tbuckley/cabot-search huggingface dataset:
Abstract 3854: Lymphatic endothelial progenitors promote tumor lymphatic formation through cell-cell fusion
Authors: Shaswati Athaiya, Lisa Volk-Draper, Emma Cox, Natalya Zinkevich, Sophia Ran
Journal: Cancer Research (2025)

Abstract Introduction: Bone marrow (BM) derived myeloid-lymphatic endothelial cell progenitors (M-LECP) promote formation of tumor lymphatics and metastasis to lymph nodes. Regenerative capacity of BM progenitors to many other lineages is mediated through cell-cell fusion, a process that efficiently inserts a pro-mitotic message directly into damaged or division-restricted cells. We aimed to determine whether M-LECP use a similar mechanism to induce division of tumor lymphatic endothelial cells (LEC) which is an essential step towards the formation of new sprouts. Methods: Fusogenic markers were determined in M-LECP differentiated by Th2 and TLR4 ligands as well as in RAW264.7 macrophages by qPCR, flow cytometry, and immunohistochemistry (IHC) applied to mouse and clinical breast cancers. Fusion of myeloid and lymphatic cells stably expressing GFP and mCherry tags, respectively, was quantified using flow cytometry and microscopy by determining the percent of yellow cells resulting from merging of green- and red-colored cell partners. Fusion of lymphatic progenitors in vivo was determined in female chimera mice bearing MDA-MB-231 or EMT6 breast tumors that have been grafted with male BM prior to tumor implantation. Staining for LEC-specific markers in combination with probes for Y-chromosome quantified tumor lymphatic vessels fused with BM progenitors. Results: 10% to 25% of myeloid cells fused with co-cultured LEC quantified by two independent methods. M-LECP and RAW264.7 macrophages expressed a variety of fusogenic markers such as SIRP-a, CD36, DAP12, Stabilin-1, and DC-Stamp. These proteins were also expressed in M-LECP residing in human and mouse breast tumors. In vivo models showed up to 48% of tumor lymphatic vessels containing nuclear Y-chromosome indicating fusion. Supporting the hypothesis, Y-chromosome in LEC nuclei correlated with mitotic markers, nuclei doubling, lymphatic formation, and metastasis to nodes. Both in vitro and in vivo assays showed dependency of fusion on Th2 and TLR4 pathways. Conclusion: We show for the first-time using in vivo and in vitro assays that bone marrow derived myeloid-lymphatic progenitors induced by Th2 or TLR4 ligands are able to fuse with LEC. This event correlated with LEC proliferation and ultimately, metastatic behavior. These findings suggest a fundamentally novel mechanism of generating new lymphatic sprouts triggered by fusion with lymphatic endothelial cell precursors. Citation Format: Shaswati Athaiya, Lisa Volk-Draper, Emma Cox, Natalya Zinkevich, Sophia Ran. Lymphatic endothelial progenitors promote tumor lymphatic formation through cell-cell fusion [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 3854.
Abstract 2549: The aged tumor microenvironment limits T cell control of breast cancer
Authors: Jia Meng, Denise Goh, Kai Soon Ng, Xinru Lim, Jeffrey Lim, Lee Hong Song, Jabed Iqbal, Darren Wan-Teck Lim, Elaine Hsuen Lim, Joe Yeong
Journal: Cancer Research (2025)

Abstract Introduction: Breast cancer is the leading cause of cancer-related death among women worldwide and the most commonly diagnosed invasive cancer. Given that the risk of developing cancer increases dramatically with age and is often paralleled with a progressive decline in immune function, breast cancer presents unique challenges for understanding how aging influences tumor development. Amid a globally aging population, the etiology and effect of age-related immune dysfunction in cancer remains unclear. Methods: To address this, we investigated the major cellular determinants of aging in an orthotopic mouse model using EO771 breast carcinoma cells on young (2-month-old) and old (27-month-old) BALB/c mice separately. 21 days post inoculation, tumors were immuno-profiled with extensive flow cytometry and multiplex immunohistochemistry. Young and aged human breast biopsies were processed to generate tumor-infiltrating lymphocytes, which were subsequently analyzed using single-cell RNA sequencing. Results: We observed that tumor size increased with mice age, while the frequencies infiltrating CD4 and CD8 T cell decreased. Specifically, CD8 T cell exhaustion is significantly induced in aged breast tumors: quantification by flow cytometry and multiplex immunohistochemistry shows a consistent upward trend in CD39+CD8 T, PD-1+CD8 T, and TOX+CD8 T cells in 27-month-old mice. Complemented with a detailed single-cell RNA sequencing analysis of over 5, 000 T cells from young and aged human breast biopsies, we verified the presence of exhausted CD8 T cell subsets in the aged tumor microenvironment, characterized by Pdcd1, Havcr2 and Entpd1 high expression. Conclusions: Our findings demonstrate that limited priming of CD8+T cells in the aged tumor microenvironment within breast cancer, primarily restricts tumor control in aging. Further studies are ongoing to expand the cohort and investigate age-related responses to immunotherapy in immunopathological context with advance single-cell spatial technologies. Citation Format: Jia Meng, Denise Goh, Kai Soon Ng, Xinru Lim, Jeffrey Lim, Lee Hong Song, Jabed Iqbal, Darren Wan-Teck Lim, Elaine Hsuen Lim, Joe Yeong. The aged tumor microenvironment limits T cell control 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 2549.
Abstract 5332: Targeting CDK2 in estrogen receptor-positive/RB-deficient breast cancer
Authors: Chang-Ching A. Lin, Pamela Luna, Khushi Ahuja, Dan Ye, Yisheng V. Fang, Alec Trub, John Bisi, Jay Strum, Patrick Roberts, Jeon Lee, Ariella B. Hanker, Carlos L. Arteaga
Journal: Cancer Research (2025)

Abstract The estrogen receptor-positive (ER+) subtype continues to be the leading cause of breast cancer-related mortality worldwide. Although CDK4/6 inhibitors (CDK4/6i) have extended survival of patients with ER+ breast cancer, resistance to these therapies is inevitable. RB1 loss-of-function alterations are a well-established mechanism of resistance to CDK4/6i, occurring in approximately 10% of ER+ breast cancer patients who progress on CDK4/6i. With the broad use of CDK4/6i as the standard treatment, the population of patients with ER+/RB-deficient breast cancer is expected to rise, highlighting an urgent need for effective targeted therapies and therapeutic strategies for this drug-resistant subtype. Using a genome-wide CRISPR screen in ER+ RB1 knockout (RBKO) T47D breast cancer cells, we identified CDK2 as an essential gene. Additionally, analysis of the DepMap dataset further confirmed CDK2 as a top essential gene in cancer cells with low RB1 mRNA expression, suggesting an RB-independent role for CDK2 and its potential as a therapeutic target in cancers with RB deficiency. Supporting this hypothesis, siRNA-mediated silencing of CDK2 (siCDK2) in MCF7 RBKO cells and in lung (H596 and H1155), prostate (Du-145), and triple-negative breast (MDA-MB-468) cancer cells harboring somatic RB1 mutations or deletions led to the accumulation of cells in the G1 phase and a reduction of cells in the S phase, indicating an overall delay in cell cycle progression. Similarly, treatment of MCF7 RBKO cells with a CDK2-specific small molecule inhibitor, INX-315, also resulted in suppression of G1-to-S cell cycle progression. In line with the cell cycle analysis, gene set enrichment analysis (GSEA) of RNA-seq data revealed a significant downregulation of the E2F Hallmark gene signature (q&amp;lt;0.0001) in MCF7 RBKO cells transfected with siCDK2 vs. control siRNA. Notably, the therapeutic combination of INX-315 and fulvestrant (a selective ERα degrader) synergistically suppressed the growth of MCF7 RBKO xenografts and ER+/RB1-deleted patient-derived xenografts in mice. Treatment with this combination reduced Ki67 levels more potently than each monotherapy or vehicle. These findings collectively identify CDK2 as a promising therapeutic target for ER+/RB-deficient breast cancer and support clinical testing of CDK2- and ERα-tagerted combination therapies in this refractory population. Citation Format: Chang-Ching A. Lin, Pamela Luna, Khushi Ahuja, Dan Ye, Yisheng V. Fang, Alec Trub, John Bisi, Jay Strum, Patrick Roberts, Jeon Lee, Ariella B. Hanker, Carlos L. Arteaga. Targeting CDK2 in estrogen receptor-positive/RB-deficient 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 5332.
Abstract 7481: Genomic aberration-derived signature in lung adenocarcinoma improves patient prognosis and therapy stratification
Authors: Xiang Wang, Zijian Zhang, Jian-Rong Li, Jianjun Zhang, Chao Cheng
Journal: Cancer Research (2025)

Abstract Background: Lung cancer is the leading cause of cancer-related mortality worldwide, with a poor prognosis due to late-stage diagnoses. While advances in targeted therapies and immune checkpoint blockade therapies (ICBT) have improved survival outcomes for subsets of non-small cell lung cancer (NSCLC) patients, the clinical heterogeneity and variable response rates to these therapies remain significant challenges in precision medicine. Identifying robust biomarkers for stratifying patients and tailoring personalized treatments remains a critical unmet need. Methods: We developed the Genomic Aberration-derived Signature for Patient Stratification (GASPS), a novel statistical framework integrating genomic and transcriptomic data. GASPS models the effects of driver genomic aberrations—mutations, amplifications, and deletions—on gene expression to define actionable gene signatures. Using lung adenocarcinoma (LUAD) data from The Cancer Genome Atlas (TCGA), we identified and validated driver gene signatures across independent NSCLC datasets, including TRACERx. The clinical relevance of these signatures was assessed for their ability to predict prognosis and treatment response. Results: GASPS defined 38 driver genomic aberration signatures, which consistently outperformed genomic aberration status in predicting patient outcomes. Hierarchical clustering of signature scores stratified patients into subgroups with distinct survival patterns. Notably, the EGFR-Mut and EGFR-Amp signatures demonstrated contrasting prognostic and predictive associations: EGFR-Mut was linked to favorable prognosis and chemotherapy sensitivity, whereas EGFR-Amp was associated with poor prognosis and increased tumor proliferation. The STK11-Mut signature emerged as a robust biomarker for resistance to ICBT, correlating with reduced immune infiltration and a "cold" tumor microenvironment. Validation across multiple datasets confirmed the generalizability of these findings. Conclusion: The GASPS framework provides a powerful tool for integrating genomic and transcriptomic data to derive clinically actionable gene signatures. These signatures offer superior prognostic and predictive capabilities, enabling better patient stratification and advancing personalized treatment strategies for NSCLC. While demonstrated in LUAD, this framework is adaptable to other cancer types, paving the way for broader applications in precision oncology. Citation Format: Xiang Wang, Zijian Zhang, Jian-Rong Li, Jianjun Zhang, Chao Cheng. Genomic aberration-derived signature in lung adenocarcinoma improves patient prognosis and therapy stratification [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 7481.
Abstract 3979: Genomic determinants of canine tumor-associated macrophage polarization
Authors: Rachel V. Brady, Kristen B. Farrell, Eric P. Palmer, Sunetra Das, Dawn L. Duval, Douglas H. Thamm
Journal: Cancer Research (2025)

Abstract There is poorly understood variability both between and within cancer types in their ability to maintain an immunosuppressive microenvironment and polarize tumor-associated macrophages (TAMs). Identifying genetic biomarkers of cancers that strongly polarize TAMs would enable the discovery of novel therapeutic targets and support the stratification of patients for appropriate immunotherapy. Our aim, therefore, was to correlate gene expression data from cancer cell lines with phenotypic changes in canine macrophages. We harvested standardized tumor-conditioned medium (TCM) from twenty-five canine cancer cell lines with bulk RNA-sequencing data available. Primary monocyte-derived macrophages were obtained from three canine donors and polarized with the twenty-five different TCMs. After a washout period, supernatants were collected, and polarization changes of the macrophages were assessed via secretory products using ELISA and a multiplex cytokine/chemokine assay. For each analyte measured, a modified z-score was used to rank each cell line’s ability to stimulate the secretion of that analyte from macrophages. Multiple regression analysis and pairwise comparison analysis (composed of “strong” and “weak” stimulators) were performed against the full transcriptome. Many significantly differentially expressed genes were identified in the cancer cell lines with the strongest ability to polarize macrophages. For example, cell lines with MVB12A upregulated, a gene involved in selecting cargo for exosomes, had the highest ability to stimulate VEGF production from macrophages. This was subsequently confirmed by depleting the TCM of exosomes which resulted in a significant decrease in VEGF production. Multiple other genes involved in macrophage immunosuppression were upregulated, while those involved in cell adhesion and metastasis prevention were downregulated. In conclusion, canine cancer cell lines have varying abilities to polarize primary macrophages, irrespective of histologic type, as measured by secretory products. The cell lines capable of potent polarization had relevant differentially expressed genes and pathways. These are currently being explored to identify novel biomarkers and therapeutic targets. Citation Format: Rachel V. Brady, Kristen B. Farrell, Eric P. Palmer, Sunetra Das, Dawn L. Duval, Douglas H. Thamm. Genomic determinants of canine tumor-associated macrophage polarization [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 3979.
Abstract 5313: Spatial transcriptomics reveals clone-specific features of primary and metastatic tumors in triple-negative breast cancer
Authors: Yu-Ting Kang, Tzu-Hung Hsiao
Journal: Cancer Research (2025)

Abstract Breast cancer has become the most commonly diagnosed malignancy, with metastasis remaining the leading cause of mortality, particularly in triple-negative breast cancer (TNBC). In this study, we applied spatial transcriptomics with an 8 μm resolution to analyze the primary tumor and lung metastasis, occurring six months post-recurrence, of a TNBC patient, encompassing a total of 1, 033, 074 bins. Through this analysis, six tumor clusters (T0-T5) with distinct gene expression profiles were identified. Among these, T0 and T3 were the predominant clusters observed in the metastatic tumor. T0 was primarily distributed in the tumor core, while T3 localized at the tumor boundary. Both clusters exhibited high expression of VIM, a marker associated with epithelial-mesenchymal transition (EMT). Differentially expressed gene (DEG) analysis revealed that T3 displayed elevated levels of genes associated with extracellular matrix (ECM) remodeling pathways. Trajectory analysis indicated that T3 represented the most advanced differentiation stage as a subclone. Our findings provide insights into the dynamic spatial heterogeneity and metastatic progression of primary and metastatic TNBC tumor subtypes. Citation Format: Yu-Ting Kang, Tzu-Hung Hsiao. Spatial transcriptomics reveals clone-specific features of primary and metastatic tumors 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 5313.
Abstract 3060: The cyclopeptide enniatin a inhibits the chaperone hsp90 and induces mitophagy in breast cancer cells
Authors: Vamsi Krishna Kommalapati, Asif Elahi, Nada M. Eisa, Michael A. Serwetnyk, Abdessamad Debbab, None siva panda, Daniela Marasco, Brain Blagg, Ahmed Chadli
Journal: Cancer Research (2025)

Abstract Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in protecting the proteome. In cancer cells, this Hsp90 function is hijacked to promote cancer cell proliferation. Except for the Pimitespib (TAS-116), approved for clinical use in Japan in 2022, no Hsp90 inhibitors have yet been approved by the FDA. One of the main side effects of the current Hsp90 inhibitors tested in the clinic is their induction of the heat shock response (HSR). Therefore, identifying new inhibitors that destabilize the oncoproteins clients of Hsp90 without inducing HSR is an attractive strategy to harness the clinical potential. We previously reported that the natural product Enniatin A (EnnA) is a novel Hsp90 inhibitor satisfying this criterion. Here, we report that EnnA potently induces mitophagy in breast cancer cells. The cytoplasmic form of Hsp90 has been shown to be more abundant in the mitochondria of tumor cells compared to mitochondria of normal tissues. We show that EnnA can enter multiple compartments of cancer cells, including the mitochondria, and inhibits Hsp90. Furthermore, we show that EnnA induces mitochondrial dynamics impairment as reflected by loss of mitochondrial membrane potential, reduced oxygen consumption rate, and loss of ATP production. We also show that targeting Hsp90 by EnnA reduced the level of cox4, a component of the electron transport chain, leading to parkin-mediated mitophagy. Our data indicate that EnnA represents a member of a new class of Hsp90 inhibitors that impair mitochondrial function in cancer cells and is a promising compound to treat breast cancer. Citation Format: Vamsi Krishna Kommalapati, Asif Elahi, Nada M. Eisa, Michael A. Serwetnyk, Abdessamad Debbab, siva panda, Daniela Marasco, Brain Blagg, Ahmed Chadli. The cyclopeptide enniatin a inhibits the chaperone hsp90 and induces mitophagy in breast cancer cells [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 3060.
Abstract 7487: Genetic and genomic knowledge, attitudes, and beliefs among Hispanic/Latinos with colorectal cancer
Authors: Charite Ricker, Daisy Hernandez, Itzya Ulloa, Elena Taylor, Blanca Ovalle, Bo Yuan, Juan Pablo Lewinger, Rosa Barahona, Caryn Lerman, Julie O. Culver, Mariana Stern, John Carpten, Heinz-Josef Lenz, Lourdes A. Baezconde-Garbanati
Journal: Cancer Research (2025)

Abstract Background: Knowledge, attitudes, and beliefs (KAB) about genetics impacts engagement in genetics and genomics research, but there is a lack of data about these constructs among Hispanic/Latinos (H/L). Methods: Adult H/L patients with colorectal cancer were recruited at a public (Los Angeles General) and a private (USC Norris Cancer Hospital) hospital to complete a cross-sectional survey assessing KAB. Recruitment and survey administration was done in Spanish or English. Results: Preliminary analysis of 56 surveys found that most participants were from the public hospital (93%), born outside the US (84%), Spanish speaking (71%), and male (63%); median age was 55 years and acculturation was low [1.89 (SD 1.25); scale 1-5]. Low to mid-range scores were found for genetic literacy [3.45 (SD 1.49); scale 1-7], genetic knowledge [9.63 (SD 6.03); scale 0-25], cancer knowledge [2.20 (SD 1.24); scale 0-5]; and tumor genomics knowledge [3.62 (SD 0.78); scale 0-6]. Although 51% agreed they would want to be contacted for future research, 33% expressed uncertainty. When asked about genetic research, &amp;gt; 90% agreed it is medical progress. Almost 90% would want to know if their disease was hereditary, &amp;gt;80% would inform relatives about genetic results, and 29% agreed they were concerned about genetic testing impacting their ability to stay in this country. Conclusion: Participants had limited genetic literacy, genetic, cancer and tumor genomics knowledge. Most expressed interest and positive feelings towards genetic testing and genomic research; however, there were uncertainties and concerns to consider in future research to improve H/L engagement in genetics research. Citation Format: Charite Ricker, Daisy Hernandez, Itzya Ulloa, Elena Taylor, Blanca Ovalle, Bo Yuan, Juan Pablo Lewinger, Rosa Barahona, Caryn Lerman, Julie O. Culver, Mariana Stern, John Carpten, Heinz-Josef Lenz, Lourdes A. Baezconde-Garbanati. Genetic and genomic knowledge, attitudes, and beliefs among Hispanic/Latinos with colorectal 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 7487.