tbuckley/cabot-search huggingface dataset:
Abstract LB065: Regulation of age-related lipid metabolism in ovarian cancer
Authors: Jingjia Mo, Bella Mendieta, Alexander J. Adams, Lukas Bleichner, Katherine Wiest, Hannah Lee, Zhiqing Huang
Journal: Cancer Research (2025)

Abstract The mortality rate of ovarian cancer (OC) remains the highest among female gynecological malignancies. Advanced age is the highest risk factor for OC development and progression, yet little is known about the role of the aged tumor microenvironment (TME). We conducted RNA sequencing and lipidomic analysis of young and aged gonadal adipose tissue from rat xenografts before and after OC formation. The rates of tumor formation (p=0.047) and tumor volume (p=0.002) were significantly higher in the aged rats than in their young counterparts. RNA seq data showed significant differences in gene expression profiles between the groups of young and aged rat adipose tissues (p&amp;lt;0.05), including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3. At the time of tumor generation, there were also changes in the lipid components within the gonadal adipose tissues of young and aged rats, with higher levels of free fatty acids (FFA) and triglycerides (TG) in aged rats. Furthermore, the aged TME showed changes in immune cell composition, especially inflammation-related cells including neutrophils, myeloid dendritic cells, CD4+ T cells (non-regulatory), and mast cell activation (p&amp;lt;0.05). The correlation between S100a8, S100a9, neutrophil, and omega-5, FFA 18:3 levels was also determined. Additionally, omega-5, which is downregulated in aged rats, inhibited OC cell proliferation in vitro (p&amp;lt;0.001). Our study suggests that the aged TME promotes OC proliferation resulting from age-related changes in gene/pathway expression, lipid metabolism, and immune cell distribution. Targeting the aging adipose microenvironment, particularly lipid metabolism, is a promising therapeutic strategy for OC and warrants further investigation. Citation Format: Jingjia Mo, Bella Mendieta, Alexander J. Adams, Lukas Bleichner, Katherine Wiest, Hannah Lee, Zhiqing Huang. Regulation of age-related lipid metabolism in ovarian 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 LB065.
Abstract LB060: NMNAT-mediated NAD+ metabolism promotes glioma growth by modulating p53 post-translational modifications and nuclear atypia
Authors: Jiaqi Liu, Xianzun Tao, Yi Zhu, Xiang Gao, Tijana Canic, Kai Ruan, Zoraida Diaz-Perez, Sakir Humayun Gultekin, Priyamvada Rai, Qunfeng Dong, Grace Zhai
Journal: Cancer Research (2025)

Abstract Gliomas are highly malignant brain tumors with poor prognosis and short survival. Nicotinamide adenine dinucleotide (NAD+) plays a critical role in cancer progression, yet anti-cancer therapies targeting NAD+ synthesis have had limited clinical success due to an incomplete understanding of its mechanisms. Here, we demonstrate the essential role of the NAD+ synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) in glioma progression and its novel contribution to nuclear atypia. Analysis of the patient glioma transcriptomics dataset (GAPIA) indicated a strong correlation between high NMNAT transcription levels and poorer disease-free survival in low grade glioma (LGG) and glioblastoma multiforme (GBM). Utilizing quantitative statistical analysis to assess the size and circularity of about 3 million cells in glioma tissue samples from 19 patients, we identified the significant association between NMNAT1 protein level and increased nuclear atypia in different types of gliomas. Mechanistic studies in human glioma cells and a Drosophila glial neoplasia model revealed that NMNAT enhances glioma growth by promoting NAD+-dependent post-translational modifications poly(ADP-ribosyl)ation (PARylation) and deacetylation of p53, thereby attenuating the pro-apoptotic activity of p53. Additionally, NMNAT1 disrupts nuclear lamina integrity by altering lamin A/C distribution, further contributing to nuclear atypia and glioma progression. These findings uncover a novel tumorigenic mechanism involving NMNAT's regulation of nuclear architecture and NAD+-mediated metabolic signaling pathways, highlighting its roles in glioma growth and nuclear atypia. This study underscores NMNAT as a potential therapeutic target in glioma treatment. Citation Format: Jiaqi Liu, Xianzun Tao, Yi Zhu, Xiang Gao, Tijana Canic, Kai Ruan, Zoraida Diaz-Perez, Sakir Humayun Gultekin, Priyamvada Rai, Qunfeng Dong, Grace Zhai. NMNAT-mediated NAD+ metabolism promotes glioma growth by modulating p53 post-translational modifications and nuclear atypia [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 LB060.
Abstract LB454: Targeting the epithelial-stromal cell crosstalk in metastatic pancreatic cancer
Authors: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook
Journal: Cancer Research (2025)

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is a devastating disease with a 5-year survival of 13%. However, if detected at an earlier stage, PDA has a 5-year survival of more than 30%. Accordingly, the dismal prognosis can be ascribed to late diagnosis after the disease has metastasized, most frequently to the liver. However, work to develop treatments have been largely designed for primary PDA cells residing in hypoxic &amp; nutrient deficient tumor microenvironment (TME) of the pancreas. It is likely that these treatments will not be equally effective against metastasized PDA cells in a vascularized and nutrient rich organ such as the liver. This calls for treatments specific to the metastatic niche. The primary PDA TME has been extensively studied. We and others have shown that immune and stromal populations engage in extensive crosstalk promoting proliferation of cancer cells and resistance to treatments such as immunotherapy and chemotherapy. However, how these crosstalk mechanisms promote the establishment and growth in the PDA metastatic niche remain less understood. Here, we show a unique crosstalk between fibroblasts and cancer cells, specifically in the metastatic niche, that can be targeted for therapeutic benefit. In this study, we compare the TME of primary PDA with the liver metastatic niche. Syngeneic KPC (Kras+/LSL-G12D;Trp53+/LSL-R172H; Pdx1-Cre) cells were injected orthotopically in the pancreas to establish primary tumors or in the liver through hemi spleen surgeries. Single cell RNA sequencing revealed unique population of fibroblasts in the liver metastatic niche. Using CellChat, we identified upregulation of the HGF-MET signaling axis specifically in the liver. We also verified our murine data in human CAFs grown out from patient tissues. We next knocked out Met via CRISPR and our data show significant increase in survival in mice. Next, we used the MET inhibitor- XL-184 (Cabozantinib) as a treatment option and our data show significant reduction in metastatic tumors and increased survival in vivo. Overall, we have found a unique epithelial and stromal crosstalk in the liver that can be targeted to treat metastatic PDA. Citation Format: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook. Targeting the epithelial-stromal cell crosstalk in metastatic pancreatic 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 LB454.
Abstract LB077: Identifying therapeutic vulnerabilities in lobular breast cancer
Authors: Darcie D. Seachrist, Salendra Singh, Saul Castillo, Najla Fakhruddin, Ruth A. Keri
Journal: Cancer Research (2025)

Abstract Invasive lobular breast cancer (ILC) is less responsive to chemotherapy and tamoxifen than other breast cancers, leading to a higher risk of recurrence and poor survival for patients with this disease. Loss of CDH1, a key component of adherens junctions, is a defining feature of ILC that manifests as single-file discohesive tumor cells in the stroma and suggests a unique microenvironment signaling network impacts disease course. We hypothesize that identifying key features of the tumor-stroma interface that are prognostic of ILC patient outcomes will provide new targets for suppressing and preventing the progression of this disease. To accomplish this, we have initiated spatial transcriptomic studies to identify the ILC tumor and adjacent stromal transcriptomes by using an in-house generated tissue microarray (TMA) coupled with outcomes data. This robust TMA comprises &amp;gt;100 ILC tumors, adjacent normal stroma, 46 paired metastatic lymph nodes, and at least 8 years of patient outcomes data. To determine if long-archived tissue can provide quality data, we performed a pilot analysis of 2 short-archived and 6 long-archived ILC tumors ranging from 3-28 years. We observed no differences in the normalized expression values between short and long-archived tissues, and principal component analysis of normalized unfiltered gene expression revealed no clear separation of samples based on archival age. We also confirmed decreased CDH1 expression in ILC compared to normal epithelium and increased LOXL1 expression in ILC stroma compared to normal-adjacent stroma, suggesting that prognostic gene expression analyses will not be significantly skewed by variable RNA integrity. We also uncovered enrichment of the Hedgehog signaling (Hh) pathway and the ligand-receptor pair, IHH-BOC, in ILC-adjacent stroma. The Hh pathway is a known poor prognostic indicator in many solid cancers and an emerging therapeutic target in breast cancer. Moreover, IHH is associated with worse outcomes in ILC. Together, these early studies validate the use of long-archived tissue in spatial transcriptomic studies and suggest that Hh inhibition may be a viable strategy for treating ILC. We are currently expanding these studies to include the whole cohort of ILC tumors and paired metastatic lymph nodes to identify essential genes or pathways that are associated with ILC patient survival and can serve as future candidates for therapeutic targeting in this disease. Citation Format: Darcie D. Seachrist, Salendra Singh, Saul Castillo, Najla Fakhruddin, Ruth A. Keri. Identifying therapeutic vulnerabilities in lobular 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 LB077.
Abstract LB389: R-loop formation triggers STING-mediated anti-tumor immunity following inactivation of a cyclin-dependent kinase
Authors: Yi Bao, Yu Chang, Ke Ding, Arul M. Chinnaiyan
Journal: Cancer Research (2025)

Abstract We previously identified that the inactivation of a cyclin-dependent kinase defines an immunogenic molecular subtype of prostate cancer, characterized by genomic instability and enhanced intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that inactivation of this cyclin-dependent kinase or suppression of its paralog activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced expression of kinase correlates with improved survival and treatment response. Mechanistically, depletion or targeted degradation of the kinase induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, degradation of the kinase significantly delays tumor growth and exhibits synergistic effects with anti-PD1 therapy in various syngeneic tumor models. This combination enhances STING activity and promotes the infiltration and activation of CD8+ T cells within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings identify a cyclin-dependent kinase as promising therapeutic targets for enhancing ICB efficacy, highlighting their potential to amplify STING-mediated anti-tumor immunity. This work provides a mechanistic framework for leveraging antagonists of the kinase in combination with ICB to improve clinical outcomes in cancer therapy. Citation Format: Yi Bao, Yu Chang, Ke Ding, Arul M. Chinnaiyan. R-loop formation triggers STING-mediated anti-tumor immunity following inactivation of a cyclin-dependent kinase [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 LB389.
Abstract LB194: Revolutionizing cancer treatment with the first SHP2 PROTAC
Authors: Junrong Liu, Liying Zhou, Xiaobo Li, Wenming Li
Journal: Cancer Research (2025)

Abstract SHP2 is a mediator in tumor-related signaling pathway, a suppressor of PD-1, associated with solid tumors and leukemias. SHP2 is recognized as a driver in myeloid leukemia. Inhibition of SHP2 has potential to reverse progression of myeloid leukemia, rather than eradicating differentiated leukemic cells. However, SHP2's bifunctional roles-encompassing both phosphatase-dependent and -independent activities-pose challenges for therapeutic targeting. SHP2 inhibitors, like JAB3312, is limited to inhibiting phosphatase activity and evaluated in combination regimens rather than as standalone therapies. To address limitations, we developed a PROTACs with a novel, high-affinity as warhead. This strategy enables complete degradation of SHP2, we developed a novel SHP2 degrader TDS0593, exhibited superior preclinical performance. In vitro, TDS0593 achieved dose-dependent SHP2 degradation, with a Dmax of 91.7% and a DC50 of 1.145 nM in MV411 leukemia cells. Mechanistic studies confirmed TRD209 acts via ubiquitin-proteasome pathway, as validated by TAK-243 and MG132 blockade assays. In vivo, TDS0593 demonstrated potent antitumor efficacy. In MV411 xenograft models, at 2.5 mg/kg (QD) achieved &amp;gt;90% TGI, a 5 mg/kg (QD) dose resulted in complete TGI. In order to established mouse model, leukemia HSC from donor mice with CD45.2 cells has been transplanted into CD45.1 mice. In murine models, administration of TDS0593 resulted in a significant reduction in proportion of myeloid cells both in PB and BM. The number of myeloid stem and progenitor cells in the BM approached normal levels. TDS0593 corrects the aberrant differentiation pathway of hematopoietic stem cells to a certain extent, highlighting its potential as an etiological treatment for myeloid leukemia. Notably, TRD209 showed greater potency in solid tumor PDX, with a 0.5 mg/kg (QD) dose achieving &amp;gt;99% TGI. Immunohistochemical analysis confirmed suppression of p-ERK1/2 expression in tumors either. TDS0593 represents a first-in-class SHP2 degrader with potential to overcome the limitations of current inhibitors by targeting both phosphatase-dependent and -independent activities. TDS0593 offer a novel strategy for the treatment of myeloid leukemia by correcting aberrant myeloid-biased differentiation of HSC/HSPC. This innovative approach aims to rectify the underlying dysregulation in hematopoietic differentiation processes, achieving efficacy in myeloid leukemia. Citation Format: Junrong Liu, Liying Zhou, Xiaobo Li, Wenming Li. Revolutionizing cancer treatment with the first SHP2 PROTAC [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 LB194.
Abstract LB093: Circadian misalignment between cancer cells and immune cells drives immune escape
Authors: Chuqian Liang, Zunpeng Liu, Qi Zhang, Tao Zhang, Bingqiu Xiu, Gongwei Wu, Stuart Benjamin Fass, Li-Lun Ho, Manolis Kellis, Myles Brown
Journal: Cancer Research (2025)

Abstract The circadian clock profoundly influences cancer biology, including tumor progression, immune dynamics, and therapeutic efficacy. However, a comprehensive understanding of circadian regulation within the tumor microenvironment (TME) remains elusive. To address this gap and elucidate the diurnal cancer cell-immune interaction landscape of the TME, we generated a temporal single-cell epigenomic and transcriptomic atlas from mouse breast tumors sampled at four time points across a 24-hour cycle with a total of more than 100,000 cells with both modalities. We identified 6 main cell types including epithelial, mesenchymal, plasmablasts, T/NK cells, B cells and myeloid cells, and further classified into 14 cell subclasses and 36 cell subtypes. Significant time-of-day-dependent fluctuations in immune cell infiltration were observed, with T cells predominating in the TME during nighttime, accompanied by a decrease in macrophage populations. We characterized the rhythmic genes across cell subclasses including Cancer epithelial cells, Cancer-associated fibroblasts, CD4+/CD8+T cells, B cells, Macrophages/Monocytes, Neutrophils, and Natural killer T cells. Integrated analysis of circadian gene modules revealed cell subclass-specific regulatory patterns characterized by variations in amplitude and acrophase. Mechanistic analysis further highlighted a circadian misalignment between Cancer epithelial cells and immune cells, wherein the peak phases of cell cycle and antigen-processing activities in cancer epithelial cells were desynchronized with the activation, antigen recognition, and anti-tumor cytotoxicity peak phases of immune cells. These misalignments indicate a potential mechanism by which Cancer epithelial cells evade immune surveillance. Our findings provide a single-cell multiomic atlas of circadian regulation in breast cancer TME, uncovering rhythmic tumor-immune interactions and providing translational perspective on combining chronotherapy with immunotherapy. Citation Format: Chuqian Liang, Zunpeng Liu, Qi Zhang, Tao Zhang, Bingqiu Xiu, Gongwei Wu, Stuart Benjamin Fass, Li-Lun Ho, Manolis Kellis, Myles Brown. Circadian misalignment between cancer cells and immune cells drives immune escape [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 LB093.
Abstract LB084: Fzd7 promotes melanoma growth via fostering an immunosuppressive tumor microenvironment
Authors: Minakshi Nihal, Sheikh A. Umar, Nihal Ahmad, Hao Chang
Journal: Cancer Research (2025)

Abstract Melanoma is one of the deadliest skin neoplasms and its incidence has been increasing at a continuous pace. Standard monotherapies, FDA-approved targeted, combination, and immunological therapies have shown limited efficacy against melanomas. Frizzled 7 (Fzd7), a member of typical G protein coupled receptor (GPCR), plays an important role in stem cell biology, cancer development and progression. The mammalian frizzled gene family mediates canonical and non-canonical Wnt signaling pathways, which are highly activated in melanoma. We found that Fzd7 is highly expressed in multiple melanoma cell lines. To determine the role of Fzd7 in melanoma, we used siRNA to knockdown (KD) Fzd7 in YUMM1.7 cells and found Fzd7 promotes melanoma invasion. We observed similar phenotype in Yumm1.7 Fzd7 knockout (KO) cells generated by CRISPR/Cas9. Interestingly, Fzd7 KO cells showed significant reduction in primary tumor growth when grafted in C57BL/6 mice. To understand the mechanism of Fzd7 in melanoma, bulk RNA-Seq was performed. The top 6 differentially downregulated genes were Ace, Cacng7, Gas6, Htatip2, Pcdhb15, and Pcdhb20. We validated the changes by RT-qPCR in all three clones. KD of all these genes reduced invasion in Yumm1.7 cells. Gas6 activates melanoma drivers MAPK, PI3K and JAK/STAT via immune evasion. We found that Fzd7 KO tumors showed reduced Gas6 expression, and more TIL (CD4+, CD8+ cells) compared to WT YUMM1.7 cells, suggesting an immunosuppressive role of Fzd7 in melanoma. Overall, our results demonstrate that Fzd7 is involved in multiple aspects of melanomagenesis such as angiogenesis, cell adhesion, ion channeling and KO of Fzd7 fosters a robust antitumor response to inhibit melanoma growth. Citation Format: Minakshi Nihal, Sheikh A. Umar, Nihal Ahmad, Hao Chang. Fzd7 promotes melanoma growth via fostering an immunosuppressive tumor microenvironment [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 LB084.
Abstract LB341: A meta-analysis of cancer neoantigens curated from the literature
Authors: Zeynep Kosaloglu-Yalcin, Nina Blazeska, Hannah Carter, Morten Nielsen, Stephen Schoenberger, Alessandro Sette, Bjoern Peters
Journal: Cancer Research (2025)

Abstract The Cancer Epitope Database and Analysis Resource (CEDAR) aggregates cancer epitope data from peer-reviewed studies, providing a structured repository of epitope-specific T cell, antibody, and MHC ligand assays. Neoantigens, arising from somatic mutations in cancer cells, represent a class of tumor-specific epitopes with potential for precision immunotherapy and as biomarkers for patient prognosis and therapeutic response. The curated neoantigen dataset in CEDAR includes data on over 23,000 neopeptides that were experimentally tested for T cell recognition. Around 4,000 neoepitopes had at least one reported positive T cell assay outcome. Our study harnesses CEDAR’s curated dataset to conduct a meta-analysis on neoantigens across various cancers, identifying factors contributing to neoantigen immunogenicity and their prevalence among patient populations. Citation Format: Zeynep Kosaloglu-Yalcin, Nina Blazeska, Hannah Carter, Morten Nielsen, Stephen Schoenberger, Alessandro Sette, Bjoern Peters. A meta-analysis of cancer neoantigens curated from the literature [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 LB341.