tbuckley/cabot-search huggingface dataset:
Abstract 4914: Mapping the cancer immune landscape in colorectal adenocarcinoma using multiplexed imaging and AI based analysis
Authors: Vasundhara Agrawal, Lisa Arvidson, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Samuel Jensen, Arindam Bose
Journal: Cancer Research (2024)

Abstract Colorectal cancer is a high burden cancer in the United States, leading to the second highest cause of cancer deaths. Despite chemotherapeutic intervention and surgical resection, recurrent disease may occur in some patients and typically, has a poorer prognosis. Thus, there is a demand for advanced therapies such as immunotherapies for improved clinical outcomes. An in-depth understanding of the colon cancer microenvironment is necessary to improve outcome in this subset of patients. Spatial biology approaches are well positioned to comprehensively uncover the molecular and biological mechanisms of cancer cell aggression in colorectal cancer. Here, we visualized nearly 30 biomarkers in colon adenocarcinoma (CAC) tissue using the Cell DIVE multiplexed imaging workflow and validated antibodies from Cell Signaling Technology (CST®). Using this approach, we were able to probe multiple pathways of interest in cancer progression, such as vascularization of tumor tissue, immune cell responses, and cell proliferation. Together, these data allow the creation of a spatial map of tumor cell aggression and offer predictive value for the progression of the disease. Deep molecular and architectural insights on this level are possible only with a spatial biology approach and offer multiple downstream hypotheses to further understand cancer progression and interrogate the heterogeneity within the tumor microenvironment. Citation Format: Vasundhara Agrawal, Lisa Arvidson, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Samuel Jensen, Arindam Bose. Mapping the cancer immune landscape in colorectal adenocarcinoma using multiplexed imaging and AI based analysis [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 4914.
Abstract 3760: The importance of optimizing DNA extraction conditions for formalin fixed paraffin embedded tissues
Authors: Matthew G. Butler, Benedicta Forson, Maria Cowen, Jayanthi Ramprakash, Dana Ruminski Lowe, Yves Konigshofer
Journal: Cancer Research (2024)

Abstract The pre-analytic extraction of Formalin Fixed Paraffin Embedded Tissues (FFPETs) appears to have a profound effect on the ability to obtain meaningful data from the DNA therein. FFPETs represent important materials in Pathology that are used to diagnose and analyze cancer. As part of preparing FFPETs, the formalin fixation step preserves the structure of tissues through covalent modifications but can also damage nucleic acids through that same process. Over the last decade, the emergence of Molecular Pathology, which benefits from gentler fixation compared to Histopathology and especially Immunohistopathology, has led to changes in how FFPETs are prepared. However, the remnant FFPETs from over a decade ago may be far from representative of what is now prepared for Molecular Pathology by many laboratories. Here we discuss our optimization of FFPET extraction for gently fixed samples. When we prepared our Seraseq FFPE Homologous Recombination Deficiency (HRD) reference standards using fixation conditions that are recommended for Molecular Pathology and extracted the resulting FFPETs using generic conditions, our initial coverage data from Whole Genome Shotgun (WGS) sequencing was difficult to analyze for changes in copy number across the genome. A major contributor to nonuniform coverage was identified as the formalin reversal step, where deparaffinized proteinase K-digested tissue is heated in water to near boiling to attempt to detach formaldehyde from nucleic acids through hydrolysis. Given the gentler fixation conditions, this step was found to be mostly unnecessary, and omitting it improved the resulting data substantially. A reason for this appears to be that the gentler fixation conditions that are now in use may not protect the DNA from the effects of near-boiling water, where the lack of salt lowers the melting temperature of double stranded DNA fragments and causes them to denature unless they have a higher GC content. Different kits used for the extraction of nucleic acids from FFPETs may benefit from different optimizations to obtain improved sequencing data from today’s Molecular pathology samples, and reference standards that represent such samples provide a useful tool for such optimizations. Citation Format: Matthew G. Butler, Benedicta Forson, Maria Cowen, Jayanthi Ramprakash, Dana Ruminski Lowe, Yves Konigshofer. The importance of optimizing DNA extraction conditions for formalin fixed paraffin embedded tissues [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 3760.
Abstract 3788: EpCAM+ DCCs isolated from the bone marrow of breast cancer patients display high stemness and potency scores
Authors: Elia Raya, Huiqin Koerkel-Qu, Laura Rudhart, Lisa-Marie Köhler, Anna Damboeck, Christoph Irlbeck, Catherine Botteron, Melanie Werner-Klein, Stephan Seitz, Christoph Klein
Journal: Cancer Research (2024)

Abstract Metastatic dissemination of cancer cells from primary to distant sites often occurs early and it has been shown that their detection is linked to poor outcomes. Eradication of disseminated cancer cells (DCC) has therefore become the primary goal of adjuvant therapies. Since the phenotype of DCC is largely unknown, we set out to search, isolate, and molecularly characterize these candidate metastasis founder cells from bone marrow of breast cancer patients, years before manifestation of metastasis. We screened more than 200 bone marrow samples of breast cancer patients with no evident metastasis (UICC stage M0) for EpCAM-positive cells. EpCAM positive cells in the bone marrow of healthy donors were used as a negative control. In addition, we isolated DCC from breast cancer patients with manifest metastasis (UICC stage M1). We then performed single cell RNA sequencing after whole transcriptome amplification of the collected DCC and the healthy donor (HD) control cells. To confirm the malignant origin of picked DCCs, we projected the transcriptome data into the bone marrow atlas, inferred copy number alterations, and searched for mutations shared with the matched primary tumor. EpCAM-positive cells from control patients mostly comprised plasma cells. In contrast, DCCs derived from M0-stage breast cancer patient formed a unique, non-overlapping cluster in the bone marrow atlas. UMAP-clustering placed M1-stage DCC clearly separate from M0 stage DCC. Among the collected M0-stage DCCs, we identified at least three separate subclusters. Strikingly, M0-stage DCC displayed much higher stemness and potency scores than M1-stage DCCs, reminiscent of embryonic cells. DCCs, identified by EpCAM, display very high transcriptional stemness scores when isolated before metastatic manifestation. Upon expansion and proliferation, stemness scores are reduced indicating epithelial re-differentiation. The embryonic phenotype of M0-stage DCCs may reflect an early adaptive mechanism that enables DCC to survive in an ectopic environment and may impact on the metastatic potential of the DCC. Citation Format: Elia Raya, Huiqin Koerkel-Qu, Laura Rudhart, Lisa-Marie Köhler, Anna Damboeck, Christoph Irlbeck, Catherine Botteron, Melanie Werner-Klein, Stephan Seitz, Christoph Klein. EpCAM+ DCCs isolated from the bone marrow of breast cancer patients display high stemness and potency scores [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 3788.
Abstract 3790: HtrA3 promotes malignant progression of colorectal cancer via PI3K-AKT-FOXO1 signaling pathway
Authors: Jing Zheng, Xianhua Huang, Xian-e Peng, Yunli Wu
Journal: Cancer Research (2024)

Abstract High-temperature requirement protease A3 (HtrA3) is known to contribute to the progression of various carcinomas through tissue-specific actions, yet its precise role in colorectal cancer (CRC) remains unclear. Our study revealed that HtrA3 is significantly upregulated in CRC at both mRNA and protein levels. TCGA database analysis showed that higher HtrA3 expression in colon adenocarcinoma is linked to poorer patient survival. Moreover, increased HtrA3 expression in HCT116 cells boosted their proliferation, migration, and invasion, while decreasing HtrA3 in SW480 cells had the reverse effect. In HCT116 cells with high HtrA3 levels, there was an increase in p-PI3K, p-AKT, and p-FOXO1, which reduced upon treatment with the PI3K inhibitor LY294002. Conversely, in SW480 cells with lowered HtrA3, these molecular levels decreased and rose again after treatment with the PI3K activator 740Y-P. HtrA3 also promoted cell proliferation, migration, and invasion in the presence of LY294002 and 740Y-P. In vivo experiments demonstrated that HtrA3 overexpression accelerated xenograft tumor growth. This study confirms that HtrA3’s overexpression in CRC cells promotes their proliferation, migration, and invasion by activating the PI3K-AKT-FOXO1 signaling pathway. Therefore, HtrA3 could be a significant factor in the advancement of CRC and may serve as a potential prognostic marker for guiding targeted CRC therapies. Citation Format: Jing Zheng, Xianhua Huang, Xian-e Peng, Yunli Wu. HtrA3 promotes malignant progression of colorectal cancer via PI3K-AKT-FOXO1 signaling pathway [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 3790.
Abstract 5343: Depletion of gut microbiota with broad spectrum antibiotics drives <i>Pten</i>-null prostate cancer growth in mice
Authors: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Mitsuhisa Nishimoto, Yasunori Mori, Kazuhiro Yoshimura, Kazutoshi Fujita, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2024)

Abstract Gut microbes have the potential to be either promoters or inhibitors of cancer. Use of antibiotics during cancer therapy can lead to dysbiosis, which may affect treatment outcomes. Here, we examine the effects of broad-spectrum antibiotics on cancer progression in mice with Pten-null castration resistant prostate cancer (CRPC). After five or eight weeks, orchiectomized conditional Pten-null knockout (KO) mice aged 50 and 90 weeks were given two biweekly cycles of a broad-spectrum antibody cocktail (BSAbx), respectively. The effects of BSAbx on tumor burden were compared, and molecular and immunological responses were analyzed by quantitative IHC (qIHC) and qRt-PCR at week four after antibiotic treatment. BSAbx treatment resulted in tumor burdens of 1.2 and 2.4-fold higher than in control mice in mice aged 50 and 90 weeks, respectively. qIHC analysis of KI67 showed increased proliferation in stromal and cancer cells. Additionally, androgen receptor (AR) protein and gene expression levels of Ar and Ar target genes (Fkbp5, Tmprss2, and Timp4) were elevated in tumors of BSAbx-treated mice. Restoring gut microbiota by fecal microbiota transplantation (FMT) from KO mice CRPC after BSAbx restored AR transcriptional activity to basal levels and lessened tumor growth. FMT from non-castrated KO with castration-naïve prostate cancer or heathy wildtype mice further reduced AR Transcriptional activity. Moreover, altering the gut microbiota of CRPC mice with FMT from heathy mice resulted in a tendency for lower tumor burden, 21% reduction versus control mice. Immunologically, BSAbx treatment resulted in decreased CD11b+/GR1+ cells in tumors and were associated with decreased interferon-gamma (IFN-gamma), dendritic cell functions and T cell-mediated cytotoxicity gene signatures. Mice that received FMT form health mice showed enhanced T cell mediated immunity as demonstrated by higher IFN-gamma signatures and tumor abundances of CD8+ T cells expression IFN-gamma, TNF-alpha and the cytotoxic granule granzyme B. Our study shows that broad spectrum antibiotics caused dysbiosis and promoted prostate cancer growth in mice with Pten-null prostate cancer. The effects were partly mediated through the upregulation of AR signaling and the impairment of neutrophil and T cell-mediated immune responses in tumors. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Mitsuhisa Nishimoto, Yasunori Mori, Kazuhiro Yoshimura, Kazutoshi Fujita, Kazuto Nishio, Hirotsugu Uemura. Depletion of gut microbiota with broad spectrum antibiotics drives Pten-null prostate cancer growth in mice [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 5343.
Abstract 3782: IASLC grading system predict distant metastases for resected lung adenocarcinoma
Authors: Yuezhu Wang, Margaret R. Smith, Yin Liu, Mary E. Green, Omer A. Hassan, Alexandra M. Balmaceda, Tammy Sexton, Wencheng Li, Fei Xing
Journal: Cancer Research (2024)

Abstract The International Association for the Study of Lung Cancer (IASLC) proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, whether this new grading system is able to predict distant metastases in LUAD patients has not been evaluated. This study investigated the feasibility of using this grading system to predict the occurrence of brain and bone metastases in patients with resectable LUAD which identifies patients who have a high probability of developing distant metastases after surgery. We collected clinical information and pathological reports of 179 early stage LUAD patients who underwent resection during 2008 to 2015 from Wake Forest Comprehensive Cancer Center. All patients were followed up for 5 years and both bone and brain metastasis-free survival were calculated. Tumor grading of all samples was evaluated by both IASLC grading and predominant pattern-based grading systems. The ability of predicting distant metastases using IASLC grading and tumor stage were examined by receiver operating characteristic curves (ROC). 28 out of 179 patients developed distant metastases in five years with a median overall survival of 60 months for metastasis-free patients and 38.9 for patients with distant metastasis. Compared to predominant pattern-based grading system, IASLC grading system showed a stronger correlation with distant metastasis incidence. Complex gland pattern is enriched in patients who developed bone and brain metastases compared to metastasis-free patients. IASLC grading system also showed a superior prediction power of distant metastasis compared to tumor stage with area under curve (AUC) of 0.69 for brain metastasis and 0.71 for bone metastasis. IASLC grading system is capable of predicting the incidence of distant metastasis among early-stage invasive LUAD patients. Citation Format: Yuezhu Wang, Margaret R. Smith, Yin Liu, Mary E. Green, Omer A. Hassan, Alexandra M. Balmaceda, Tammy Sexton, Wencheng Li, Fei Xing. IASLC grading system predict distant metastases for resected lung adenocarcinoma [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 3782.
Abstract 3762: 11,000-plex aptamer based proteomics of bladder cancer urine for the discovery of novel disease biomarkers
Authors: Chandra Mohan, Kamala Vanarsa, Jessica Castillo, Long Wang, Yair Lotan
Journal: Cancer Research (2024)

Abstract In search of more accurate, non-invasive biomarkers of bladder cancer (BC), a comprehensive aptamer-based screen of urine proteins was conducted using urine samples from a BC cohort, followed by systems biology analyses. Following an initial 1317-plex screen, an extended 11,000 plex aptamer-based proteomic screen is in progress. Based on the initial screen, 30 urine proteins were next ELISA validated in an independent cohort of 68 subjects, and the results are shown in Table 1. Of 21 urine proteins that discriminated BC from urology clinic controls (UC), urine D-dimer displayed the highest ROC AUC value (0.96) and sensitivity (95%) (Table 1). Furthermore, 9 urine proteins significantly discriminated more advanced BC (T1-T4) from earlier stages (Ta-Tis), with IL-8 and MMP-12 being the best performers. Urine MMP12 exhibited the highest specificity of 80% at fixed sensitivity for identifying advanced BC. Systems biology analysis implicated molecular functions related to extracellular matrix, collagen, integrin, heparin and transmembrane tyrosine kinase signaling in BC susceptibility, with HNF4A and NFKB1 emerging as key molecular regulators. STEM analysis of the dysregulated pathways implicated a functional role for the immune system, complement and interleukins in BC disease progression. Urine C2, D-dimer, and Elastase were additionally ELISA validated in a second BC cohort of Chinese ethnicity. Thus, comprehensive proteomics and independent ELISA validation have uncovered novel urine biomarkers for initial BC diagnosis and subsequent disease progression, that warrant further head to head comparison with current diagnostic tests. Citation Format: Chandra Mohan, Kamala Vanarsa, Jessica Castillo, Long Wang, Yair Lotan. 11,000-plex aptamer based proteomics of bladder cancer urine for the discovery of novel disease biomarkers [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 3762.
Abstract 3755: Impact of antigen retrieval and other parameters on detection of FGFR2b in various solid tumors on a BenchMark ULTRA automated staining platform: Development of a new IHC assay for FGFR2b
Authors: Autumn Sky Watson, Catherine Le, Anne M. Wertheimer, Spencer Escobedo, Lisa So, Bhavani Bagevalu Siddegowda, John D. Palting, Susan Marion, Steven P. Stratton, Birte Aggeler
Journal: Cancer Research (2024)

Abstract Background: Fibroblast growth factor receptor 2b (FGFR2b) is part of the FGFR transmembrane tyrosine kinase receptor family. This protein has gained more attention in recent years as a tumor progression biomarker in numerous solid tumors. The detection of FGFR2b by immunohistochemistry (IHC) has been used recently in immunotherapy clinical trials with multiple tumor types. During IHC assay development on formalin-fixed paraffin embedded tissue, a thorough study of antigen retrieval through cell conditioning or enzyme incubation, primary antibody incubation, and detection parameters is critical to evaluate staining performance. Design: A study of an investigational anti-FGFR2b (FPR2-D) assay developed on a BenchMark ULTRA automated staining platform explored the effect of antigen retrieval and detection parameters on staining performance. VENTANA System Software was used to modify steps in the IHC staining protocol resulting in 42 permutations. Ten different solid tumors were stained with these modifications to the assay and subsequently evaluated for FGFR2b expression. Result:s The results demonstrate that the staining clarity, intensity, and dynamic range within tissue cases of FGFR2b staining can vary widely between different solid tumor types. While most permutations of the initial assay parameters had minimal impact on the staining performance and readability by a pathologist, the order of the enzyme treatment and the cell conditioning steps (in addition to increased incubation time of primary antibody) had a significant impact when comparing across different solid tumors. Detection of FGFR2b seemed to have a greater susceptibility by tumor type to the antigen retrieval process than has traditionally been observed in other biomarkers. Conclusion: The overall results of this investigation show the importance of an extensive parameter screening approach when evaluating new antibody targets and indication combinations in IHC to ensure optimal staining performance. This is critical to downstream testing and the potential use of new assays in the context of in vitro diagnostics. Citation Format: Autumn Sky Watson, Catherine Le, Anne M. Wertheimer, Spencer Escobedo, Lisa So, Bhavani Bagevalu Siddegowda, John D. Palting, Susan Marion, Steven P. Stratton, Birte Aggeler. Impact of antigen retrieval and other parameters on detection of FGFR2b in various solid tumors on a BenchMark ULTRA automated staining platform: Development of a new IHC assay for FGFR2b [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 3755.
Abstract 376: Targeting the convergence on HIF-1α of CDK4/6 and MAPK pathway: Implications for enhanced anticancer strategies
Authors: Shuai Zhao, Lanlan Zhou, Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Hypoxia-inducible factor 1-alpha (HIF-1α) plays a pivotal role in orchestrating cellular responses to hypoxia, influencing cancer cell survival and progression. Our previous work identified a non-canonical mechanism wherein Smurf2 mediates HIF-1α degradation under CDK4/6 inhibition. Through proteomic analysis, we discovered that serine 451 phosphorylation occurs on HIF-1α but not in palbociclib-treated samples. Point mutations at this site, substituting serine with alanine, resulted in decreased HIF-1α levels and enhanced interaction with Smurf2. Intriguingly, under palbociclib treatment, we observed phosphorylation at the serine 643 site. This site has been previously associated with MAPK-dependent regulation of HIF-1α localization and activity (Ilias Mylonis, et al., 2006), particularly relevant given the reported MAPK reliance in acquired CDK4/6 inhibitor-resistant scenarios (Renée de Leeuw, et al., 2018). To explore therapeutic implications, we investigated the impact of combined CDK4/6 (palbociclib) and MEK1/2 inhibition (trametinib, selumetinib, PD98059, U0126). Dual inhibition robustly reduced HIF-1α expression in colorectal cancer cells (HCT116, SW480) and suppressed HIF-1α activity in luciferase reporter assays. This effect extended to synergistic inhibition of cell viability under both normoxia and hypoxia in HCT116 and SW480 cells. Such effect is also applicable to other cancer types and cell lines (e.g. U251). In summary, our findings unveil a phosphorylation site on HIF-1α associated with CDK4/6 activity, influencing its protein stabilization. This discovery supports the rationale for combining CDK4/6 and MEK1/2 inhibition as a promising strategy in the treatment of solid tumors. Citation Format: Shuai Zhao, Lanlan Zhou, Shengliang Zhang, Wafik S. El-Deiry. Targeting the convergence on HIF-1α of CDK4/6 and MAPK pathway: Implications for enhanced anticancer strategies [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 376.