tbuckley/cabot-search huggingface dataset:
Abstract 5431: The mitochondrial protease, YME1L regulates interferon signaling and is essential for AML growth and differentiation
Authors: Yihe Zhang, Rose Hurren, Yongran Yan, Marcela Gronda, Dakai Ling, Karen Kai-Lin Fang, Andrea Arruda, Mark D. Minden, Aaron D. Schimmer
Journal: Cancer Research (2025)

Yeast Mitochondrial Escape 1-Like 1 (YME1L) is an ATP-dependent metalloprotease located in the inner mitochondrial membrane. Here, we examined the expression and function of this protease in AML. YME1L protein was expressed in 6/7 tested AML cell lines. In 17 of 23 primary AML samples, YME1L protein was &amp;gt; 2-fold higher than normal hematopoietic cells. High YME1L mRNA expression was associated with lower five-year survival rates in AML patients.To assess the dependency of AML cells on this protease, we knocked down YME1L with shRNA in OCI-AML2, NB4, TEX, and THP-1 AML cell lines. YME1L knockdown reduced AML cell proliferation in these tested lines. In addition, the depletion of YME1L reduced the clonogenic growth of leukemia cells, and decreased the engraftment of AML cells into the marrow of immune-deficient NS-GF mice. Thus, YME1L is essential for AML cells and leukemia-initiating cells. To understand the mechanisms of action of this protease and the downstream consequences of its depletion, we measured changes in gene expression after the knockdown of YME1L in OCI-AML2 cells. By RNA sequencing, knockdown of YME1L upregulated genes associated with defense response to viruses, response to type I interferon, and type I interferon signaling pathways, consistent with viral mimicry and induction of interferon (IFN) signaling. Using real-time PCR we confirmed the importance of YME1L in regulating these pathways. Knockdown of YME1L upregulated the expression of beta and gamma IFN, as well as downstream interferon-stimulated genes ISG15, IFI44, and IFIT2. Upregulation of IFN pathways and induction of viral mimicry, can promote the differentiation of AML cells. Therefore, we assessed the differentiation of leukemic cells after the knockdown of YME1L. Knockdown of YME1L induced the differentiation of OCI-AML2 cells as evidenced by upregulation of CD14 protein expression.In summary, YME1L is overexpressed in a subset of AML cells. This protease is essential for AML cells and controls differentiation by regulating IFN and viral mimicry pathways. Citation Format: Yihe Zhang, Rose Hurren, Yongran Yan, Marcela Gronda, Dakai Ling, Karen Kai-Lin Fang, Andrea Arruda, Mark D. Minden, Aaron D. Schimmer. The mitochondrial protease, YME1L regulates interferon signaling and is essential for AML growth and differentiation [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 5431.
Abstract 4308: BRD8 is a therapeutic vulnerability for overcoming resistance to dual ER/HER2 blockade therapy in HR+/HER2+ breast cancer
Authors: Ang Gao, Parth Khatri, Gui Ma, Peng Liu, Mark Burkard, Kari Wisinski, Charles Perou, Huy Dinh, Wei Xu
Journal: Cancer Research (2025)

Abstract Hormone receptor (HR)-positive, HER2-positive breast cancers often develop resistance to endocrine and anti-HER2 therapies due to the heterogeneous expression of estrogen receptor (ER) and HER2 and the crosstalk of these growth-promoting pathways. However, how anti-HER2 agents activate ER and other growth-promoting pathways remains unknown. Single-cell RNA sequencing of BT474 breast cancer cells identified Bromodomain Containing Protein 8 (BRD8), an acetyl-lysine reader protein in the histone acetylase EP400 complex, as a pivotal mediator to activate ER in response to neratinib treatment. BRD8 expression was rapidly induced by various anti-HER2 agents (neratinib, lapatinib, and trastuzumab), and its depletion disrupted the crosstalk between ER and HER2 signaling pathways and rendered HR+/HER2+ cells and PDxOs more sensitive to anti-HER2 agents. BRD8, ER, and ER target genes are co-induced by neratinib in single-nucleus RNA and ATAC sequencing of a patient-derived xenograft (PDX). SnATAC-seq also reveals that the activated genes share open chromatin regions enriched in ER, forkhead box (FOX), and ETS family transcription factors (TF) binding motifs. FOX family TFs are well-known for regulating estrogen signaling, and ETS proteins have been shown to promote tumorigenesis. Since EP400 enhances H2AZ deposition and acetylation on chromatin, we performed H2AZ and H2AZac ChIP-sequencing in the presence or absence of BRD8 and neratinib treatment. We found that, in response to neratinib treatment, BRD8 activates ER, FOX, and ETS target genes through modulating H2AZac deposition and chromatin decompaction. This finding coincides with RNA-sequencing where BRD8 promotes cell growth in an ER-dependent and -independent manner. In line with these findings, patients who responded poorly to the anti-HER2 therapies exhibited higher levels of BRD8 target gene signature as compared to the responders. Furthermore, BRD8 knockout ablates the ER and HER2 signaling crosstalk and re-sensitizes neratinib-resistant HR+/HER2+ cells to neratinib. In summary, this work not only explains why ER signaling is activated upon anti-HER2 therapies but also identifies BRD8 as a druggable vulnerability for treating HR+/HER2+ breast cancer. Citation Format: Ang Gao, Parth Khatri, Gui Ma, Peng Liu, Mark Burkard, Kari Wisinski, Charles Perou, Huy Dinh, Wei Xu. BRD8 is a therapeutic vulnerability for overcoming resistance to dual ER/HER2 blockade therapy in HR+/HER2+ 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 4308.
Abstract 3995: Investigating the role of sphingosine kinase 2 and p53 in bioprinted head and neck cancer 3D models
Authors: Thaís Moré Milan, Luda Lin, Sara Sartini, Alberto Mendoza Valderrey, Alice Soragni, Andréia Machado Leopoldino
Journal: Cancer Research (2025)

Abstract Head and neck squamous cell carcinoma (HNSCC) presents a high incidence of recurrences and metastasis. Alterations in sphingolipids metabolism caused by deregulation of sphingosine kinase 2 (SK2) is related to tumor progression. Additionally, the interaction between SK2 and p53 has been found to promote aggressive behavior in HNSCC (Milan et al, 2024). However, SK2 deregulation in HNSCC and SK2/p53 crosstalk remains to be fully investigated. Our goal is to explore the interaction between sphingosine kinase 2 and p53 in HNSCC cell lines and patient organoids. We leverage 3D HNSCC models generated by bioprinting HNSCC cell lines expressing different p53 and SK2 levels with extracellular matrix components in high throughput-compatible mini-ring format (Phan et al, 2019; Tebon et al, 2023; Al Shihabi et al, 2024). We then investigated metabolic activity, organoids size, and quantified both SK2 and p53 protein levels. Given that p53 misfolding and aggregation has been reported as contributing to tumor progression in several cancers, we have determined its folding status by multiplexed immunofluorescence using conformation-specific antibodies in the presence or absence of SK2 activity and p53 aggregation inhibitors. Combined inhibition of SK2 activity by Opaganib and p53 aggregation by ReACp53 (Soragni et al, 2016) decreased organoid size, ATP levels, and p53 aggregation. Single agent and combinatorial treatment with ReACp53 and Opaganib also resulted in elevated γH2AX levels. Our studies highlight a complex interplay between SK2 and p53 in HNSCC, resulting in more aggressive disease. Combinatorial targeting of these proteins could offer a potential therapeutic strategy for HNSCC. Funding: CAPES, CNPQ and FAPESP Grant n.2023/15046-8 Citation Format: Thaís Moré Milan, Luda Lin, Sara Sartini, Alberto Mendoza Valderrey, Alice Soragni, Andréia Machado Leopoldino. Investigating the role of sphingosine kinase 2 and p53 in bioprinted head and neck cancer 3D models [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 3995.
Abstract 4300: AT1965, a novel mRNA cap 2′O methylation inhibitor, exerts potent antitumor activity and enhances chemotherapy efficacy
Authors: Arshit Narang, Vinay S. Mahajan, Shiladitya Sengupta
Journal: Cancer Research (2025)

Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′-O positions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases. N-7 methylation is essential for RNA translation and stability. Recent studies have highlighted the critical role of 2′O methylation of the cap in enabling the innate immune system to distinguish self-RNA from foreign RNA through pattern recognition receptors, such as RIG-I. Despite advances in understanding RNA modifications, the therapeutic potential of targeting RNA capping enzymes remains unexplored. Here, we report that AT1965, a novel mRNA cap 2′O methylation inhibitor, exhibits potent antitumor effects and significant synergy with cabazitaxel, an FDA-approved anticancer agent. Subcutaneous Lewis Lung Carcinoma (LLC) tumors were established in C57BL/6 mice, divided into three groups: untreated controls, those treated with cabazitaxel alone, and those treated with cabazitaxel in combination with AT1965. The combination therapy resulted in a mean tumor size reduction of 23.6%, while tumors in the other groups increased in size. Mechanistically, AT1965 impairs mRNA stability and translation of key oncogenic transcripts, sensitizing tumors to cytotoxic agents. These findings underscore the potential of RNA capping enzymes as therapeutic targets in cancer. Future studies should explore the application of AT1965 in other tumor models and its potential to synergize with diverse chemotherapeutics. Citation Format: Arshit Narang, Vinay S. Mahajan, Shiladitya Sengupta. AT1965, a novel mRNA cap 2′O methylation inhibitor, exerts potent antitumor activity and enhances chemotherapy efficacy [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 4300.
Abstract 5446: Development of a novel TCR based bispecific platform for cancer therapy
Authors: Danqing Wu, Li Hu, Lini Huang, Beilei Shi, Lijun Wang, Xuan Wu, Shiyong Gong, Chengbin Wu
Journal: Cancer Research (2025)

Abstract TCR-T therapies emerged as a new generation of therapeutics targeting solid tumors with high specificity but are not “off-the-shelf”. TCR based T-cell engagers follow the same concept, however it remains challenging to generate such molecules containing TCRs, which usually requires extensive engineering and optimization to achieve good solubility and functionality. To solve this problem, we developed a “plug-n-play” technology, namely TCR-Fab in tandem (T-FIT) fusion protein, for generating off-the-shelf TCR based therapeutics. The design of T-FIT was optimized by comparing recombinant production yield and purity in various formats with different spacers, binding valencies and TCR-Fab geometries. The selected T-FIT format showed IgG like production properties across different TCRs and Fabs. Based on the T-FIT format and our proprietary CD3 antibody, we generated 3 TCR based T-cell engagers, targeting NY-ESO-1, MAGE-A3 and Survivin respectively, and validated the T-FIT platform in preclinical functional assays. All three T-FIT molecules demonstrated potent redirected T-cell lysis activity against target positive cells in vitro. The MAGE-A3 and Survivin targeting T-FIT molecules also showed complete tumor inhibition in xenografted models. Citation Format: Danqing Wu, Li Hu, Lini Huang, Beilei Shi, Lijun Wang, Xuan Wu, Shiyong Gong, Chengbin Wu. Development of a novel TCR based bispecific platform for cancer therapy [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 5446.
Abstract 5232: Tumor-adipose microenvironment drives progression in advanced oral squamous cell carcinoma
Authors: Gyeongmin Kang, Mi Rim Lee, Sumin Kang, Yu-Sun Lee, Hye Won Shon, Jiyoung Lee, Sung Weon Choi, Sun Il Choi, Yun-Hee Kim
Journal: Cancer Research (2025)

Abstract Advanced oral squamous cell carcinoma (OSCC) is an aggressive cancer with a recurrence rate of 40-60%, and lymph node metastasis (LNM) occurs in 50% of cases, serving as a critical prognostic factor. Recent evidence suggests that fatty acid oxidation (FAO) enhances cancer cell survival, invasiveness, and therapeutic resistance. OSCC's histological proximity to dense adipose tissue provides a unique opportunity for cancer cells to acquire energy from the adipose environment, underscoring the importance of elucidating the tumor-adipose interactions in OSCC progression and metastasis. In this study, we investigated the impact of the tumor-adipose microenvironment on OSCC progression, focusing on interactions between adipocytes and cancer cells. Human adipose-derived stem cells (ADSCs) were differentiated into adipocytes and co-cultured with the OSCC cell line YD10B for three weeks to induce cancer-associated adipocytes (CAAs). Co-cultured adipocytes exhibited fibroblast-like phenotypic changes, reduced expression of adipogenic differentiation markers, and increased free fatty acid release. Inflammatory cytokines (e.g., IL-6) and tumor-promoting proteins (e.g., IGFBP-2) were upregulated. YD10B cells exposed to co-cultured adipocytes showed enhanced proliferation, invasion, and epithelial-mesenchymal transition (EMT) signaling. Adipocytes and cancer cells both showed increased expression of matrix metalloproteinases (MMP-2 and MMP-9), indicating mutual reinforcement of tumor aggressiveness. Collectively, these findings indicate that adipocytes, through their interaction with OSCC cells, undergo changes to acquire a CAA-like phenotype , which support tumor progression by providing fatty acids as an energy source and promoting aggressive phenotypes, including proliferation, invasion, and LNM. Targeting tumor-adipocyte interactions could offer novel therapeutic strategies to mitigate OSCC progression and improve outcomes. Citation Format: Gyeongmin Kang, Mi Rim Lee, Sumin Kang, Yu-Sun Lee, Hye Won Shon, Jiyoung Lee, Sung Weon Choi, Sun Il Choi, Yun-Hee Kim. Tumor-adipose microenvironment drives progression in advanced oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5232.
Abstract 4312: CTR9 controls the mammary luminal lineage and susceptibility to carcinogen/hormone-induced breast tumors
Authors: Gui Ma, Ang Gao, Mingshan Hu, Ngai Ting Chan, Yidan Wang, Wei Xu
Journal: Cancer Research (2025)

CTR9 encodes a key component of the human RNA polymerase II (RNAPII)-associated factor complex (hPAFc). CTR9 loss-of-function variants are predisposed to rare myeloid malignancies and Wilms tumors. Although CTR9 promotes the growth of estrogen receptor (ER)-positive breast cancer cells and controls the expression of 90% of ER-target genes, the roles of CTR9 in mammary gland development and breast cancer etiology in vivo remain unknown. About 0.1 % of breast cancer patients were found to harbor loss of function CTR9 mutations based on TCGA data. Analyzing normal mouse mammary gland scRNA-seq data reveals that CTR9 is highly expressed in luminal cells, which is confirmed by immunofluorescence staining in human breast tumors. To study the effects of the loss-of-function of CTR9 on mammary gland development, we generated a mammary gland-specific CTR9 knockout (KO) mouse using MMTV-Cre and CTR9 loxP system. CTR9 depletion from mammary epithelial cells was validated using qPCR, Western blot, and IHC. Loss of CTR9 in C57B/6 female mice led to increased duct branching and elongation during puberty and increased alveologenesis during pregnancy. This observation coincides with the detection of expanded mammary stem cells by flow cytometry in the 6-week-old mouse mammary glands. When treated with DMBA and progestin (MPA) to induce mammary tumors, both wild-type (WT) and CTR9 null mice began to develop tumors 6 weeks after the last DMBA treatment, but CTR9 null mice exhibited a markedly enhanced susceptibility to carcinogen/hormone-induced mammary tumors as compared with the WT counterparts. To detect changes during the early stage of tumorigenesis, we profiled the stem and luminal progenitor cell populations in the mammary gland 4-week after the last DMBA treatment. Remarkably, CTR9 depletion enhanced the stem cell and luminal progenitor populations while decreasing the mature luminal cells. CTR9 KO mammary gland had elevated Ki67 levels, decreased ER and PR, decreased mature luminal cells, and increased expression of KRT15, a luminal progenitor marker. The CTR9 null mammary gland expressed lower levels of KDM5A and higher levels of H3K4me3 as compared to the wild-type mice. Taken together, our findings establish that CTR9 depletion blocks the terminal differentiation of luminal cell lineage possibly through epigenetic regulation of histone methylation, and renders the mammary glands more susceptible to carcinogen/hormone-induced tumors. Citation Format: Gui Ma, Ang Gao, Mingshan Hu, Ngai Ting Chan, Yidan Wang, Wei Xu. CTR9 controls the mammary luminal lineage and susceptibility to carcinogen/hormone-induced breast tumors [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 4312.
Abstract 5426: Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer
Authors: Mingxin Zuo
Journal: Cancer Research (2025)

Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies including triple-negative breast cancer (TNBC). Here, we aimed to identify the essential metabolic adaptations that support mitochondrial quality control with the goal to uncover actionable metabolic vulnerabilities with therapeutic potential. Using an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, coupled with functional experimental analyses, we define an alternative mechanism to mitophagy enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC that facilitates extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of the cancer cell sphingolipid onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-mediated compensatory mitophagy and subsequent cancer cell death in vitro and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse models of TNBC as well as in human xenograft models. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment. Citation Format: Mingxin Zuo. Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in 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 5426.
Abstract 6438: Decoding the archetypes and ecotypes of triple-negative breast cancer in responses to chemotherapy
Authors: Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Aatish Thennavan, Jianzhuo Li, Tuan Tran, Min Hu, Mitchell Rao, Anna Casasent, Elizabeth Ravenberg, Gaiane Margishvili Rauch, Alyson Clayborn, Debu Tripathy, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin
Journal: Cancer Research (2025)

Abstract Triple-negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer. The pillar of treatment is chemotherapy, but only half of the patients have a complete response and good survival. To resolve inter- and intra-tumoral heterogeneity and determine their clinical associations, we performed single-cell RNA-sequencing and spatial transcriptomics methods including Visium and Xenium on treatment-naïve samples of TNBC patients in the ARTEMIS clinical trial. We find that TNBC was classified into 4 major archetypes at patient level: luminal secretory-associated, basal-associated, immunoreactive, and luminal androgen receptor. At cell level, cancer cells exhibited intratumoral heterogeneity in 13 gene expression metaprograms. The TNBC tumor microenvironment (TME) consisted of 49 distinct immune and stromal cell states, many of which were reprogrammed relative to normal breast tissues from disease-free women. We further identified 8 ecotypes of cancer cells and TME cell states that co-occurred among patients and were associated with specific archetypes and chemotherapy response groups. In contrast to previous work on T-cells, our data showed the importance of macrophage cell states and cancer cell metaprograms for interferon signaling, HLA expression and cell cycle activity that were associated with chemotherapy response. To facilitate a clinical application, we developed a 13-gene-based model to predict response. Collectively, this study provides new insights into the natural biology of untreated TNBC tumors and their association with chemotherapy response. Citation Format: Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Aatish Thennavan, Jianzhuo Li, Tuan Tran, Min Hu, Mitchell Rao, Anna Casasent, Elizabeth Ravenberg, Gaiane Margishvili Rauch, Alyson Clayborn, Debu Tripathy, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin. Decoding the archetypes and ecotypes of triple-negative breast cancer in responses to chemotherapy [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 6438.