tbuckley/cabot-search huggingface dataset:
Abstract 2421: Development and validation of an AI-based model for lymphocyte identification in NSCLC H&amp;E image using spatial transcriptomics
Authors: Seo Hye Park, Haenara Shin, Hosub Park, Jaemoon Koh, Kwon Joong Na, Hongyoon Choi
Journal: Cancer Research (2025)

Abstract Background: Spatial transcriptomics (ST) enables the integration of gene expression data with spatial context in tissue samples, providing high-resolution insights without requiring single-cell dissociation. With subcellular resolution, ST offers a precise method for annotating cell types, surpassing traditional approaches based on manual pathologic annotation. Conventional AI models for pathology images typically rely on annotations from pathologists to label cellular compositions in hematoxylin and eosin (H&amp;E)-stained slides. In contrast, our AI model leverages training data generated from subcellular resolution ST, providing a distinct advantage by achieving higher accuracy and objectivity in identifying specific cell types. In this study, we focus on lymphocyte identification in non-small cell lung cancer (NSCLC) pathology images to demonstrate the capabilities of this approach. Methods: This model analyzes H&amp;E slide images obtained from surgical specimens of NSCLC patients. The training dataset consisted of ST data (Xenium, 10X genomics) and H&amp;E images from 90 NSCLC samples collected from a single institution. After aligning ST data with H&amp;E images, cell-type masks were generated for lymphocyte labeling. For performance evaluation, 456 patches (256 × 256 pixels, 0.45 µm/pixel) were randomly selected from 30 NSCLC H&amp;E slide images. Two pathologists independently annotated lymphocytes in these patches. Of the 456 patches, 355 with consistent annotations between the two pathologists were selected for model evaluation. The consensus annotations served as the reference standard to assess the model's performance in lymphocyte identification. Results: This model achieved an AUROC of 0.8411, indicating high diagnostic accuracy. The optional threshold was determined to be 0.3870, with specificity and sensitivity of 72.76% and 78.92%. Compared to two pathologists’ consensus annotations, the model showed a sensitivity of 81.66%, specificity of 69.70%, and accuracy of 77.29% for lymphocyte identification. Conclusion: This AI model trained from subcellular ST provides a robust performance for analyzing the distribution of lymphocytes in NSCLC H&amp;E images. This model offers an innovative approach to analyzing the composition of cells from H&amp;E images, demonstrating its potential contribution to TME research and the development of precision medicine. Citation Format: Seo Hye Park, Haenara Shin, Hosub Park, Jaemoon Koh, Kwon Joong Na, Hongyoon Choi. Development and validation of an AI-based model for lymphocyte identification in NSCLC H&amp;E image using 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 2421.
Abstract 704: Primary versus delayed surgery in fibrolamellar carcinoma
Authors: Paul M. Kent, Tomoaki Kato, Abhinar Humar, Oliver Fisher, Matthew Dixon, Christopher Seder, Tom Stockwell
Journal: Cancer Research (2025)

Abstract Background: Fibrolamellar carcinoma (FLC) is a rare, primary liver cancer of young adults without liver disease, distinct from hepatocellular carcinoma (HCC), usually presenting as advanced stage. FLC has been thought of as a "surgical disease." Because of a lack of data, and a legacy of FLC being mislabeled as “fibrolamellar HCC, ” recommendations have been similar to HCC with upfront surgery considered for all new diagnosis and systemic therapy reserved for those deemed inoperable. Our foundation has assembled the largest collection of FLC cases to date. We reviewed surgery data in FLC stratified by stage and systemic therapy. Methods: We report 216 cases of FLC from our own database and 24 from the medical literature that included: Information about demographics, surgery, systemic therapy, staging, time to relapse and overall survival. We defined “localized” as confined to the liver (AJCC stage 1), “regional” as regional lymph node involvement at surgery (AJCC stage 2 and 3), and “metastatic” (AJCC stage 4) as distant metastasis. Results: Of 155 patients with initial surgery, 44 (28%) had adjuvant systemic therapy and 85 ‘unresectable’ patients had neo-adjuvant therapy converting 31 patients to have delayed surgery (36%). Relapses were nearly universal (89% at 5 years). There was 100% 10-year survival for localized disease, but frequent relapses nonetheless. Adjuvant therapy gave regional patients a survival advantage. Neo-adjuvant therapy benefited metastatic patients as well as providing as significant delay in time to relapse. Benefit to 54 metastatic patients who had neoadjuvant therapy but no surgery was also seen. [Table1] Conclusion: Primary surgery for localized FLC offers excellent long-term control, but regional and metastatic FLC should be considered systemic diseases and systemic therapy before surgery should be considered before committing to initial resection. Neoadjuvant therapy can covert unresectable patients to resectable, and adjuvant therapy appears to benefit all non-localized patients. Citation Format: Paul M. Kent, Tomoaki Kato, Abhinar Humar, Oliver Fisher, Matthew Dixon, Christopher Seder, Tom Stockwell. Primary versus delayed surgery in fibrolamellar 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 704.
Abstract 2: CAV1-ITGA3 axis attenuates cancer stemness in a preclinical murine model of triple-negative breast cancer
Authors: Naveen Chintala Ramulu, Shilpa Thota, Rizwana Begum, Dhirendra Pratap Singh, Biplov Sapkota, Dayanidhi Raman, Joseph Francis
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is a notoriously aggressive phenotype with enhanced metastatic and relapse potential. Caveolin-1 (CAV1), a structural component of caveolae is linked to multiple processes involved in primary tumor progression and metastasis. Notably, an upregulation of CAV1 expression level enhances the metastatic capability of TNBC. Previous findings from our lab have demonstrated that CRISPR/Cas9-mediated knockout (KO) of CAV1 mitigates BC metastasis to the lungs in a 4T1 mouse model of mammary carcinoma via integrin alpha 3 (ITGA3) dysregulation. Breast cancer is a heterogenous disease with cancer stem-like cells of high plasticity that recapitulate the primary tumor at a distant metastatic site, CAV1-KO 4T1 cells may likely have an impact on regulation of cancer stemness. In order to investigate this, we evaluated one of the cancer stemness markers, ALDH1A1; pluripotency transcription factors (SOX2, OCT4 and NANOG); and drug efflux transporters (ABCB1, ABCC1, and ABCG2). In support of our hypothesis, data from in vitro CAV1-KO cells and the in vivo CAV1-KO tumors demonstrated a significant downregulation of cancer stemness parameters as compared to control tumors. Based on these findings, we conclude that CAV1-KO may regulate cancer stemness in a 4T1 mouse model of TNBC. Isolation of breast cancer stem cells (BCSCs) based on ALDH1 activity, morphological characterization, and 3D-functional assays will further solidify the role of CAV1 in cancer stemness and its invasive potential. Overall, we identified a novel role for CAV1 in regulating cancer stemness. CAV1-based targeted therapy has tremendous potential to augment treatment outcomes for TNBC. Citation Format: Naveen Chintala Ramulu, Shilpa Thota, Rizwana Begum, Dhirendra Pratap Singh, Biplov Sapkota, Dayanidhi Raman, Joseph Francis. CAV1-ITGA3 axis attenuates cancer stemness in a preclinical murine model of triple-negative 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 2.
Abstract 1691: Tumor treating fields (TTFields) sensitize BRCA wild type pancreatic cancer cells to treatment with FOLFIRINOX
Authors: Hila Ene, Kerem Ben Meir, Hila Gabay, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Yoram Palti
Journal: Cancer Research (2025)

Abstract Background: FOLFIRINOX is a first-line chemotherapy treatment for patients with advanced pancreatic cancer and good performance status. This combination regimen of fluorouracil, oxaliplatin, irinotecan and leucovorin seems to be more effective in BRCA-mutated tumors due to the platinum-based component, acting by the induction of DNA damage. Tumor treating fields (TTFields) are electric fields that disrupt cellular processes crucial for cancer cell viability. TTFields have shown efficacy in preclinical pancreatic cancer models, and to reduce expression of proteins from the BRCA-dependent DNA repair pathway in various cancer types. The current study examined the potential use of TTFields to sensitize BRCA wild-type pancreatic cancer cells to treatment with FOLFIRINOX. Methods: Human pancreatic BRCA wild-type cancer cells BxPC3 and AsPC1 were treated with TTFields, using the inovitro device (Frequency: 150 kHz; Intensity: 0.7 V/cm RMS for BxPC3 cells; 1 V/cm RMS for AsPC1 cells). FOLFIRINOX was administered to the cells at increasing concentrations, with or without co-treatment with TTFields. After 72h of treatment, cell count, colony formation, and apoptosis were measured. For mechanistical insight, RNA was isolated from TTFields-treated and control samples following 24- and 48-hours treatment and examined by RNA-sequencing and real-time PCR. Additionally, protein was isolated from 72-hours treated samples and examined by Western blot. Results: TTFields application to the pancreatic cells together with FOLFIRINOX reduced cell count and colony formation and induced apoptosis relative to FOLFIRINOX or TTFields alone. TTFields downregulated DNA damage repair, DNA replication, and cell cycle related processes, with reduced expression of several central players in the BRCA DNA damage repair pathway. Conclusions: Application of TTFields together with FOLFIRINOX exhibits potential improvement relative to FOLFIRINOX alone in treatment of pancreatic cancer cells lacking background BRCA mutations. This outcome may be rationalized based on downregulation of key DNA repair pathways. Citation Format: Hila Ene, Kerem Ben Meir, Hila Gabay, Rotem Engelman, Eyal Dor-On, Adi Haber, Moshe Giladi, Yoram Palti. Tumor treating fields (TTFields) sensitize BRCA wild type pancreatic cancer cells to treatment with FOLFIRINOX [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 1691.
Abstract 3829: Dissecting the role of chemotherapy-induced host responses in post-therapy metastatic relapse of breast cancer
Authors: Chaojia Chen, Guangwen Ren, Zheng Gong, Jiayuan Shi
Journal: Cancer Research (2025)

Abstract Chemotherapy-elicited host responses are regarded as a primary mechanism compromising therapeutic efficacy. Clinical evidence indicates that chemotherapy can elevate the risk of distant metastasis in certain breast cancer patients, which was also extensively observed and studied in preclinical models. In a neoadjuvant chemotherapy model, non-labeled mouse and human breast cancer cells were injected into the mouse mammary fat pad, followed by the administration of three doses of doxorubicin to mimic chemotherapy treatment. Luciferase-labeled breast cancer cells were injected into the left ventricle of the mice to establish a systemic metastasis model. In vivo bioluminescence-imaging revealed a striking increase in metastasis to the lung and liver after chemotherapy in all breast cancer mouse models, without significant metastasis to other organs. This effect was even more pronounced in NSG mice (severe immunodeficiency), suggesting that non-immune components may contribute to chemotherapy-induced metastasis. To further explore the host responses post-chemotherapy in the lung and liver, we performed single-cell RNA sequencing (scRNA-seq) to analyze non-immune cell changes following chemotherapy. This analysis identified an increased Postn (Periostin) positive mesenchymal cells subcluster in chemotherapy treated group, with upregulating collagen-processing genes, such as Col1a1 and Col3a1. Spatial transcriptomic analysis further revealed that Postn, along with collagen genes Col1a1 and Col3a1, was localized to the lung interstitial space, suggesting that extracellular matrix (ECM) remodeling in this region may facilitate metastatic colonization. We are currently investigating the role of Postn in chemotherapy-induced host responses and evaluating whether therapeutic targeting of Postn could prevent chemotherapy-induced metastasis. Citation Format: Chaojia Chen, Guangwen Ren, Zheng Gong, Jiayuan Shi. Dissecting the role of chemotherapy-induced host responses in post-therapy metastatic relapse of 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 3829.
Abstract 2646: Ankrd1 enhances lamellipodia formation and cell motility in clear cell renal cell carcinoma
Authors: Hiromi Ito, Yuki Takai, Sei Naito, Takafumi Narisawa, Norihiko Tsuchiya
Journal: Cancer Research (2025)

Abstract Introduction: Clear cell renal cell carcinoma (ccRCC) displays more mesenchymal traits compared to other cancers. These traits include mesenchymal motility, which involves membrane protrusions like lamellipodia formed by actin polymerization. Ankyrin repeat domain 1 (Ankrd1) is regulated by YAP and ERK5, and contains structures that facilitate protein-protein interaction. Ankrd1 has been linked to epithelial-mesenchymal transition (EMT), cancer progression, and drug resistance in various cancers. However, its role in ccRCC remains unexplored. This study investigates Ankrd1 expression, regulation, and function in ccRCC. Methods: We analyzed Ankrd1 expression using the TCGA database and tissue samples via immunohistochemistry. Regulation of Ankrd1 was examined by observing its response to YAP inhibitor and ERK5 inhibitors. Functional studies included siRNA, MTS assay, cell invasion assay, Western blotting, and immunofluorescence imaging. Results: High Ankrd1 expression correlated with poor prognosis of ccRCC patients in TCGA cohort. In tissue samples, metastatic tissues showed higher Ankrd1 levels compared to primary tissues in the same patients. YAP regulated Ankrd1 in all ccRCC cell lines, while ERK5 influenced expression in some ccRCC cell lines. Ankrd1 silencing reduced cell viability under low-density conditions, where YAP activity is prominent. Ankrd1 silencing decreased cell motility, whereas overexpression enhanced motility without altering EMT-related protein levels. Ankrd1 co-localized with F-actin in lamellipodia stimulated by TPA. Ankrd1 silencing altered cell shape and reduced lamellipodia formation. Ankrd1 also interacted and co-located in lamellipodia with Talin-1. Ankrd1 depletion repressed activation of integrin pathway by Talin-1. Conclusion: Ankrd1 is critical for lamellipodia formation and cell motility in ccRCC. Citation Format: Hiromi Ito, Yuki Takai, Sei Naito, Takafumi Narisawa, Norihiko Tsuchiya. Ankrd1 enhances lamellipodia formation and cell motility in clear cell renal 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 2646.
Abstract 2396: Gene fusion and variant-aware isoform detection with functional prediction from long-read RNA sequencing
Authors: Colette Felton, Andrea Galvez, Leanne Sayles, Christopher Vollmers, Alejandro Sweet-Cordero, Angela Brooks
Journal: Cancer Research (2025)

Abstract Although most cancer variant profiling is done with short-read-based methods, many cancers are driven by structural variants that are difficult to detect with these methods. Our current approach to understanding driver mutations is also limited to single variants and rarely considers the context in which they are expressed. Alterations in the expression and splicing of genes containing variants can both impact their tumorigenicity and allow them to develop resistance to therapies. We present FLAIR3, which generates a custom transcriptome from long-read RNA sequencing and identifies SNVs, insertions, deletions, and gene fusions from alignment to this transcriptome. We show that this improves accuracy above alignment to the genome or annotated transcripts. FLAIR3 then integrates these variants with the transcripts to predict functional changes to the amino acid sequence. We apply this approach to patient-derived osteosarcoma cell lines, a cancer whose pathology is driven by complex structural variation. In these samples, we identify more complex changes to previously identified amplified drivers such as alternative splicing of MYC and alternative splicing of a gene fusion in CCNE1. We also identify a novel set of actionable cancer gene alterations not previously detected by short-read methods. This includes a large deletion in KEAP1 and a number of novel gene fusions, including TP53 and other genes fused with intergenic regions and a complex 4-locus fusion in NOTCH1 not detected by any preexisting tools. We then validated the protein sequence of novel fusions with Quantum-Si protein sequencing. This analysis shows that long-read RNA sequencing can detect novel variants in actionable cancer genes and that integrating splicing and variant alterations provides the most complete picture of gene alterations in cancer. Citation Format: Colette Felton, Andrea Galvez, Leanne Sayles, Christopher Vollmers, Alejandro Sweet-Cordero, Angela Brooks. Gene fusion and variant-aware isoform detection with functional prediction from long-read RNA sequencing [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 2396.
Abstract 293: DNMT1 promotes escape from chemotherapy-induced senescence in acute myeloid leukemia
Authors: Manna Ahmed, Dharmendra Kashyap, Hannah Kim, Cihangir Duy
Journal: Cancer Research (2025)

In addition to inducing cell death, chemotherapy can trigger cellular senescence in cancers as a side effect that is typically viewed beneficial for hindering cancer progression. However, acute myeloid leukemia (AML) cells can evade chemotherapy-induced senescence (CIS), leading to therapy failure and disease recurrence. To reduce the risk of AML recurrence, we investigated the mechanisms underlying CIS escape in AML that remain largely elusive. To achieve this, we developed an ex vivo AML recurrence model using primary patient-derived AML cells following exposure to chemotherapy (Ara-C). To minimize potential confounding effects caused by genetic heterogeneity, we utilized single-cell-expanded monoclonal AML populations. These populations were analyzed following CIS escape through integrative transcriptome and DNA methylome profiling. Our analyses revealed that, beside random DNA methylation changes, AML clones gained gene-specific promoter DNA hypermethylation sites associated with transcriptional silencing after CIS escape. This gained transcriptional silencing was conserved across five genetically independent AML specimens, suggesting a shared mechanism underlying AML recurrence after CIS. Using CRISPR-based epigenome-editing tools, we demonstrated that these acquired promoter DNA hypermethylation sites enhanced the survival fitness of AML cells during CIS. To identify the DNA methyltransferase (DNMT) responsible for this epigenetic silencing, we conducted knockdown experiments and identified DNMT1 as the key mediator. Both genetic and pharmacological inhibition of DNMT1 effectively blocked AML cells from escaping CIS. Overall, targeting DNMT1 disrupted CIS escape in AML cells, offering a therapeutic strategy to mitigate the risk of relapse driven by senescence-like leukemia cells. Citation Format: Manna Ahmed,Dharmendra Kashyap,Hannah Kim,Cihangir Duy. DNMT1 promotes escape from chemotherapy-induced senescence in acute myeloid leukemia [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 293.
Abstract 3418: IL6/1 fusion cytokine as a novel adjuvant for manufacturing of T cells for the treatment of ovarian cancer
Authors: Sejal Tarun Sharma, Rahul Das, Lisa Barroilhet, Manish Patankar, Jacques Galipeau
Journal: Cancer Research (2025)

Background: Autologous adoptive T cell therapy (ACT) is an emerging approach for the treatment of ovarian cancer. ACT is more effective if T cells manufactured ex vivo exhibit memory phenotype rather than exhaustive. IL-6 cytokine is known to effect T cell activation, proliferation, survival, and polarization whereas IL-1β is known to augment in vivo expansion of antigen-primed CD8 and CD4 T cells, CD8+ T cell compartmentalization, and activation of T cells by antigen presenting dendritic cells. Due to known effects of these cytokines, we developed a novel biological product, IL6/1, a chimera of IL-6 and IL-1β, for effective manufacturing of T cells for ACT against ovarian cancer. We demonstrate that manufacturing of modified T cells with IL6/1 fusion cytokine improves T cell biological properties and hope to improve success of ACT in ovarian cancer. Methods: Media from the HEK293 cells lentivirally transduced with IL6/1 was used to purify and characterize the fusokine. T cells were isolated from healthy donor PBMCs by negative selection and activated with IL2, anti CD3 - CD28 beads in the presence IL6, IL1β, IL6 + IL1β, IL6/1, conditional media, or no treatment control. Flow cytometry was used to monitor (a) T cell proliferation, (b) expression of CD45Ra, CD45Ro, CD3, CD4 and CD8 to define T cell phenotype and (c) assess cell death by labeling with annexin V and DAPI. Western blotting was performed to study the mechanism of action of IL6/1. Two-way ANOVA was used for statistical analysis. Results: IL6/1 enhanced human T cell survival and increased the CD4 and CD8 memory (CD45Ro+) T cells as compared to vehicle controls or T cells exposed to IL6 or IL1β. T cells exposed to IL6/1 also showed a 10-15% increase in protection from cell death and apoptosis as compared to vehicle controls and T cells exposed to IL-6 or IL1β. Western blotting showed an increase in phosphorylation of STAT3, suggesting the involvement of this key signaling molecule in IL6/1-mediated T cell activation. Conclusion: These findings suggest that IL6/1 fusion cytokine holds promise as a novel adjuvant for increasing the efficacy of T cell manufacturing for therapy in ovarian cancer. Overall, the IL6/1 fusion cytokine represents a novel approach to promote T cell survival, and memory T cell proliferation. Ongoing studies are focusing on evaluating the efficacy of IL6/1-based adjuvants in combination with ACT for the treatment of ovarian cancer in relevant mouse models. Citation Format: Sejal Tarun Sharma, Rahul Das, Lisa Barroilhet, Manish Patankar, Jacques Galipeau. IL6/1 fusion cytokine as a novel adjuvant for manufacturing of T cells for the treatment of ovarian 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 3418.