ workflow on the AVITI™ sequencer provides a rapid, accurate, and robust solution for targeted sequencing, offering significant advancements in turn-around time for hematology malignancy research. Citation Format: Kyle S. Metcalfe, Benjamin J. Krajacich, Xiaodong Qi, Kelly Wiseman, Marina McCowin, Shawn Levy, Junhua Zhao. A novel integrated target capture and rapid sequencing workflow for myeloid malignancy mutation detection within 12 hours [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 4080.
Abstract 4202: PD-L1 promotes DNA double-strand-break repair and radioresistance in cancer
Authors: Zhen Shu, Bhakti Dwivedi, Jeffrey Switchenko, David Yu, Xingming Deng
Journal: Cancer Research (2025)

Abstract Resistance to radiotherapy is a major barrier during cancer treatment. Using genome-scale CRISPR/Cas9 screening, we identified that the CD274 gene, which encodes PD-L1, confers lung cancer cell resistance to ionizing radiation (IR). Depletion of endogenous PD-L1 retarded the repair of IR-induced DNA double-strand breaks (DSBs). Treatment of lung cancer cells with IR or glycosylation inhibitor tunicamycin resulted in translocation of PD-L1 from the membrane into nucleus in a manner that is dependent on deglycosylation of PD-L1 at N219. CMTM6 transports PD-L1 from the cytoplasm into the nucleus via direct interaction. PD-L1 loss downregulated non-homologous end joining (NHEJ) while overexpression of PD-L1 upregulated NHEJ. Mechanistically, after IR exposure, PD-L1 was recruited to DSB sites to form foci, and to interact with Ku in the nucleus. PD-L1 not only enhanced Ku binding to DSB DNA but also facilitated binding of Ku to other NHEJ factors. PD-L1 deglycosylation and its interaction with Ku occurred in a cell cycle-dependent manner. Interaction between the IgC domain of PD-L1 and the core domain of Ku is required for PD-L1 to accelerate NHEJ-mediated DSB repair and produce radioresistance. Thus, PD-L1, in addition to its immune inhibitory activity, also acts as a mechanistic driver for NHEJ-mediated DSB repair in cancer. Specifically targeting this novel function of PD-L1 may represent an attractive strategy for cancer therapy. Citation Format: Zhen Shu, Bhakti Dwivedi, Jeffrey Switchenko, David Yu, Xingming Deng. PD-L1 promotes DNA double-strand-break repair and radioresistance in 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 4202.
Abstract 4204: A novel triple combination therapy in small cell lung cancer targeting DNA damage repair as a mechanism of resistance
Authors: Ashley Sanchez Sevilla Uruchurtu, Kevin Kwon, Shengliang Zhang, Tyler Roady, Wafik S. El-Deiry
Journal: Cancer Research (2025)

Small cell lung cancer (SCLC) accounts for approximately 15% of new lung cancer cases in the US every year. Treatment options remain limited and 5-year survival rates have languished at around 7% for the past decade. SCLC is notorious for its response to standard etoposide-platinum doublet therapy; initially responsive, it almost always relapses and no longer responds to first-line treatments. The DNA damage response (DDR) has been credibly posited as a targetable mechanism of resistance to DNA-damaging agents. For our experiments, we added prexasertib to our prior combination of imipridone ONC201 (dordaviprone) and small molecule lurbinectedin, previously shown to be synergistic. Prexasertib is a dual inhibitor of Chk1 and 2, protein kinases in the DDR pathway that regulate downstream cell cycle checkpoint (CCC) proteins particularly implicated in G1/S transition and G2 entry. Synergy scores and western blot data from experiments in four cell lines (H1048, H1882, H1105, H1417) point to the role of the DDR-CCC pathway in SCLC treatment resistance and offer a novel treatment modality for testing in vivo, with the ultimate view to progress into the clinic. Citation Format: Ashley Sanchez Sevilla Uruchurtu, Kevin Kwon, Shengliang Zhang, Tyler Roady, Wafik S. El-Deiry. A novel triple combination therapy in small cell lung cancer targeting DNA damage repair as a mechanism of resistance [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 4204.
Hierarchically structured conductive hydrogels for electrically programmable drug delivery in a diabetic wound healing electronic patch
Authors: Zhe-Wei Lin, Yo-Lin Chen, Wan-Lou Lei, Chi-Yao Ku, Pin-Yu Su, Li-Chia Tai, Tsung-Heng Tsai, Yu-Te Liao, Andrew E-Y Chuang, Wei-Chen Huang
Journal: Journal of Controlled Release (2025)
Abstract 6353: <i>Path2Space</i>: An AI approach for cancer biomarker discovery via histopathology inferred spatial transcriptomics
Authors: Eldad D. Shulman, Emma M. Campagnolo, Roshan Lodha, Amos Stemmer, Thomas Cantore, Beibei Ru, Andrew Wang, Tom Hu, Maclean Nasrallah, Danh-Tai Hoang, Kenneth Aldape, Eytan Ruppin
Journal: Cancer Research (2025)

Abstract Motivation: The rise of spatial transcriptomics (ST) is transforming our understanding of tumor heterogeneity by enabling high-resolution, location-specific mapping of gene expression across the tumor microenvironment. However, the translational potential of spatial transcriptomics is still limited by its high cost, hindering the assembly of large patient cohorts needed for robust biomarker discovery. Approach: Here we present Path2Space, a deep learning model trained on spatial transcriptomics data to predict spatial gene expression directly from histopathology slides. Studying breast cancer, the model was first trained on one ST breast cancer patient cohort and further independently tested and validated on two other ST cohorts. Results: Path2Space identifies 4, 500 genes whose spatial expression is robustly predicted in all three cohorts, markedly more accurate than existing ST predictors. Second, we show that based on the inferred ST, Path2Space accurately infers cell-type abundances in the tumor microenvironment (TME). Thirdly, Applying Path2Space to the TCGA breast cancer cohort, we identify three TME spatially grounded subsets of patients that have markedly different survival rates. Fourth, analyzing two large breast cancer patient cohorts treated with trastuzumab, we show that the heterogeneity of the inferred HER2 levels across the tumor microenvironment is predictive of response, concordant with the bystander hypothesis. Finally, we develop a spatially interpretable model for predicting trastuzumab response directly from the H&amp;E-slides. Interestingly, this model’s performance surpasses that of existing response prediction models that use measured bulk multi-omics data. Conclusions: Path2Space is the first approach capable of robustly delineating the tumor microenvironment on an unprecedented scale directly from the tumor slides. It heralds the upcoming development of robust spatially grounded biomarkers of patients survival and treatment that promises to transform precision oncology in both the developed and developing worlds. Citation Format: Eldad D. Shulman, Emma M. Campagnolo, Roshan Lodha, Amos Stemmer, Thomas Cantore, Beibei Ru, Andrew Wang, Tom Hu, Maclean Nasrallah, Danh-Tai Hoang, Kenneth Aldape, Eytan Ruppin. Path2Space: An AI approach for cancer biomarker discovery via histopathology inferred spatial transcriptomics [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 6353.
Abstract 2654: MTAP deficiency is highly homogeneous in advanced, muscle-invasive urothelial carcinoma of the urinary bladder
Authors: Natalia Gorbokon, Viktor Reiswich, Florian Lutz, Sebastian Dwertmann Rico, Henning Plage, Maximilian Lennartz, Margit Fisch, Sarah Minner, Elena Bady, Lisa Hornsteiner, Ronald Simon, Guido Sauter, Henrik Zecha, Stefan Steurer, Thorsten Schlomm, Lukas Bubendorf, David Horst, Thorsten Ecke, Stefan Koch, Martina Kluth, Florian Viehweger, Morton Freytag
Journal: Cancer Research (2025)

Abstract Complete expression loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) is caused by homozygous 9p21 deletion and results in a critical vulnerability of cancer cells towards drugs targeting multiple different pathways. MTAP deficiency is common in urothelial cancer, but data on its intratumoral heterogeneity - a potential obstacle for targeted therapies - are lacking. To study the heterogeneity of MTAP expression loss and 9p21 deletions in advanced primary urothelial cancers of the urinary bladder, a tissue microarray (TMA) was constructed from 5 different sites from different tissue blocks of 105 pT2-4 urothelial carcinomas and analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In addition, all 1-15 tumor containing blocks (average 6.1) from 41 consecutive pT2-4 carcinomas were analyzed by IHC. Complete absence of MTAP staining (MTAP deficiency) was seen in 132 of 385 interpretable TMA samples. All 80 samples with a complete MTAP expression loss and FISH data had a homozygous 9p21 deletion while there were no cases with homozygous deletions within 148 samples with retained MTAP expression (100% FISH/IHC concordance). On a patient level, there was a homogeneous MTAP deficiency in 33%, a heterogeneous MTAP deficiency in 1% and a retained MTAP expression in 66% of these 98 tumors with at least 3 interpretable TMA samples. Among the 41 consecutive pT2-4 carcinomas from which whole sections were analyzed, MTAP was homogeneously deficient in 34%, heterogeneously deficient in 4.9% and homogeneously retained in 61%. It is concluded that MTAP deficiency is mostly homogeneous in advanced urothelial carcinoma. MTAP IHC is a near perfect surrogate for the detection of homozygous 9p21 (MTAP) deletions. Drugs targeting MTAP-deficiency could be highly useful in a relevant subset of invasive urothelial bladder cancers. Citation Format: Natalia Gorbokon, Viktor Reiswich, Florian Lutz, Sebastian Dwertmann Rico, Henning Plage, Maximilian Lennartz, Margit Fisch, Sarah Minner, Elena Bady, Lisa Hornsteiner, Ronald Simon, Guido Sauter, Henrik Zecha, Stefan Steurer, Thorsten Schlomm, Lukas Bubendorf, David Horst, Thorsten Ecke, Stefan Koch, Martina Kluth, Florian Viehweger, Morton Freytag. MTAP deficiency is highly homogeneous in advanced, muscle-invasive urothelial carcinoma of the urinary bladder [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 2654.
Abstract 4088: Optimized workflow for isolating nuclei from FFPE tissue sections for snRNAseq
Authors: Lea Eich, Svetlana Khorkova, Nojan Jelveh, Lilian Martinez Carrera, Olaf Hardt, Carsten Poggel, Benjamin Theek
Journal: Cancer Research (2025)

Background: Formaldehyde fixed and paraffin embedded (FFPE) tissue sections are a valuable resource in cancer research due to the long-term preservation of clinical samples. However, these tissues present significant challenges for molecular analysis due to fixation-induced crosslinking. This study describes an optimized workflow that enables efficient isolation of nuclei from FFPE tissues, compatible with the Chromium Single Cell Gene Expression Flex Assay for downstream gene expression analysis. Methods: FFPE tissue sections from different tissue types (i.e., breast-, lung-, and colon-cancer) were subjected to a deparaffinization and rehydration process, followed by a combined gentleMACS based mechanical dissociation and enzymatic digestion to obtain nuclei. Our new dissociation protocol was benchmarked against a Liberase TH based dissociation. Key modifications of our protocol include the selection of an optimized enzyme mix and a digestion buffer composition to enhance nuclei yield and purity. Nuclei purity and yield were quantified using flow cytometry and an automated cell counter, respectively, while RNA metrics, such as DV200, were assessed via the Agilent TapeStation. The isolated nuclei were then processed using 10x Genomics Chromium Single Cell Gene Expression Flex Assay to validate their suitability for RNA profiling. Results: The optimized protocol successfully isolated nuclei from a variety of FFPE tissue types, often yielding sufficient nuclei from a single 25um FFPE tissue scroll. The following Chromium Single Cell Gene Expression Flex Assay confirmed the superior performance of our new dissociation workflow for RNA profiling. Cell Rangers QC metrics for median UMI counts, median genes, and median reads per cell were improved on average by 61%, 53%, and 59%, respectively. Furthermore, mitochondrial gene expression was reduced on average by 63% compared to the control, suggesting a cleaner nuclei sample. Conclusion: The optimized workflow provides a significant advancement for utilizing FFPE samples in single-cell gene expression studies. By enabling efficient nuclei isolation from FFPE sections, this protocol allows for comprehensive transcriptomic analysis using the Chromium Single Cell Gene Expression Flex Assay, with minimal background, unlocking the potential of archived tissues in retrospective and translational research. Citation Format: Lea Eich, Svetlana Khorkova, Nojan Jelveh, Lilian Martinez Carrera, Olaf Hardt, Carsten Poggel, Benjamin Theek. Optimized workflow for isolating nuclei from FFPE tissue sections for snRNAseq [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 4088.
Abstract 4843: TET2 oxidizes chromatin-associated regulatory RNA m5C to potentiate anti-tumor immunity
Authors: Ying Qing, Dong Wu, Yangchan Li, Keren Zhou, Keith Leung, Wei Li, Le Xuan Truong Nguyen, Lei Dong, Chao Shen, Meilin Xue, Zhenhua Chen, Kitty Wang, Lillian Sau, Mike Fernandez, Zhaoxu Xu, Yuan Che, Tingting Tang, Miao Sun, Li Han, Zhicong Zhao, Meiling Chen, Mingjiang Xu, Lili Wang, Guido Marcucci, Rui Su, Xiaolan Deng, Jianjun Chen
Journal: Cancer Research (2025)

Current immunotherapies have shown limited success in treating acute myeloid leukemia (AML) due to immune evasion, which often stems from epigenetic dysregulation of immune-related pathways. TET2, a well-studied DNA 5-methylcytosine dioxygenase, is frequently mutated and recognized as a tumor suppressor in AML. While TET2 deficiency in hematopoietic stem/progenitor cells (HSPCs) has been associated with elevated inflammation, TET2 has also been reported to promote inflammatory interferon (IFN) signaling in solid tumors, enhancing tumor responses to immunotherapies. Despite these findings, the precise role of TET2 in the response of established AML to anti-tumor immunity and the underlying molecular mechanisms remain poorly understood. By use of both syngeneic and xeno-transplantation AML mouse models, including patient-derived xenotransplantation (PDX) models, as well as in vitro co-culture systems with primary AML cells and T cells, our results revealed that TET2 sensitizes AML cells to T cell-mediated immunity by promoting the transcription of IFN-stimulated genes (ISGs). Mechanistically, we employed UHPLC-QQQ-MS/MS and optimized bisulfite-mediated 5-methylcytosine (m5C) sequencing and demonstrated that chromatin-associated regulatory RNAs (carRNAs) are modified with m5C and TET2 removes m5C from target carRNAs such as LINE1, which subsequently prevents carRNA degradation mediated by SRSF2. Loss of TET2 in AML cells leads to increased m5C levels on carRNAs and decreased LINE1 abundance, which in turn suppresses ISG transcription, facilitating immune evasion. Collectively, this study clarifies the immune-promoting role of TET2 in established AML and elucidates a previously unappreciated molecular mechanism by which TET2 promotes ISG transcription through carRNA m5C oxidation and thereby facilitates immune response. Our findings underscore the therapeutic potential of targeting the TET2-carRNA m5C-ISG pathway to overcome AML immune evasion and improve immunotherapy outcomes in AML. Citation Format: Ying Qing, Dong Wu, Yangchan Li, Keren Zhou, Keith Leung, Wei Li, Le Xuan Truong Nguyen, Lei Dong, Chao Shen, Meilin Xue, Zhenhua Chen, Kitty Wang, Lillian Sau, Mike Fernandez, Zhaoxu Xu, Yuan Che, Tingting Tang, Miao Sun, Li Han, Zhicong Zhao, Meiling Chen, Mingjiang Xu, Lili Wang, Guido Marcucci, Rui Su, Xiaolan Deng, Jianjun Chen. TET2 oxidizes chromatin-associated regulatory RNA m5C to potentiate anti-tumor immunity [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 4843.
Abstract 6340: Pancreatic cancer specific <i>Bmal1</i>-floxed mice reduced malignant potentials and prolonged survival
Authors: Jinsuk Kim, Yukino Oshima, Ichie Kajiwara, Tomoaki Itaya, Tomoya Kuramochi, kaori saito, Taira Wada, Takahiro J. Nakamura, Shigeki Shimba, Hideaki Ijichi, Makoto Sano, Takahiro Suzuki
Journal: Cancer Research (2025)

Abstract Introduction: Dysregulation of clock genes has been reported in pancreatic ductal adenocarcinoma (PDAC), but the effects of the dysregulation on circadian rhythm, PDAC carcinogenesis, progression and prognosis remain unclear. To investigate the effects of dysfunctional Bmal1, a major clock gene, we compared KPPC (LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+) and KPPBC (LSL-KrasG12D/+; Trp53flox/flox; Bmal1flox/flox; Pdx-1cre/+) transgenic mice with PDAC. Methods: Six-week-old KPPC and KPPBC mice were housed in wheel cages, and the circadian rhythms were measured until the humane endpoint. Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. Results: KPPBC mice retained wheel activity at the terminal stage and prolonged the survival rate compared to KPPC mice. The pancreatic tumor volume of KPPBC mice was smaller than that of KPPC mice. The proliferative Ki67 index and invasive frequency of PDAC in KPPBC mice were lower than in KPPC mice. Local MPO+ tumor-associated neutrophils (TANs) and arginase-1+ M2-like tumor-associated macrophages (TAMs) mice decreased in KPPBC mice compared to KPPC mice, whereas iNOS+ M1-like TAMs and CD8+lymphocytes increased in KPPBC mice compared to KPPC mice. Indeed, gastrocnemius muscle atrophy with cachexia was observed in both mice groups at the terminal stage, but average area of the gastrocnemiusmuscle in KPPBC mice was larger than in KPPC mice. Plasma levels of IGF-I and IGF-II in KPPBC mice were higher than in KPPC mice. The proliferation of PDAC cell lines with Bmal1-deficient was slower than that of PDAC cell lines with wild type of Bmal1 in vitro. Conclusions: These results suggest that inhibition of the proliferative potential of Bmal1-floxed PDAC could result from the direct effect of Bmal1 deficiency and alteration of tumor microenvironment. Meanwhile, the delay of gastrocnemius muscle atrophy in KPPBC mice may be due to an increase in cytokines such as IGF-I and IGF-II. Citation Format: Jinsuk Kim, Yukino Oshima, Ichie Kajiwara, Tomoaki Itaya, Tomoya Kuramochi, kaori saito, Taira Wada, Takahiro J. Nakamura, Shigeki Shimba, Hideaki Ijichi, Makoto Sano, Takahiro Suzuki. Pancreatic cancer specific Bmal1-floxed mice reduced malignant potentials and prolonged survival [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 6340.