tbuckley/cabot-search huggingface dataset:
Abstract 2185: Mechanism of antitumor effects of saffron in human prostate cancer cells
Authors: Mohammad Khan, Kaitlyn Hearn, Christian Parry, Mudasir Rashid, Hassan Brim, Hassan Ashktorab, Bernard Kwabi-Addo
Journal: Cancer Research (2024)

Abstract Prostate cancer is the most common malignancy in men in the USA and the second leading cause of cancer deaths. Several studies have suggested the antitumor properties of saffron in many types of cancers including prostate. The objective of this study was to carry out in vitro studies of saffron-treated prostate cancer cells to ascertain the effects of saffron on key intermediates in prostate carcinogenesis. Our studies demonstrate significant inhibition of cell proliferation of androgen-sensitive prostate cancer cell lines via apoptotic pathways. We also demonstrate statistically significant down-regulation of DNA methyltransferase; COMT, MGMT, EHMT2, and SIRT1 in saffron-treated prostate cancer cells. In addition, saffron-treated prostate cancer cells displayed statistically significant dysregulation of DNA repair intermediates; WRN, p53, RECQ5, MST1R, and WDR70 in a time-dependent manner. Furthermore, Western blot analysis demonstrated that saffron treatment induced changes in the expression of other key genes; DNMT1, DNMT3b, MBD2, CD44, HDAC3, c-Myc, NF-kB, TNFα, AR, N-RAS and PTEN in prostate cancer cells. Collectively, our findings demonstrate important mechanistic targets of saffron mediating anti-tumor properties in prostate cancer. These findings suggest that the use of saffron supplements alongside standard treatment protocols may yield beneficial effects for individuals with prostate cancer. Citation Format: Mohammad Khan, Kaitlyn Hearn, Christian Parry, Mudasir Rashid, Hassan Brim, Hassan Ashktorab, Bernard Kwabi-Addo. Mechanism of antitumor effects of saffron in human prostate cancer cells [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 2185.
Abstract 2918: Potential for a novel therapeutic target: Effects of lactate &amp; lactylation in expression of key regulatory cancer proteins
Authors: Christos P. Costeas, Connor Purcell, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract The purpose of our study is to investigate the immunologic, metastatic, and gene regulation effects of lactate in the context of cancer in normoxic and hypoxic conditions to identify novel biomarkers and potential therapeutic targets. We aim to modify the in-vitro cancer microenvironment to show how lactate and lactylation can be exploited using existing cancer treatments. While hyperlactatemia is defined as lactate levels between 2 mmol/L and 4 mmol/L (Foucher et al 2023), tumor biopsies have demonstrated extracellular concentrations as high as 40 mM (Pérez-Tomás et al 2020). Through CTG viability assays we identified lactate concentrations that PANC1 cells can survive, which are in agreement with the in-vivo findings of Brizel et al (2001). We observed pancreatic cancer cells achieving over 50% viability for 5 days at 50 mM lactate concentrations while at 30 mM on day 5 they proliferated past their initial plating numbers. Furthermore, Brizel et al (2001) found that patients with high tumor lactate concentrations had a significantly higher incidence of metastatic relapse. Through our scratch assay, we show qualitative evidence of increased mobility and inferred migration potential of PANC1 at 7.5mM [lactate] compared to the absence of lactate. We have also observed increased migration at higher lactate concentrations for which we are pursuing quantitative measurements to evaluate significance. Migration experiments will be followed by the investigation of gene regulation (eg. mRNA seq, lactylation profile) involved in the observed increased mobility. Lactate has been shown to affect immune regulation, namely suppression of iNKT (Fu et al, 2020), macrophages (Yang et al, 2020), dendritic cell differentiation and antigen recognition/presentation (Wang et al, 2022), however not much is known about its effect on NK cells and their cytokine expression. Through NK92MI/PANC1 cocultures we show the effects of lactate concentration on the killing ability of NK cells (in the works). And plan on investigating the cytokine profile leading to the phenotypic killing differences. Lastly, via lactate-titrated incubation of PANC1 cells in normoxia we have demonstrated a positive correlation of HIF1a expression, pan-lactyllysine lactylation, and microenvironment lactate concentration. We speculate HIF1a inhibition post-lactate-sensitization may induce cancer killing and we will investigate this theory in normoxia and hypoxia using existing treatment options. Citation Format: Christos P. Costeas, Connor Purcell, Wafik S. El-Deiry. Potential for a novel therapeutic target: Effects of lactate &amp; lactylation in expression of key regulatory cancer proteins [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 2918.
Abstract 1505: Unraveling diepafitaxis: Investigating ECM stiffness and microarchitecture in tumor spheroid migration
Authors: Hsiang-Pei Chen, Ya-Chu Tsai, Ting-Yuan Tu
Journal: Cancer Research (2024)

Abstract Background: Metastasis, accounting for up to 90% of cancer-related deaths, remains one of the least understood aspects of cancer progression. Recent research has shifted focus from solely biological hallmarks to the physical characteristics of cancer, such as the stiffness and microarchitecture of the extracellular matrix (ECM), which play pivotal roles in metastatic advancement. We previously introduced the concept of 'diepafitaxis' to describe a unique mechanism driving the interface-mediated tropism of tumor spheroids at matrix-surface boundaries. This phenomenon suggests that cancer cells preferentially migrate along a 2D 'interfacial' track formed by heterogeneous 3D ECM structures, facilitating invasion and dispersion. However, the exact mechanisms by which interfacial components, stiffness, and structural attributes influence cell movement remain debated. To investigate this, we have developed a microfluidic chip with a precisely controlled stiffness of the hydrogel matrix-matrix interface (MMI), aiming to shed light on specific diepafitatic behaviors. Method: We developed a polydimethylsiloxane (PDMS)-based microfluidic chip using a traditional photolithographic process. This chip features three channels, with the center channel designed to precisely control various MMI stiffness combinations: stiff vs soft (t-o), stiff vs stiff (t-t) and soft vs soft (o-o). MDA-MB-231 breast cancer spheroids (BCS), representing an in vitro tumor model, were embedded in the top gel. We observed the dynamic behavior of these cancer spheroids over a 24-h period using differential interference contrast (DIC) microscopy. Result: The study revealed that BCS exhibited more pronounced dispersion in a soft homogeneous ECM compared to a stiff ECM in 3D environments. Interestingly, when BCS were near an MMI, a stiffer MMI (t-t) significantly enhanced BCS invasiveness and single-cell migration, more so than t-o, and notably more than o-o. We previously described this phenomenon as '2.5D migration,' where cells migrate in a ventral 2D manner within a sandwiched 3D gel structure. This diepafitatic behavior was further analyzed for its response to gravitational effects and the influence of chemotaxis, induced by introducing VEGF on one side of the microfluidic channel. Conclusion: Conclusively, our study demonstrates that the stiffness and structure of the ECM, particularly at MMI, significantly influence the invasive behavior and migration patterns of BCS, underscoring the critical role of mechanical microenvironments in cancer metastasis. Citation Format: Hsiang-Pei Chen, Ya-Chu Tsai, Ting-Yuan Tu. Unraveling diepafitaxis: Investigating ECM stiffness and microarchitecture in tumor spheroid migration [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 1505.
Abstract 2186: Bacterial lung cancer therapeutics from soil bacteria in New York City
Authors: Dhruba Deb, Tal Danino
Journal: Cancer Research (2024)

Abstract The microbiome's diverse functions in human health have generated increasing interest in using live bacteria for cancer therapy. Due to their natural presence in colon, lung and breast tissue, bacterial therapies have been augmented using synthetic biology in order to treat infections, inflammation, and cancer. One major challenge is finding safe and effective host species and therapeutic payloads for a particular type of cancer. Here we explored the vast diversity of microbial isolates in the environment as a valuable source of novel therapeutic compounds that can be expressed by bacteria. Specifically, we isolated and identified soil bacteria from 25 local parks, and investigated their secreted compounds for anti-cancer activity using monolayer and 3D-spheroid cultures of lung cancer. Through metagenomic analysis, toxicology assays, varied growth conditions, and bacteria-cancer co-culture experiments, we found Bacillus spp. isolates from Manhattan parks' soil that secreted products with high, dose-dependent cytotoxicity against lung cancer models. We also demonstrate that Bacillus subtilis, a model organism for gram-positive bacteria, can colonize lung cancer tumor spheroids, pointing to its use as a viable strain for bacteria cancer therapy. The work presented here underscores the potential of harnessing environmental microbial diversity for the development of gram positive species and their compounds as cancer therapeutics. Citation Format: Dhruba Deb, Tal Danino. Bacterial lung cancer therapeutics from soil bacteria in New York City [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 2186.
Abstract 2919: Targeting regulatory T cells to boost immunity against melanoma
Authors: Wanying Miao, Yingai J. Jin, Vaibhav Jain, Simon Gregory, Jennifer Y. Zhang
Journal: Cancer Research (2024)

Abstract Tumor-infiltrated regulatory T-cells (Treg) restrict the function of effector T-cells and thereby promote tumor growth. Disrupting the immunosuppression of Treg cells presents an attractive strategy for cancer immunotherapy; However, the risk of autoimmunity, resulting from systemic Treg depletion, limits its therapeutic effectiveness. Here, we show that genetic depletion of Ube2n in Treg cells inhibits tumor growth which is correlated with a markedly enhanced infiltration of cytotoxic immune cells. Notably, the deletion of Ube2n in a fraction of Treg cells was sufficient to produce a long-lasting anti-tumor effect, without apparent systemic autoimmune responses. The antitumor effect persists following adoptive T-cell transfer to an otherwise immunodeficient mouse tumor model. Through flow cytometry, immunostaining and T-cell targeted single-cell sequencing analyses, we demonstrate that the loss of Ube2n dampens Treg suppressive function, as indicated by markedly increased numbers of cytotoxic CD8 T-cells in the tumor microenvironment (TME). Further, differentially expressed genes analyses show a downregulation of Mki67 and an upregulation of Ifng in Ube2n deficient Tregs, concomitant with amplification and activation of effector T-cells. Our findings uncover a hitherto unexplored role of Ube2n in orchestrating the differentiation and functions of Treg in TME, highlighting the therapeutic potential of targeting this pathway to enhance and reprogram anti-tumor immunity. Citation Format: Wanying Miao, Yingai J. Jin, Vaibhav Jain, Simon Gregory, Jennifer Y. Zhang. Targeting regulatory T cells to boost immunity against melanoma [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 2919.
Abstract 3274: Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer
Authors: Junpei Yamaguchi, Toshio Kokuryo, Yukihiro Yokoyama, Masaki Sunagawa, Taisuke Baba, Tomoki Ebata
Journal: Cancer Research (2024)

Abstract Background and Aims: Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. Methods: To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1−/−) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. Results: The deficiency of TFF1 was associated with increased EMT markers of cancer cells (Snail and Zeb1) in mouse models of pancreatic cancer, KPC. Analysis of the survival of patients who underwent chemotherapy for recurrent pancreatic cancer revealed that the expression of TFF1 in cancer cells was associated with better survival. Also, in the mouse model of pancreatic cancer, KPC mice showed improved survival when treated with gemcitabine, the KPC/TFF1KO mice did not. Pancreatic cancer cell lines were administered with gemcitabine and/or chemically synthesized TFF1, revealing that addition of TFF1 downregulated gemcitabine-induced EMT markers (Snail, Slug, ZEB1, and αSMA), Wnt pathway activation (β-catenin, TCF7, and EPHB3). In addition, TFF1 inhibited the expression of cancer stemness markers (CD133 and NANOG3) and the ability to form tumor sphere. Importantly, TFF1 accelerated the apoptosis of cancer cells induced by gemcitabine in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model. Also, KPC mice with combined treatment showed the better survival rather than gemcitabine-alone treatment, with lower expression of CD133, high expression of ZEB1, and lower nuclear translocation of β-catenin. Conclusion: These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity. Citation Format: Junpei Yamaguchi, Toshio Kokuryo, Yukihiro Yokoyama, Masaki Sunagawa, Taisuke Baba, Tomoki Ebata. Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic 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 3274.
Abstract 1504: Tumor microenvironment-mediated regulation of early dissemination and colonization in breast cancer via BAZ2A-containing remodeling complexes
Authors: Miriam Kokal-Ribaudo, Nora Jahnen, Saba Sameri, Fulvia Ferrazzi, Renato Liguori, Christoph A. Klein, Gernot Längst, Hedayatollah Hosseini
Journal: Cancer Research (2024)

Abstract The molecular mechanisms governing invasion, dissemination, extravasation, and early metastatic colonization remain incompletely understood. In the BALB-neuT mouse model, we found that most metastases originate from disseminated cancer cells (DCCs) that left the primary site early in tumorigenesis, i.e. when lesions are still small. Consequently, we investigated whether cellular density and the tumor microenvironment synergize to generate the plasticity needed during metastasis. RNA-sequencing analyses of murine breast cancer cells in low cellular density (LD) and high cellular density (HD) conditions revealed distinct profiles of differentially expressed genes. Notably, we identified the enrichment of ribosomal RNA (rRNA) and chromatin remodeling pathways in LD conditions. Interestingly, once these cells were treated with Wnt4 and Rankl, factors secreted by the tumor microenvironment, the expression profile of genes involved in proliferation, migration and stemness as well as epigenetic-related factors changed drastically. Specifically, cells in LD conditions treated with Wnt4 and Rankl displayed induced migration and stemness phenotypes, whereas under HD conditions, these signals induced proliferation. Among the chromatin-remodeling pathways, we found that BAZ2A along with the rRNA regulating network were primarily upregulated in migratory cancer cells. Immunostaining of primary and metastatic lesions in murine and human breast cancer samples showed an upregulation of BAZ2A in early/microlesions compared to more advanced and proliferative macroscopic lesions. Taken together, these results indicate that cell density, tumor microenvironmental factors and BAZ2A-containing chromatin regulating complexes play pivotal roles in regulating cancer cell plasticity in breast cancer. Additional sequencing and functional analyses will be performed to dissect the specific components of this mechanism and evaluate their impact on the in vivo colonization of breast cancer models. Citation Format: Miriam Kokal-Ribaudo, Nora Jahnen, Saba Sameri, Fulvia Ferrazzi, Renato Liguori, Christoph A. Klein, Gernot Längst, Hedayatollah Hosseini. Tumor microenvironment-mediated regulation of early dissemination and colonization in breast cancer via BAZ2A-containing remodeling complexes [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 1504.
Abstract 5342: Evaluation of autologous and allogeneic T cell-based therapies in <i>ex-vivo</i> and <i>in-vivo</i> xenograft tumor models
Authors: Sherry Liu, Jasmine Borroel, Carmen Sunico, Emily Eastwood, Bridget Corcoran, Bianca Carapia, Jantzen Sperry, Jonathan Nakashima, Rajeev Shrimali
Journal: Cancer Research (2024)

Abstract The field of adoptive T cell-based immunotherapy, including tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR) &amp; Chimeric antigen receptor (CAR) - T cells, has undergone unprecedented growth, specifically later in delivering effective and durable clinical response. Notable success with CAR-T cells is limited to hematological malignancies while clinical gains with solid tumors is still a challenge. Solid tumors’ heterogenous target expression and loss, T cell status and metabolic fitness, T cell trafficking into the tumor, and the hostile immunosuppressive tumor microenvironment (TME) have hampered T cell efficacy in the patients. There is a lack of clinically relevant solid tumor models for the translation of T cell-based therapies into the clinic. We report the development of translational ex-vivo and in-vivo platforms for evaluating cell line-derived and patient-derived xenografts (CDX and PDX) models (BarneyOI™️ model), validated with hCD3 T-cells, autologous TILs and/or allogeneic 3rd generation CAR-T cells (scFv(HER2)-CD28-4-1BB-CD3zeta CAR-T). Anti-hPDL1 but not anti-hPD1 significantly enhanced hCD3 T-cell and autologous TIL-mediated killing of tumor cells in an ex-vivo co-culture assay using Incucyte-based live cell imaging. Also, a dose-dependent killing of HER-2 expressing CDX (A549 &amp; Colo205) and PDX was observed with HER-2 targeting CAR-T cells in an ex-vivo co-culture assay. This was in concordance with the activation, effector function, and differentiation status of the CAR-T cells, immune phenotype by Cytek aurora spectral flow cytometry. Further, to imitate the patient population and the effect of solid TME, HER-2 targeting CAR-T cells were assessed for their in-vivo efficacy and immune response differences in the subcutaneous and orthotopically implanted HER-2 expressing PDX in immunodeficient NOG mice. Our findings highlight the importance of testing T cell-based immune therapies in the appropriate translational tumor models with better certainty of clinical outcome. Citation Format: Sherry Liu, Jasmine Borroel, Carmen Sunico, Emily Eastwood, Bridget Corcoran, Bianca Carapia, Jantzen Sperry, Jonathan Nakashima, Rajeev Shrimali. Evaluation of autologous and allogeneic T cell-based therapies in ex-vivo and in-vivo xenograft tumor models [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 5342.
Abstract 4901: High-resolution spatial transcriptomics identifies candidate genes facilitating perineural invasion
Authors: Deniz Guney Olgun, Peter L. Wang, Ryan Zhao, Dennis H. Gong, William L. Hwang
Journal: Cancer Research (2024)

Abstract Perineural invasion (PNI), or the invasion of cancer to the space surrounding nerves, is associated with poor prognosis, but the underlying molecular factors that drive its initiation and progression are poorly understood. To explore this systematically, we applied a 6000-plex spatial transcriptomic panel with subcellular resolution to curated microarrays from 5 pancreatic ductal adenocarcinoma (PDAC) patients spanning different stages of tumor-nerve involvement. With this preliminary cohort, we explored malignant cell signatures associated with invasion and adaptation to the intraneural environment. Strikingly, we observed enrichment of a classical-like malignant transcriptional program marked by genes involved in glucose and lipid metabolism in nerve-invading malignant cells. Despite the known association of chemoresistance with serine dependence, these cells also exhibited upregulation of genes involved in serine biosynthesis, suggesting that intraneural invasion may offer an orthogonal path of treatment evasion. Overall, our findings indicate that nerve-invasive cancer cells adopt a unique transcriptomic signature within the neuronal microenvironment. Further studies will aim to uncover the relevance of these signatures to survival within the nerve environment and treatment resistance. Citation Format: Deniz Guney Olgun, Peter L. Wang, Ryan Zhao, Dennis H. Gong, William L. Hwang. High-resolution spatial transcriptomics identifies candidate genes facilitating perineural invasion [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 4901.