tbuckley/cabot-search huggingface dataset:
Abstract 2993: Intraductal xenografts model ERα-positive invasive lobular carcinoma of the breast
Authors: George Sflomos, Laura Battista, Patrick Aouad, Fabio De Martino, Valentina Scabia, Athina Stravodimou, Ayyakkannu Ayyanan, Assia Ifticene-Treboux, Philipp Bucher, Maryse Fiche, Giovanna Ambrosini, Cathrin Brisken
Journal: Cancer Research (2021)

Abstract Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E-cadherin. It has clinical features distinct from other estrogen receptor-positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. By xenografting lobular cells to the milk ducts, we recapitulate the human disease, including invasion and metastasis to clinically relevant organs. Using patient-derived intraductal xenografts from lobular and non-lobular ER+ HER2- tumors to compare global gene expression we identify extracellular matrix modulation as a lobular carcinoma cell-intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Pharmacological treatment and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC. This is the first study of a hormone-responsive ER+ preclinical lobular model that mimics their clinical counterparts and opens opportunities for the development and evaluation of therapies. Citation Format: George Sflomos , Laura Battista, Patrick Aouad, Fabio De Martino, Valentina Scabia, Athina Stravodimou, Ayyakkannu Ayyanan, Assia Ifticene-Treboux, RLS, Philipp Bucher, Maryse Fiche, Giovanna Ambrosini, Cathrin Brisken. Intraductal xenografts model ERα-positive invasive lobular carcinoma of the breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2993.
A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling
Authors: William W. Du, Jindong Xu, Weining Yang, Nan Wu, Feiya Li, Le Zhou, Sheng Wang, Xiangmin Li, Alina T. He, Kevin Y. Du, Kaixuan Zeng, Jian Ma, Juanjuan Lyu, Chao Zhang, Chi Zhou, Katarina Maksimovic, Burton B. Yang
Journal: Circulation Research (2021)

Background: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrhythmia and progressive heart failure. The underlying mechanisms remain unclear. We performed high-throughput RNA sequencing to analyze circular RNA profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA–derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 (inhibitor of growth protein 4) and C8orf44-SGK3 (serum and glucocorticoid-inducible kinase-3) promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn-transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared with WT (wild type) mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload–induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.
Role of systemic immune-inflammation index in patients treated with salvage radical prostatectomy
Authors: P. Rajwa, V.M. Schuettfort, F. Quhal, K. Mori, S. Katayama, E. Laukhtina, R.S. Motlagh, H. Mostafaei, B. Pradere, N.C. Grossmann, A. Aulitzky, A. Paradysz, P.I. Karakiewicz, H. Fajkovic, K. Zimmermann, A. Heidenreich, P. Gontero, S.F. Shariat
Journal: European Urology (2021)
Abstract 726: Correlation between T cell infiltration subtypes and intratumoral hormone levels in endometrial cancer
Authors: Yasuhiro Miki, Fuka Onuma, Kiyoshi Takagi, Erina Iwabuchi, Takashi Suzuki, Hironobu Sasano, Kiyoshi Ito
Journal: Cancer Research (2021)

Abstract T cells in the tumor microenvironment, or tumor-infiltrating lymphocytes (TILs), have been recognized to play a critical role in tumor immunity. TILs are heterogeneously defined, and different T cell subsets have various effects. The properties of some T cell markers, such as CD3, CD4, CD8, and forkhead box P3 (FOXP3), are poor prognostic factors in several types of cancers. The effects of sex steroid hormones on T cell function in inflammation are known, and estrogen and androgen regulate the secretion of cytokines to enhance and attenuate, respectively, the immune response. While intratumoral estrogen and androgen synthesis plays an important role in the progression of cancer cells in hormone-dependent cancers, the relationship between intratumoral hormone levels and TIL subtypes is unclear. In this study, we examined the correlation between intratumoral hormone concentrations and expression scores of TIL markers in endometrial cancer. We employed frozen and formalin-fixed paraffin-embedded (FFPE) tissues of 19 endometrial cancer tissues (G1, n=6; G2, n=5; G3, n=6; Serous, n=2). Hormone concentrations were measured by LC-MC/MS from the frozen sample, and immunohistochemistry of T cell markers was performed using FFPE tissues. The five T cell markers examined in this study were CD3 (total T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), FOXP3 (regulatory T cells), and thymocyte selection-associated HMG box (TOX) (exhausted T cells). The number of intratumoral CD3 in an arbitrary two-field (magnification, ×200) was counted and used as the CD3 score. Similarly, the number of other markers was counted, and the ratio to CD3 was used as the score for each marker. A correlation was found between TOX and CD8 using correlation between markers. The median scores for CD3 and CD8 were significantly higher in type 1 (G1 and G2) than in type 2 (G3 and serous) (CD3, p=0.031; CD8, P=0.031). The CD4 score had a positive correlation with estrogen (estrone, r2=0.591; estradiol, r2=0.501) and androgen (dihydrotestosterone, r2=0.327) concentrations. There was a poor negative correlation between cortisol concentration and CD8 score (r2=0.203). Estrogen and androgen at the tumor in situ were considered to affect TILs, especially CD4 positive T cells. It is also suggested that cortisol acts on immunosuppression, even locally in the tumor. This study showed the potential of a combination of immunotherapy and hormone therapy in endometrial cancer. Citation Format: Yasuhiro Miki, Fuka Onuma, Kiyoshi Takagi, Erina Iwabuchi, Takashi Suzuki, Hironobu Sasano, Kiyoshi Ito. Correlation between T cell infiltration subtypes and intratumoral hormone levels in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 726.
Near‐Infrared Light‐Triggered Polyprodrug/siRNA Loaded Upconversion Nanoparticles for Multi‐Modality Imaging and Synergistic Cancer Therapy
Authors: Gaizhen Kuang, Hongtong Lu, Shasha He, Hejian Xiong, Jie Yu, Qingfei Zhang, Yubin Huang
Journal: Advanced Healthcare Materials (2021)

Abstract Stimuli‐responsive nanosystems have been widely applied as effective modalities for drug/gene co‐delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co‐delivery, as well as multi‐modality imaging‐guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri‐modality imaging and near‐infrared (NIR) light‐activated drug/gene on‐demand delivery. The photoactivatable platinum(IV) (Pt(IV))‐backbone polymers (PPt) and the siRNA targeting polo‐like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)‐coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a “nanotransducer” to convert NIR light (980 nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on‐demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T 1 ‐weighted MR, and UCL tri‐modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image‐guided and NIR light‐activated platinum‐based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light‐controlled drug/gene delivery and multi‐modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.
Abstract 2250: Genomic and transcriptomic analyses of desmoid tumor reveals enrichment of transforming growth factor beta responsive signature
Authors: Changhee Park, Kum-Hee Yun, Sanghoon Song, Jin Kyung Lee, Jiyeon Ryu, Bitna Oh, Sunjin Hwang, Ki Baik Hahm, Seung-Jin Kim, Seung Hyun Kim, Chan-Young Ock, Hyo-Song Kim
Journal: Cancer Research (2021)

Abstract Introduction: Desmoid tumor is a rare aggressive tumor where there is no satisfying systemic treatment. Previous studies showed increased expression of transforming growth factor-β (TGF-β) in the desmoid tumor. Here, we analyzed genomic and transcriptomic data of tumor samples from patients with desmoid tumor to evaluate therapeutic applicability of inhibition of TGF-β response. Methods: We collected pre-treatment desmoid tumor samples from 31 patients in Yonsei cancer center, (YCC)-desmoid cohort and performed targeted next-generation sequencing and whole RNA sequencing. To compare the data with other cancer types, we used whole exome sequencing and whole RNA sequencing data from sarcoma patients from Yonsei Cancer Center (YCC-sarcoma cohort, n = 17 and n =53, respectively) and The Cancer Genome Atlas (TCGA, n = 9,235). Transcriptomic data was normalized throughout the three cohorts to reduce batch effect. To evaluate the enrichment of TGF-β responsive signature (TBRS) in tumor and microenvironment, we calculated the mean expression values of fibroblast-TBRS (F-TBRS) from previous study. Results: In the two sarcoma cohorts (YCC-desmoid and YCC-sarcoma cohorts), desmoid tumor samples had the highest F-TBRS score among the various types of sarcoma. When compared with other cancer types in TCGA, desmoid tumor samples showed the higher F-TBRS than all other cancer types except for pancreatic adenocarcinoma. In the desmoid tumor samples, CTNNB1, GNAQ, and APC mutations were the top 3 frequent mutations (23, 19, and 2 samples, respectively). In the merged two sarcoma cohorts, CTNNB1/APC mutation and GNAQ mutation were both associated with higher enrichment in F-TBRS (p &amp;lt; 0.001, respectively). Conclusion: Desmoid tumors are enriched with expression of genes associated with TGF-β response of fibroblast compared with other cancer types including other sarcomas. In addition, CTNNB1, APC and GNAQ mutations were associated with higher enrichment in TBRS. Therapeutic intervention to decrease the TGF-β response of fibroblast by using TGF-β receptor inhibitor may show clinical benefit in patients with desmoid tumors. Citation Format: Changhee Park, Kum-Hee Yun, Sanghoon Song, Jin Kyung Lee, Jiyeon Ryu, Bitna Oh, Sunjin Hwang, Ki Baik Hahm, Seung-Jin Kim, Seung Hyun Kim, Chan-Young Ock, Hyo-Song Kim. Genomic and transcriptomic analyses of desmoid tumor reveals enrichment of transforming growth factor beta responsive signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2250.
In vivo reprogramming of pathogenic lung TNFR2 <sup>+</sup> cDC2s by IFNβ inhibits HDM-induced asthma
Authors: Samira Mansouri, Himanshu Gogoi, Mauricio Pipkin, Tiago N. Machuca, Amir M. Emtiazjoo, Ashish K. Sharma, Lei Jin
Journal: Science Immunology (2021)

Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2+ conventional DC2 subset (cDC2s) that induces regulatory T cells (Tregs) maintaining lung tolerance at steady state but promotes TH2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2+ cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed TH2-promoting pathogenic TNFR2+ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2+ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung Treg induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2+ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy.
Abstract 581: Prognostic implication of circulating tumor-derived KRAS mutation in pancreatic ductal adenocarcinoma
Authors: Min Kyeong Kim, Dong-Eun Lee, Yun Hee Kim, Sang Jae Park, Sang Myung Woo, Sun-Young Kong
Journal: Cancer Research (2021)

Abstract Circulating tumor DNA (ctDNA) has been evaluated as potential biomarkers for prognosis in pancreatic adenocarcinoma(PDAC) including our previous study, which proved KRAS mutation as a prognostic marker through the quantitative analysis. Then we investigated in a larger samples to validate the results of previous studies. Total of 213 PDAC patients has been enrolled in this study and the median age was 66 years old and 120 males (56.1%). Plasma was separated by established centrifugation method and ctDNA was extracted from 2.0 mL plasma using a QIAamp Circulating Nucleic Acid Kit (Qiagen Cat# 61504, Hilden, Germany) or a Chemagic cfDNA 2K kit (PerkinElmer, Waltham, Massachusetts, U.S.). Extracted ctDNA was quantified using the Qubit dsDNA HS Assay Kit (Thermo Fisher Scientific, USA). The detection of KRAS mutation was performed using QX200 Droplet Digital PCR System (Biorad, USA) by KRAS screening multiplex droplet digital PCR kit which covers seven common mutation sites (Biorad, USA) and compared with that in 93 matched formalin-fixed paraffin-embedded (FFPE) tissues. Mutant concentration and fractional abundance were analyzed by QuantaSoft software (Biorad, USA). The KRAS mutation rates in tissue and ctDNA were 98.9% and 82.8%, respectively, and the concordance rate between them was 78 of 93 samples (83.9%). Univariable analyses demonstrated that KRAS fraction (Hazard ratio (HR), 1.59; 95% CI, 1.02-2.49; P = 0.040) were significant factors for PFS, whereas KRAS mutation concentration (HR, 1.69; 95% CI, 1.03-2.77; P = 0.038) and KRAS fraction (HR, 1.88; 95% CI, 1.17-3.02; P = 0.010) for OS. This study proved the usefulness of the KRAS mutation of ctDNA as a prognostic marker in PDAC. (This study was supported by National cancer center, Korea, Grant no. 1910192) Citation Format: Min Kyeong Kim, Dong-Eun Lee, Yun Hee Kim, Sang Jae Park, Sang Myung Woo, Sun-Young Kong. Prognostic implication of circulating tumor-derived KRAS mutation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 581.
Abstract 2271: Potential small-molecule inhibitors of the Tiam1 oncogene product
Authors: Claire Fritz, Michaela Stamper, Stephen Valentino, Lynn Ulatowski, Meghana Gupta, Varsha Thakur, Stacey Chung, Nick DeHann, Christian Laggner, Danny Manor
Journal: Cancer Research (2021)

Abstract T-cell lymphoma invasion and metastasis-inducing factor (Tiam)1 is an established proto-oncogene that drives cancer cell migration and metastasis. The correlation between Tiam1 integrity and patient survival, epithelial-mesenchymal transition, and angiogenesis, render it as an important prognostic factor in multiple human malignancies. Tiam1 is a guanine nucleotide exchange factor (GEF) that facilitates the activation of the small GTPase Rac1, thereby controlling cytoskeletal organization, cell polarity, motility, and invasion. In light of the clinical relevance of Tiam1 signaling, we investigated the utility of small molecule inhibitors that target Tiam1 as a therapeutic intervention strategy. We used an in silico computational approach to screen 10 million compounds for candidate drugs that bind to a select patch on Tiam1's surface. We then identified 13 compounds that inhibit the migration of Tiam1-expressing A549 cells without affecting overall viability. Our studies open the door for a new targeted therapy approach in Tiam1-relevant cancers. Citation Format: Claire Fritz, Michaela Stamper, Stephen Valentino, Lynn Ulatowski, Meghana Gupta, Varsha Thakur, Stacey Chung, Nick DeHann, Christian Laggner, Danny Manor. Potential small-molecule inhibitors of the Tiam1 oncogene product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2271.
Oncologic and patient-reported outcomes after robot-assisted radical prostatectomy in men 75 years or older
Authors: S. Hatakeyama, K. Togashi, T. Okamoto, Y. Kojima, H. Iwamura, N. Fujita, T. Narita, T. Hamaya, T. Yoneyama, H. Yamamoto, T. Yoneyama, Y. Hashimoto, C. Ohyama
Journal: European Urology (2021)
The multifaceted involvement of exosomes in tumor progression: Induction and inhibition
Authors: Wen‐Jie Gu, Yi‐Wen Shen, Li‐Jun Zhang, Hong Zhang, Dale G. Nagle, Xin Luan, San‐Hong Liu
Journal: MedComm (2021)

Abstract As key performers in intercellular communication, exosomes released by tumor cells play an important role in cancer development, including angiogenesis, cancer‐associated fibroblasts activation, epithelial‐mesenchymal transformation (EMT), immune escape, and pre‐metastatic niche formation. Meanwhile, other cells in tumor microenvironment (TME) can secrete exosomes and facilitate tumor progression. Elucidating mechanisms regarding these processes may offer perspectives for exosome‐based antitumor strategies. In this review, we mainly introduce the versatile roles of tumor or stromal cell derived exosomes in cancer development, with a particular focus on the biological capabilities and functionalities of their diverse contents, such as miRNAs, lncRNAs, and circRNAs. The potential clinical application of exosomes as biomarkers in cancer diagnosis and prognosis is also discussed. Finally, the current antitumor strategies based on exosomes in immunotherapy and targeted delivery for chemotherapeutic or biological agents are summarized.
Abstract 1577: Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma
Authors: Lauren C. Morehead, Brian S. Koss, Katherine F. Wallis, Alan J. Tackett, Isabelle Racine Miousse
Journal: Cancer Research (2021)

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized melanoma therapy. Still, the 5-year survival for advanced melanoma is only 50%. This leads to two questions: what makes some tumors less responsive to ICIs, and what can be done to increase responsiveness? Prior research suggests that hypoxia in the tumor microenvironment (TME) decreases the efficacy of ICIs, and metformin, an antihyperglycemic and caloric restriction mimetic (CRM), is able to reverse this condition. We hypothesize that other CRMs will also increase responsiveness to ICIs through hypoxia, and potentially other mechanisms. We chose three CRMs to study alongside metformin: hydroxycitrate, resveratrol, and sulforaphane. To identify pathways and understand more about CRMs effect on tumor hypoxia, we performed a proteomics experiment on B16F10 murine melanoma cells treated with all four CRMs. Proteomics analysis was done with a tandem mass tag labeling. To determine effect of caloric restriction mimetics on immunotherapy efficacy, B16F10 cells will be injected subcutaneously in immunocompetent male and female C57BL/6J mice, separated into four groups: 1) no treatment control, 2) ICI therapy only, 3) CRM therapy only, 4) ICI + CRM combination. Our preliminary data shows that, like metformin, additional CRMs decrease oxidative phosphorylation in cancer cells. This supports the hypothesis that the other CRMs may function similarly to metformin in the TME. We started testing the effect of four CRMs on tumor growth and hypoxia in an animal model. Our ultimate goal is to improve responsiveness to immune checkpoint inhibitors in patients with metastatic melanoma. Citation Format: Lauren C. Morehead, Brian S. Koss, Katherine F. Wallis, Alan J. Tackett, Isabelle Racine Miousse. Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1577.