tbuckley/cabot-search huggingface dataset:
Abstract LB130: Gfi1 controls the formation of effector-like CD8 T cells during chronic infection and cancer
Authors: Lewis Zhichang Shi, Oluwagbemiga A. Ojo
Journal: Cancer Research (2025)

Abstract During chronic infection and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to exhausted effector-like cells. Generation of effector-like cells is essential for the control of chronic infections and cancers, albeit limited. However, the precise cues and mechanisms directing their formation and maintenance are incompletely understood. Here, we find that the transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells during chronic LCMV Clone 13 infection and tumor progression. Deletion of Gfi1 in T cells disrupts the chromatin accessibility and transcriptomic programs needed for the development of LCMV-specific exhausted CD8 T cells, diminishing the formation of effector-like and terminally exhausted (Term-Exh) cells while increasing progenitors and newly identified Ly108+CX3CR1+ cells. Ly108+CX3CR1+ cells have a distinct chromatin profile and represent a transitory subset between progenitor and effector-like/Term-Exh cells. Similarly, Gfi1 loss impairs the formation of terminally differentiated tumor-infiltrating CD8 T cells (CD8 TILs) from progenitors, decreases cytokine production in CD8 TILs, and renders tumor-bearing mice less responsive to anti-CTLA-4. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells. Citation Format: Lewis Zhichang Shi, Oluwagbemiga A. Ojo. Gfi1 controls the formation of effector-like CD8 T cells during chronic infection and 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 LB130.
Abstract LB452: The role of dysregulated retinoid receptors in colorectal cancer
Authors: Bruce M. Boman, Brooke Coulbourne, Anh Nguyen, Caroline Facey, Chi Zhang
Journal: Cancer Research (2025)

Abstract The retinoic acid (RA) signaling pathway plays an essential role in regulating cell differentiation in the colon. Our Goal is to determine how aberrant retinoid receptor expression might promote colorectal cancer (CRC) development through dysregulated retinoic acid signaling. Rationale: Retinoid receptors are often abnormally expressed or mutated in human CRCs. So, aberrant expression or mutation of RA receptors could lead to incomplete differentiation and increase CRC growth. Indeed, we previously reported that CRC cell lines harboring mutations in RA receptors (RAR, RXR) have drug resistance to all-trans RA (ATRA). Hypothesis: Aberrant RA receptor expression leads to dysregulated RA signaling that contributes to CRC development. Accordingly, we investigated RA receptor components of the RA signaling pathway including RARs, RXRs, PPARs and determined if aberrant RA expression predicts CRC patient survival. We discovered a signature of six RA receptor genes that are differentially expressed between normal colon and CRC, and that also predicts poor CRC patient survival. We found that up to 22% of CRCs have RA receptor mutations, but mutation status did not predict patient survival. However, we did find that frequency of retinoid receptor mutation was higher (&amp;gt;2X-fold) in early-onset CRC (EOCRC, age &amp;lt; 45) compared to late-onset CRC. NanoString profiling experiments revealed: i). induction of wild-type APC expression in APC-mutant CRC cells increases expression of RA receptors in response to ATRA; ii). A specific RA receptor expression profile characterizes ALDH+ versus LGR5+ stem cells. Conclusions Since RA receptor expression predicts CRC patient survival, it provides a mechanism by which dysregulated RA signaling could promote tumor behavior and drive colon tumorigenesis. Since the rate of retinoid receptor mutation was increased in EOCRC, this indicates that aberrant RA signaling may be a predisposing factor for early CRC development. Citation Format: Bruce M. Boman, Brooke Coulbourne, Anh Nguyen, Caroline Facey, Chi Zhang. The role of dysregulated retinoid receptors in colorectal 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 LB452.
Abstract LB351: AXIN2 promotes WNT-target gene expression via cross-feedback between WNT and retinoic acid signaling pathways based on transcriptionally co-regulated components
Authors: Chi Zhang, Gilberto Schleiniger, Caroline Facey, Lynn Opdenaker, Bruce Boman
Journal: Cancer Research (2025)

Abstract APC mutation is the most common colorectal cancer (CRC) driver mutation, yet CRC patients carrying APC mutation have more favorable survival compared to those with only wild-type APC. Through NanoString transcriptome profiling, flow cytometry, western blot and Genomic Data Commons/The Cancer Genome Atlas (GDC/TCGA) RNA-seq data analysis, we discovered that instead of functioning as a negative regulator of WNT signaling, AXIN2 up-regulates WNT-target gene expression in CRC cells carrying mutant APC. To further explore the mechanism of this novel function of AXIN2, we hypothesize that AXIN2 up-regulates WNT-target gene expression through down-regulation of WNT-signaling activity and up-regulation of retinoic acid (RA) signaling activity in CRC cells with mutant APC. To test this hypothesis, we conducted ChIP-seq data analysis and identified a set of WNT- and RA - signaling pathway component genes that are transcriptionally co-regulated by both WNT- and RA-signaling activity. This finding led to our WNT- and RA- signaling transcriptional co-regulation model in which the sequential arrangement of TCF/LEF and RAR/RXR transcription factors determines the responsiveness of target gene transcription to WNT- or RA- signaling activity. Such difference in responsiveness was confirmed by CRC patient RNA-seq results from GDC/TCGA. We then implemented the transcriptional co-regulation model mathematically into an ordinary differential equation (ODE) model, and fitted the model to CRC patient RNA-seq data. Simulation results of our model are consistent with our western blot results on WNT-target gene expression in AXIN2-modulated CRC cell lines. Overall, our findings support our hypothesis that the AXIN2 positively regulates expression of WNT-target genes in CRC cells carrying mutant APC via cross-talk between WNT- and RA- signaling pathways, based on transcriptional co-regulation of pathway components. Citation Format: Chi Zhang, Gilberto Schleiniger, Caroline Facey, Lynn Opdenaker, Bruce Boman. AXIN2 promotes WNT-target gene expression via cross-feedback between WNT and retinoic acid signaling pathways based on transcriptionally co-regulated components [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 LB351.
Abstract LB109: An automated approach for real-time monitoring of circulating tumor cells (CTC) tumoroid development
Authors: Hao-Ting Lee, Po-Han Chen, Ting-Ying Chien, Shihpei Wu, Wei-Hsin Dai, Ting-Chun Liu
Journal: Cancer Research (2025)

Abstract Monitoring circulating tumor cells (CTC) tumoroid formation remains a critical challenge in cancer research, with current methods heavily dependent on subjective microscopic assessment. This study presents an automated methodology for quantitative and real-time monitoring of CTC tumoroid development with an advanced image segmentation AI model. Our novel approach enables objective characterization of tumoroid formation by distinguishing target cells from complex culture backgrounds, thereby eliminating personnel bias and reducing reliance on expertise. Leveraging SAM2’s enhanced tracking capabilities and improved zero-shot segmentation accuracy, our system extracts critical parameters including cell count, area, and clustering patterns. The integration of time-series image analysis enables comprehensive monitoring of culture progression and early detection of potential amplification failures. This methodology provides researchers with reliable, standardized metrics for assessing CTC culture and tumoroid-forming status prior to chemical bioactivity testing.The potential implications of this research are significant, as it highlights the ability to reduce patient waiting times by enabling early determination of culture success. This, in turn, minimizes the need for sample recollection and facilitates further application and analysis, such as anti-tumor drug testing. This advancement represents a crucial step toward optimizing personalized cancer treatment strategies. Citation Format: Hao-Ting Lee, Po-Han Chen, Ting-Ying Chien, Shihpei Wu, Wei-Hsin Dai, Ting-Chun Liu. An automated approach for real-time monitoring of circulating tumor cells (CTC) tumoroid development [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 LB109.
Abstract LB364: cIAP2 potentiates CD8+ T cells metabolic fitness and antitumor immunity
Authors: Jiazheng Sun, Qiao Wang, Dejuan Yang, Hongzhong Li
Journal: Cancer Research (2025)

Abstract Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. In this study, we perform integrative transcriptomic and proteomic analyses of emerging immuno-oncology targets across multiple clinical cohorts of melanoma undergoing anti-PD-1 treatment, examining both bulk and single-cell levels. We reveal a surprising role of CD8+ T cell-intrinsic cellular inhibitor of apoptosis 2 (cIAP2) in enhancing antitumor immunity, in contrast to its well-established role as an inhibitor of apoptotic death in tumor cells. The loss of cellular inhibitor of apoptosis protein 2 (cIAP2) expression serves as a marker of CD8+ T cell dysfunction, a critical phenotype associated with immunotherapy resistance.T cells within the solid tumor microenvironment (TME) must catabolize lipids through mitochondrial fatty acid oxidation (FAO) to generate energy during periods of nutrient stress. It is well-established that T cells enriched in FAO are highly effective in cancer control. However, endogenous tumor-infiltrating lymphocytes (TILs) and unmodified cellular therapy products do not effectively sustain bioenergetics within tumors. Here, we reveal that cIAP2 overexpression enhances the antitumor effects of CD8+ T cells by promoting their differentiation into a central memory T cell (TCM) phenotype via activation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, thereby facilitating a shift toward fatty acid metabolism.cIAP2 is a multifunctional protein that acts as an E3 ubiquitin ligase, regulating downstream targets. In this study, we employed deep learning techniques to construct a cIAP2 bait protein. We then performed docking analyses between the bait protein and a pre-established protein database. This process involved a sequential screening approach, starting with Megadock for initial screening, followed by Hdock for refined screening, and concluding with detailed one-on-one analysis using AlphaFold-Multimer. Ultimately, we identified the substrate protein monoacylglycerol lipase (MGLL). Mechanistically, we reveal that cIAP2 overexpression activates the PPAR signaling pathway by promoting the ubiquitin-proteasome degradation of MGLL. Our results indicate a complex role of cIAP2 in the tumor ecosystem, highlighting the cell-type-dependent antagonistic effects of a single target on immunotherapy. Citation Format: Jiazheng Sun, Qiao Wang, Dejuan Yang, Hongzhong Li. cIAP2 potentiates CD8+ T cells metabolic fitness and antitumor immunity [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 LB364.
Abstract LB033: Targeting autophagy in neuroblastoma: Inhibiting VPS34 to enhance anti-GD2 immunotherapy
Authors: Jiawen Zhang, Longgui Chen, Yoshinori Takahashi, Hong-Gang Wang
Journal: Cancer Research (2025)

Abstract Background: Neuroblastoma is the most common childhood extracranial solid tumor, with a 5-year survival rate of approximately 50% in patients diagnosed after 12-15 months of age with high-risk disease. While incorporating anti-GD2 monoclonal antibodies into the treatment of high-risk neuroblastoma has improved patient outcomes, a substantial proportion of patients remain unresponsive or experience disease recurrence. Therefore, there is an urgent need to enhance the efficacy of anti-GD2 immunotherapy by developing new combination regimens. Aims: Given the crucial role of autophagy in promoting tumor cell survival, it emerges as a promising target for cancer treatment. This study aims to investigate the impact of autophagy inhibition via targeting of VPS34, a critical kinase involved in autophagy, on neuroblastoma growth, with a focus on sensitizing tumors to anti-GD2 therapy. Methods: The effects of autophagy inhibition by knocking out essential autophagy genes on tumor growth were assessed in both immunocompromised and immunocompetent mouse models. We evaluated the effects of doxycycline (dox)-inducible VPS34 knockdown and VPS34 inhibitors on neuroblastoma cell survival and spheroid growth in vitro. Additionally, we examined the synergistic anti-neuroblastoma effects of VPS34 inhibition and anti-GD2 monoclonal antibodies using an in vitro NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) assay and a syngeneic mouse model. The impact of the combination therapy on the tumor microenvironment (TME) was evaluated by flow cytometry. Results: Autophagy inhibition significantly suppressed neuroblastoma tumor growth in vivo, with greater effects in immunocompetent mice compared to immunodeficient mice. Targeting VPS34 resulted in enhanced apoptosis of neuroblastoma cells, decreased spheroid growth in vitro, and a notable reduction in tumor growth in vivo. Importantly, VPS34 inhibition markedly augmented the efficacy of anti-GD2 antibody-mediated tumor suppression by promoting NK cell-mediated ADCC in vitro and fostering an antitumor immune response in the TME in vivo. Conclusion: These preclinical findings suggest that targeting VPS34 represents a promising strategy to improve the antitumor efficacy of anti-GD2 immunotherapy for patients with high-risk neuroblastoma. Citation Format: Jiawen Zhang, Longgui Chen, Yoshinori Takahashi, Hong-Gang Wang. Targeting autophagy in neuroblastoma: Inhibiting VPS34 to enhance anti-GD2 immunotherapy [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 LB033.
Abstract LB265: The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity
Authors: Eduard Porta-Pardo, Mustafa Sibai, Sergi Cervilla, Daniela Grases, Manel Esteller
Journal: Cancer Research (2025)

Abstract Tumors are dynamic ecosystems where interactions between cancer cells and the tumor microenvironment (TME) shape malignancy. Using spatial transcriptomics, we analyzed 63 untreated tumors from 10 cancer types to investigate the spatial distribution of 13 cancer hallmarks. Our findings reveal that hallmark activity is spatially organized, with distinct compartmentalization of hallmark phenotypes across neoplastic and TME regions. Hallmarks such as "Resisting Cell Death" and "Enabling Replicative Immortality" were enriched in cancer-dominant areas, while "Inducing Angiogenesis" and "Activating Invasion and Metastasis" were primarily localized to the TME. Genomic analysis showed that subclonal diversity influences hallmark specialization, with genetically distinct clones often occupying specific ecological niches. These insights suggest that hallmark activities are not uniformly distributed but instead reflect the interplay between genetic heterogeneity and tumor spatial organization. We further modeled the spatial interdependence of hallmarks between the neoplastic and TME compartments, demonstrating that hallmark activities are shaped by ecological dynamics across the tumor. For example, hallmarks such as "Sustaining Proliferative Signaling" in the TME interface strongly influenced cancer cell hallmark expression. Application of this framework to 33 bladder cancer patients from the DUTRENEO trial revealed correlations between hallmark spatial patterns and treatment response. Notably, differences in the spatial localization of "Inducing Angiogenesis" and "Resisting Cell Death" were linked to neoadjuvant chemotherapy and immunotherapy sensitivity. These findings underscore the importance of spatial hallmark distribution in determining drug efficacy and suggest that spatial hallmark signatures could serve as predictive biomarkers for personalized cancer therapy. Citation Format: Eduard Porta-Pardo, Mustafa Sibai, Sergi Cervilla, Daniela Grases, Manel Esteller. The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity [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 LB265.
Abstract LB058: Investigating the role of SIM2 and SIRT3 in mitochondrial dynamics and homeostasis in ER+ breast cancer
Authors: Hannah N. Carter, Steven W. Wall, Garhett L. Wyatt, Lilia Sanchez, Weston W. Porter
Journal: Cancer Research (2025)

Abstract Mitochondrial dynamics are essential for cellular energy regulation and homeostasis, processes crucial for normal development and breast cancer progression. Maintaining mitochondrial integrity requires a balance between fusion and fission events, which influence cellular metabolism and oxidative stress responses. Recent studies have identified Singleminded-2s (SIM2s), a tumor suppressor in mammary epithelial cells, as a regulator of mitochondrial morphology and dynamics. Our data suggest that the loss of SIM2s in estrogen receptor-positive (ER+) breast cancer cells leads to altered mitochondrial morphology, with decreased mitochondrial fusion (OPA1) and increased fission (DRP1). Additionally, SIM2 loss correlates with increased acetylation of Superoxide Dismutase 2 (SOD2) at lysine residues 68 and 122, indicating reduced SIRT3 activity. These findings suggest an interaction between SIM2 and SIRT3 in regulating mitochondrial dynamics and homeostasis. Furthermore, pharmacological inhibition of SIRT3 in SIM2-deficient cells induces synthetic lethality, highlighting SIRT3 as a potential therapeutic target for metastatic breast cancer. These results emphasize a potential relationship between SIM2 and SIRT3 and their crucial roles in mitochondrial integrity and homeostasis in ER+ breast cancer. Citation Format: Hannah N. Carter, Steven W. Wall, Garhett L. Wyatt, Lilia Sanchez, Weston W. Porter. Investigating the role of SIM2 and SIRT3 in mitochondrial dynamics and homeostasis in ER+ 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 LB058.
Abstract LB223: Discovery of INV-6452, a CDK2/4 inhibitor for the treatment of HR-positive HER2-negative breast cancer resistant to current CDK4/6 therapy
Authors: Chang Bai, Nansong Xia, Yexing Cao, Shujuan Huang, Danqi Chen, Hongjian Yang, Lishan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun
Journal: Cancer Research (2025)

Abstract CDK4/6 Inhibitors represented by palbociclib, ribociclib, abemaciclib and dalpiciclib, working through their inhibitory activities toward G1/S transition cyclin-dependent protein kinases 4 and 6 coupled with cyclins D1 and D3, have emerged as one of the mainstream therapies for HR positive HER2 negative breast cancer. However, some patients do not respond to CDK4/6 inhibitors well, and more importantly majority of patients eventually develop resistance to CDK4/6 inhibitors. Such resistance is often attributed to alterations in downstream signaling cascade, including activation of CDK2/Cyclin E activities, which can also phosphorylate retinoblastoma protein. Furthermore, cyclin E amplification/overexpression is associated with multipletumor types, with high prevalence in ovarian and endometrial cancers. Toward the goal of addressing these unmet medical needs, we have discovered and profiled INV-6452, a CDK2/4 inhibitor, and INV-2821, a highly selective CDK2 inhibitor. Both compounds showed good selectivity to CDK9, GSK3b, and CDK1. INV-6452 was highly effective in breast cancer cells that developed resistance to palbociclib in cell culture systems, while highly selective CDK4 or CDK2 inhibitors alone had limited effect. INV-6452 showed tumor inhibitory activities in multiple xenograft models including breast cancer and other tumor types. Additionally, INV-6452 had a limited impact on the proliferation and myeloid-specific differentiation of human hematopoietic stem and progenitor cells. The promising profiles of INV-6452 suggest its potential in addressing unmet medical needs, and its clinical development is being planned. Citation Format: Chang Bai, Nansong Xia, Yexing Cao, Shujuan Huang, Danqi Chen, Hongjian Yang, Lishan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun. Discovery of INV-6452, a CDK2/4 inhibitor for the treatment of HR-positive HER2-negative breast cancer resistant to current CDK4/6 therapy [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 LB223.