tbuckley/cabot-search huggingface dataset:
Abstract 899: Development of a deep learning model for cell type mapping in colorectal cancer using H&amp;E images leveraging image-based spatial transcriptomics data
Authors: Seungho Cook, Dongjoo Lee, Myunghyun Lim, Jae Eun Lee, Daeseung Lee, Hyung-Jun Im, Jung-Soo Pyo, Kwon Joong Na, Hongyoon Choi
Journal: Cancer Research (2024)

Abstract Purpose The tumor microenvironment (TME) is crucial in colorectal cancer as it influences disease progression, treatment response, and patient outcomes, providing valuable insights for personalized therapies and prognostic assessments. Here, we have developed a deep learning model by integrating hematoxylin and eosin (H&amp;E) stained images of colorectal cancer and image-based spatial transcriptomics (Xenium) to infer spatial mapping of cell types in TME only using H&amp;E images. Methods A total of 30 H&amp;E images of colorectal cancer obtained by tissue microarray were registered with image-based spatial transcriptomics data (Xenium). Utilizing a Variational Autoencoder (VAE) based model and leveraging reference single-cell data enables the acquisition of cell types for individual cells in image-based spatial transcriptomics. A convolutional neural network (CNN) model was developed using H&amp;E image as inputs to predict cell types in H&amp;E-stained tissue image patches of colorectal cancer collected from various patients. The model also estimated the cell types from H&amp;E-stained whole slide tissue image of colorectal cancer of The Cancer Genome Atlas (TCGA-COAD). Results The accuracy of the model's predictions for cell types using H&amp;E image patches was notably high and exhibited a significant concordance with the results obtained through the validation. The Intersection over Union (IoU) metric for image segmentation indicated a value of 0.66 for epithelial cells and 0.44 for TNK cells. The output of deep learning model for epithelial cells and T/NK cells from TCGA-COAD tissue images showed a correlation with human-labeled regions of cancer epithelium and immune cells. Conclusions Leveraging image-based spatial transcriptomics, we developed a deep learning model capable of discerning various cell types within the tumor microenvironment solely from H&amp;E images. This clinically translatable approach is valuable for investigating tumor microenvironment to develop biomarkers associated with various cancer therapeutics particularly immuno-oncology drugs. This approach can yield objective deep learning-based models without human labels for characterizing the tumor microenvironment in single-cell resolution, particularly regarding spatial immune distribution. Citation Format: Seungho Cook, Dongjoo Lee, Myunghyun Lim, Jae Eun Lee, Daeseung Lee, Hyung-Jun Im, Jung-Soo Pyo, Kwon Joong Na, Hongyoon Choi. Development of a deep learning model for cell type mapping in colorectal cancer using H&amp;E images leveraging image-based spatial transcriptomics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 899.
Abstract 85: Immunomics of immune-deficient mouse models before and after CD34 humanization
Authors: Hervé Luche, Lilia Hadjem, Marielle Mello, Priscilla Canavese, Fabien Angelis, Anais Joachim, Sylvie Bouilly, Frédéric Guinut, Frederic Fiore, Bernard Malissen, Ana Zarubica, Erwan Corcuff
Journal: Cancer Research (2024)

Abstract Preclinical tumor oncology research relies historically on the analysis of mouse or human tumor cell lines implanted onto severely immune-deficient mouse models carrying nude, SCID or Rag mutations on different genetical background (C57Bl/6N, BalbC, NMRI, CB17 or NOD). These lines harbor defects in several leukocyte lineages among which Tc, Bc and NKc might be affected. Humanized mice are emerging models that have been transplanted with human cells or tissues (and/or equipped with human transgenes). Currently, the most advanced strains are the nonobese diabetic, severe combined immunodeficiency (NOD-SCID) mouse with complete disruptions in the interleukin-2 (IL-2) common γ-chain (IL2R γ null) receptor (NSG) and BALB/c Rag2−/− IL2R γ null SirpaNOD mice (BRGS).1 Neonate or juvenile chimera are reconstituted in NSG, BRGS or B6 RGS with CD34+ hematopoietic progenitor cell (HPCs) from human cord blood yielding robust engraftment of a human immune system (HIS).. We genetically modified the mouse genome introducing mutations involved in Tc, Bc and NKc development. We then immuno-phenotyped over 23 lines of mouse mutants produced from the same animal house to minimize the impact of microbiota on innate immune cell populations. High content cytometry analysis of several organs was performed in a standardized manner before and after humanization. The resource obtained of these immunotypes was used to highlight similarities and differences among these lines across several genetical background and will help in selecting the most appropriate model to use for tumor implantation and CD34 or PBMC humanization. Citation Format: Hervé Luche, Lilia Hadjem, Marielle Mello, Priscilla Canavese, Fabien Angelis, Anais Joachim, Sylvie Bouilly, Frédéric Guinut, Frederic Fiore, Bernard Malissen, Ana Zarubica, Erwan Corcuff. Immunomics of immune-deficient mouse models before and after CD34 humanization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 85.
Abstract 338: Unraveling layers of proteogenomic complexity in cancer through multiomic exploration of archived FFPE tissue
Authors: Andrea J. O'Hara, Yang Han, Ilaria DeVito, Laure Turner, Haythem Latif
Journal: Cancer Research (2024)

Abstract Formalin Fixed Paraffin Embedded (FFPE) tissues are a staple in clinical diagnostics associated with solid tumor. The preserved tumor tissue can be interrogated using classical histopathology and complemented with molecular approaches to elucidate cancerous SNPs, indels, structural variants, repeat expansion, copy number expansions, and mutational burden. Increasingly, approaches are being deployed to interrogate tissue not only through individual datasets but through integrated approaches that provide spatial information that defines the tumor microenvironment. Here, we illustrate using FFPE blocks from various tissues a multiomic workflow that allows for deep exploration of the molecular underpinnings of cancerous tissue. FFPE blocks were serially sliced into various FFPE slides with a single slide H&amp;E stained. Individual slides were then utilized to explore the genome, epigenome, single cell RNA-seq, and digital spatial profiling. Genome information was captured using hybrid capture based approaches (whole exome sequencing and targeted cancer panel) followed by deep NGS on an Illumina platform and analyzed for a variety of variants and tumor mutational burden. DNA methylation was detailed using target capture probes targeting DNA methylation sites. Single cell approaches were applied to explore the transcriptome using 10X Genomics scRNAseq Flex kit. Digital spatial profiling was done using the NanoString for both transcriptomics and proteomics, with the GeoMx Whole Transcriptome Atlas and Human Core and Pan-Tumor protein panels. Aggregating these data illustrates the expanding landscape of information that can be extracted from FFPE derived tissue and the potential for novel discovery and diagnostic power integrating these complex data types holds. Citation Format: Andrea J. O'Hara, Yang Han, Ilaria DeVito, Laure Turner, Haythem Latif. Unraveling layers of proteogenomic complexity in cancer through multiomic exploration of archived FFPE tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 338.
Abstract 3486: Triple hormone receptor signatures as novel prognostic markers in breast cancer
Authors: Mohamed Omar, J. Chuck Harrell, Rulla M. Tamimi, Luigi Marchionni, Tan Ince
Journal: Cancer Research (2024)

Abstract Background: Tumor phenotype across various cancers, including breast cancer, is predominantly shaped by a synergy between genomic alterations and the cell-of-origin from which the tumor originates. These elements collectively influence crucial aspects like tumor aggressiveness, treatment response, and patient prognosis. While existing research highlights that the role of cell-of-origin in shaping the molecular architecture of breast cancer, leveraging this information for actionable clinical insights has proven challenging. Here, we introduce two robust models leveraging cellular ancestry signatures of breast luminal cells to improve patient stratification and outcome prediction. Methods: In this study, we developed a unique gene signature anchored in the expression levels of triple hormone receptors (THR)—namely androgen (AR), estrogen (ER), and vitamin D (VDR)—in breast cancer cells. Building on this, we formulated two distinct mRNA markers, THR-50 and THR-70, aimed at categorizing breast tumors based on their THR expression profiles. These markers were rigorously validated across 65 independent breast cancer studies, involving a total of 6,679 patients, utilizing Kaplan-Meier survival curves, Cox proportional hazards models, and unsupervised clustering analyses. Results: Our findings indicate that both THR-50 and THR-70 are robustly associated with overall survival and recurrence-free survival in breast cancer patients across all datasets evaluated. Importantly, these THR signatures demonstrate broad applicability across various breast cancer subtypes, grades, and treatment phases—unlike existing prognostic markers that tend to be subtype-specific. Additionally, the THR signatures have revealed four unique patient clusters with divergent survival outcomes, three of which are ER-positive and one is ER-negative. Additionally, we developed an immune-based signature (i20) which can further categorize patients within the ER-negative cluster into two subgroups: one with a highly favorable prognosis, comparable to the ER-positive subtypes, and another that is characterized by exceedingly poor survival outcomes. Conclusion: The THR-based cellular ancestry signatures open a new avenue in understanding the intricacies of breast cancer biology. These signatures offer a robust and stable framework for developing other prognostic markers, thus providing an enhanced stratification of existing breast cancer categories as well as creating new classifications with more distinct survival estimates. Citation Format: Mohamed Omar, J. Chuck Harrell, Rulla M. Tamimi, Luigi Marchionni, Tan Ince. Triple hormone receptor signatures as novel prognostic markers in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3486.
Abstract 5695: miR-5787 suppresses cancer cell growth as a Fe3O4-nanoparticles induced pivotal miRNA
Authors: Masatoshi Watanabe, Hitoshi Nakano, Chise Matsuda, Eri Usugi, Hiroshi Imai, Yoshifumi Hirokawa, Kazutoshi Iijima
Journal: Cancer Research (2024)

Abstract Nanotechnology offers great potential for cancer diagnosis and treatments. Especially, nanoparticles (NPs) have been examined and utilized as drug delivery systems, hyperthermia and combination therapy. We have examined and reported the combined effects of Fe3O4-nanoparticles (Fe3O4-NPs) with chemotherapeutic agents on prostate cancer cell in vitro. miRNAs are an important factor in cancer progression, and elucidating the miRNA-mediated intracellular network of cancer cells could suggest new cancer treatment strategies. In this study, to identify microRNAs (miRNAs) associated with anticancer effects of Fe3O4-NPs, the comprehensive expression of miRNAs by Microarray (Agilent G4780A SuperPrint G3 Human v16 miRNA 8x60K Microarray kit) in A549 (lung cancer cell line), LNCaP (androgen-dependent prostate cancer cell line) and DU145 (androgen-independent prostate cancer cell line) under Fe3O4-NPs exposure was performed. miR-5787 was one of the increased miRNAs in three cancer cell lines under Fe3O4-NPs, and its increase in miR-5787 was due to the reactive oxygen species (ROS) production by Fe3O4-NPs. The additional analysis suggested that miR-5787 might suppressed the cancer cell growth by targeting the eIF5. In this study, we identified miR5787 as a Fe3O4-NPs induced pivotal miRNA in cancer cells, and can be used as a therapeutic target. Citation Format: Masatoshi Watanabe, Hitoshi Nakano, Chise Matsuda, Eri Usugi, Hiroshi Imai, Yoshifumi Hirokawa, Kazutoshi Iijima. miR-5787 suppresses cancer cell growth as a Fe3O4-nanoparticles induced pivotal miRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5695.
Abstract 4379: RING1, a novel E3 ubiquitin ligase for CIP2A, negatively regulates smoking-induced lung tumorigenesis
Authors: In-ho Jeong, Chang-Whan Peter Lee, Hwan Jung Lim, Seong Jun Park, Ji Young Hyun
Journal: Cancer Research (2024)

Abstract Lung cancer is the second incidence rate of all new cancer diagnoses and the leading cause of cancer-related deaths globally. To develop novel diagnostic and therapeutic targets for lung cancer, there are emerging needs for molecular biological research on the occurrence and progression. Among the targets, CIP2A has been studied for promoting various cancer types, but detailed underlying mechanisms are needed to be further investigated. In this study, it was verified that CIP2A is overexpressed in lung cancer tissues, particularly amongst those with a smoking history, compared to adjacent normal tissues. CIP2A knockdown in lung cancer cells efficiently reduced cell proliferation and migration capacity. Through the mass spectrometry analysis on A549 cells overexpressing CIP2A, RING1 was identified as a candidate for E3 ligase of CIP2A. The interaction of the two proteins and ubiquitin chain regulation by RING1 was verified by immunoprecipitation. RING1 knockdown enhanced proliferation and migration of lung cancer cells, and these effects result from the upregulation of CIP2A and its downstream molecules, c-Myc and cyclin B1. To further study a trigger for RING1 expression changes in lung tumorigenesis, cigarette smoke extract (CSE) was applied for the following experiments. CSE treatment depleted RING1 mRNA, including protein expression. Decreased RING1 level led to upregulation of CIP2A and c-MYC. Collectively, these results reveal novel roles of the RING1 and CIP2A in lung cancer progression caused by smoking and propose a potential biomarker candidate for the therapeutic and diagnostic targets. Citation Format: In-ho Jeong, Chang-Whan Peter Lee, Hwan Jung Lim, Seong Jun Park, Ji Young Hyun. RING1, a novel E3 ubiquitin ligase for CIP2A, negatively regulates smoking-induced lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4379.
Abstract 7534: Tobemstomig, a novel bispecific checkpoint inhibitory antibody to preferentially block PD-1 and LAG-3 on CD8 TILs over Tregs
Authors: Laura Codarri-Deak, Patrick Aaron Weber, Valeria Nicolini, Christian Klein, Pablo Umana, Stefan Seeber, Mario Perro, Stephane Leclair
Journal: Cancer Research (2024)

Abstract Checkpoint inhibitors targeting PD-1 have shown unprecedented clinical efficacy in several cancer indications and therefore have, revolutionized the standard of care. However, despite this advancement, only ~20-30% of the patients derive durable benefit from such a treatment. One of the suggested reasons for this limited success is the expression/activation of compensatory inhibitory pathways such as LAG-3 on tumor-reactive T cells. Therefore, it is envisioned that simultaneous antagonism of PD-1 and LAG-3 receptors would overcome this adaptive resistance mechanism and allow a more profound reinvigoration of tumor-reactive T cells. LAG-3 is constitutively expressed by regulatory T cells (on Tregs) and it has been reported that its blockade increases Treg suppressive function which could potentially off-sets the benefit of blocking LAG-3 on tumor-reactive CD8 T cells.We therefore developed a 1+1 PD1-LAG3 bispecific antibody, Tobemstomig, with a unique PD-1 binder recognizing a glycoepitope and more than 20 fold higher affinity than the LAG-3 binder which recognizes a novel and differentiated binding epitope (E3). This difference in affinities allows for an avidity driven selectivity gain to PD-1 and LAG-3 double positive T cells over and the following advantages over monospecific and other bispecific aPD-1/-L1 and aLAG-3 antibodies:1.improved targeting to tumor-reactive T cells rather than Tregs due to the selectivity gain and different expression patterns of PD-1 and LAG-3 on these two T cell types, 2.reduced internalization, 3.resistance to drug-shaving by macrophages due to Fc -silencing via P329G LALA,4.increased in vitro T cell effector functions even in the presence of Tregs, 5.in-vivo targeting and expansion of CD8 TILs, including stem-like T cells, and increase in T cell effector functions and6.superior in vivo tumor control/eradication compared to combination of monospecific anti-PD1 and anti-LAG3 antibodies,in several mouse models including Panc02 in syngeneic huPD-1xhuLAG3 dtg mice and BXPC3, WSU, OCI-Ly18 and BC004 in humanized mice Tobemstomig has completed dose escalation and is currently tested in a composite proof of concept Ph2 trial in several solid tumor indications. Citation Format: Laura Codarri-Deak, Patrick Aaron Weber, Valeria Nicolini, Christian Klein, Pablo Umana, Stefan Seeber, Mario Perro, Stephane Leclair. Tobemstomig, a novel bispecific checkpoint inhibitory antibody to preferentially block PD-1 and LAG-3 on CD8 TILs over Tregs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7534.
Abstract 5356: Wild type Kirsten rat sarcoma (Kras) activation drives evasion of interferon-mediated immunity in hepatocellular carcinoma
Authors: Mang Leng Lei, Terence Kin Wah Lee
Journal: Cancer Research (2024)

Abstract Background: Immune checkpoint inhibitors (ICIs) exhibit heterogeneous efficacy in patients with advanced hepatocellular carcinoma (HCC). Currently, there are no effective biomarkers to select patients who could benefit the most from ICIs or to predict response outcomes. Increasing evidence indicates that oncogenic pathway activation is associated with the generation of an unfavorable tumor microenvironment, with consequent immunotherapy resistance. Therefore, an understanding of the immune evasive mechanism of HCC is urgently needed. Methods: Utilizing the antigen-expressing c-MycOE/Tp53KO HCC mouse model, a critical oncogenic signaling pathway in immune evasion was identified by data-independent acquisition mass spectrometry (DIA-MS) proteomics. Potential downstream pathways were investigated by scRNA-seq, immune profiling, western blot, and multiplexed immunofluorescence staining. We also examined the therapeutic potential of targeting wild-type Kras using the Kras inhibitor MRTX0902 and the MEK inhibitor trametinib to enhance the efficacy of immunotherapy in HCC. Results: We identified a significant upregulation of wild-type Kras in immune-escaped tumors, with concurrent activation of its ligand-driven EGFR and its downstream MEK/ERK signaling. Likewise, endogenous Kras overexpression in this model resulted in increased tumor burden with reduced survival time in mice, implicating the regulatory role of Kras signaling in immune evasion. Clinically, wild-type Kras showed elevated expression in HCC at both the mRNA and protein levels, and was associated with tumor recurrence and poorer patient survival. Through scRNA-seq analysis, we demonstrated that Kras hindered dendritic cell recruitment, leading to compromised Cd8+ T cell activity via the suppression of interferon-mediated Cxcl9. Wild-type Kras activation further impaired HCC recognition by T cells via the downregulation of MHC-I expression. Notably, the combination therapy of MRTX0902, trametinib, and anti-PD-1 effectively enhanced intratumoral Cd8+ T cell infiltration and demonstrated a favorable response in survival outcomes. Conclusion: This study showed that wild-type Kras, via the activation of its downstream MEK/ERK signaling, acts as a crucial immune evasive mechanism in HCC and contributes to resistance to anti-PD-1 therapy. It also provided new insights into the therapeutic potential of targeting wild-type Kras to enhance the efficacy of anti-PD-1 therapy, providing a foundation for further exploration and potential clinical applications in HCC. Citation Format: Mang Leng Lei, Terence Kin Wah Lee. Wild type Kirsten rat sarcoma (Kras) activation drives evasion of interferon-mediated immunity in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5356.
Abstract 5394: Nicotine-induced exosomal miR-3157-3p from prostate cancer cells promotes angiogenesis
Authors: Shubhangi Singh, Mohammad Aslam Khan, Shashi Anand, Sirin Saranyutanon, Sanjeev Kumar Srivastava, Seema Singh, Ajay P. Singh, Kunwar Somesh Vikramdeo
Journal: Cancer Research (2024)

Abstract Nicotine is a psychoactive component of cigarette smoke responsible for addictive properties of tobacco and is shown to promote cancer pathogenesis. We earlier reported that exosomes released from nicotine-treated prostate cancer cells played a key role in tumor angiogenesis, a process necessary to maintain the supply of nutrients and oxygen to the fast proliferating cancer cells. Here, we examined the molecular mechanisms underlying the exosome-mediated effect of nicotine on angiogenesis. For this, we screened the expression of angiogenesis-related miRNAs in the exosomes derived from LNCaP and C4-2 cells treated with vehicle or nicotine (400 nM). Highest and most differential abundance of miR-3157-3p was found in exosomes derived from nicotine-treated prostate cancer cells. Furthermore, the expression of TIMP-2 and KLF-2, established targets of miR-3157-3p, was also downregulated in endothelial cells transfected with exosomes derived from nicotine-treated prostate cancer cells or miR-3157-3p mimics. Studies are currently underway to establish direct targeting of TIMP-2 and KLF-2 by miR-3157-3p and confirm that their suppression is indeed associated with observed changes in endothelial cell growth, migration and capillary-forming ability. Citation Format: Shubhangi Singh, Mohammad Aslam Khan, Shashi Anand, Sirin Saranyutanon, Sanjeev Kumar Srivastava, Seema Singh, Ajay P. Singh, Kunwar Somesh Vikramdeo. Nicotine-induced exosomal miR-3157-3p from prostate cancer cells promotes angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5394.