tbuckley/cabot-search huggingface dataset:
Abstract 3154: The role of nuclear kinases in pancreatic carcinogenesis
Authors: Kayla LaRue, Ashley Sigafoos, Luis Flores, Brooke Tader, Martin Fernandez-Zapico
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is a devastating disease predicted to be the second leading cause of cancer deaths in the next 15 years. Thus, there is an urgent need to develop new treatment approaches based on a better understanding of cellular and molecular mechanisms controlling this dismal progression. PDAC development is marked by nuclear morphological changes likely resulting in changes in chromatin organization and gene expression. Oncogenic KRAS, present in more than 90% of tumors, plays a key role in disease initiation and progression and is sufficient to induce these nuclear morphology changes. Work from our lab has identified the nuclear lamina protein Emerin as a mediator of KRAS-induced nuclear morphology changes. Further, a BioID experiment identified a KRAS-induced interaction of Emerin with a group of nuclear kinases belonging to the ribosomal S6 kinase (RSK) and mitogen- and stress- activated protein kinase (MSK) families. In silico analysis identified candidate MSK and RSK phosphorylation sites in Emerin. Thus, we hypothesize that the nuclear kinase families RSK and MSK can act as effectors of the KRAS-Emerin axis to regulate PDAC nuclear morphology. Further studies will be done to confirm if Emerin can be phosphorylated by RSK and MSK, and to validate that this relationship is dependent on oncogenic KRAS signaling and if its nuclear morphological changes are regulated by this GTPase. Overall, this work aims to define a novel signaling axis for RSK and MSK in controlling nuclear dynamics that play a role in disease progression of PDAC, which can lead to the identification of new therapeutic targets. Citation Format: Kayla LaRue, Ashley Sigafoos, Luis Flores, Brooke Tader, Martin Fernandez-Zapico. The role of nuclear kinases in pancreatic carcinogenesis [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 3154.
Abstract 6800: The tumor progression mechanism of increasing CXCL16-CXCR6 pathway within the tumor microenvironment in TNBC
Authors: Yun sun Lee, Cham Han Lee, Seong Yun Ha, Sang Hyeob Lee, Jin Yi Yang, Young Sang Kim, Sung Moo Kim, Seong Keun Kim
Journal: Cancer Research (2024)

Abstract Background: Triple negative breast cancer (TNBC) is characterized rapid progression, higher relapse, and poor prognosis, so the establishment of an effective therapeutic target is required. CXCL16, a chemokine abundantly present in the TNBC tumor microenvironment (TME), is secreted by tumor-associated macrophages (TAM) and is known to promote tumor growth and metastasis. However, the exact mechanism through which CXCL16 facilitates tumor growth and metastasis remains unclear. This study aims to study the role of CXCL16 in the tumor progression and confirm the anti-tumor effects of CXCL16 neutralization in TNBC model. Method: MDA-MB-231 human TNBC cell lines were utilized for in vitro validation, and a syngeneic model involving 4T1 mouse TNBC cell lines and Balb/c mice was used for in vivo studies. Results: Stimulation of TNBC cells with recombinant human CXCL16 protein (rhCXCL16) activates the tumor growth signaling pathways, including pAKT and STAT3, as well as EMT markers. These results shows that CXCL16 can promote tumor growth and metastasis. Treatment with CXCL16 neutralizing antibodies inhibited the promotion of cancer growth and metastasis by rhCXCL16. Additionally, combination treatment of CXCL16 antibodies with PD-1 antibodies in the 4T1 syngeneic model increased the proportion of CD8+ T cells and CD80+ M1 like macrophages. These results shows that neutralization of CXCL16 can regulate polarization of macrophage and proportion of T cells. These regulation and changes of immune cells allow neutralization of CXCL16 control the TME to resist tumor cells, suggesting that optimal condition can be constructed to maximize the effectiveness of anti-cancer drugs. Conclusion: This study confirms that the CXCL16-CXCR6 pathway within the TME triggers tumor growth and metastasis, while neutralization of CXCL16 can inhibit tumor progression. This effect is attributed to the increase in CD8+ T cell and M1 macrophage proportions within the TME. In conclusion, these research findings propose the potential of CXCL16 as a novel biomarker and therapeutic target for TNBC. Citation Format: Yun sun Lee, Cham Han Lee, Seong Yun Ha, Sang Hyeob Lee, Jin Yi Yang, Young Sang Kim, Sung Moo Kim, Seong Keun Kim. The tumor progression mechanism of increasing CXCL16-CXCR6 pathway within the tumor microenvironment in TNBC [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 6800.
Abstract 728: Oral TGF-beta receptor1 inhibitor vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity
Authors: Sung Hee Choi, Jay Myers, Suzanne Tomchuck, Melissa Bonner, Saada Eid, Daniel Kingsley, Kristen VanHeyst, Seong-Jin Kim, Byung-Gyu Kim, Alex Y. Huang
Journal: Cancer Research (2024)

Abstract Osteosarcoma (OS) is an aggressive malignant bone cancer, with the lung as the most frequent site of metastasis. Unresectable pulmonary metastasis remains a significant challenge with a survival rate of less than 20%. Identification of novel therapeutic strategies are desperately needed. Transforming growth factor-β1 (TGF-β) is a potent immune suppressive cytokine in OS tumor microenvironment (TME). TGF-β1 expression is increased in the sera and tumor tissues of OS patients and this increase is associated with high-grade OS and lung metastases. Therefore, blocking TGF-β1 signaling may be a novel therapy for OS treatment. In this study, we show that blocking TGF-β1 signaling using the orally bioavailable small molecule TGF-βR1 inhibitor, Vactosertib, significantly inhibited OS proliferation in vitro and in vivo. Notably, Vactosertib inhibits c-Myc expression in the OS cells and oral administration of Vactosertib significantly reduces OS growth in vivo. Vactosertib increased immune effectors (e.g., IFNγ+CD8+ cells and NK cells) and inhibited immune suppressors (e.g., M2-like TAM, MDSC) in the OS TME. Our results suggest that inhibition of TGF-β1 signaling is an effective therapeutic strategy against OS through a multi-pronged approach that targets tumor intrinsic and extrinsic factors to achieve optimal immune-effector functions and maximal clinical response. Citation Format: Sung Hee Choi, Jay Myers, Suzanne Tomchuck, Melissa Bonner, Saada Eid, Daniel Kingsley, Kristen VanHeyst, Seong-Jin Kim, Byung-Gyu Kim, Alex Y. Huang. Oral TGF-beta receptor1 inhibitor vactosertib promotes osteosarcoma regression by targeting tumor proliferation and enhancing anti-tumor immunity [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 728.
Abstract 1478: Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal cancer cells
Authors: Jerika Durham, Josiane Weber Tessmann, Bernhard Hennig, Yekaterina Zaytseva
Journal: Cancer Research (2024)

Abstract Background: Chronic exposure to long-term exposures to per- and polyfluoroalkyl substances (PFAS), widely known as “forever chemicals”, has been associated with multiple negative health outcomes including increased risk of cancer. Perfluorooctanesulfonic acid (PFOS), a “long-chain” subtype of PFAS, has high bioaccumulation potential with a long elimination half-life. PFOS is frequently detected in drinking water leading to its high absorption through the gastrointestinal tract. Recent studies demonstrate that PFAS exposures promote intestinal inflammation and gut barrier dysfunction. However, how a long-term PFOS exposure affects colorectal cancer (CRC) progression is not known. Therefore, the purpose of this study is to delineate the effect of PFOS exposure on CRC cell proliferation and test the potential mitigation strategy for the harmful effects of PFOS. Methods: SW480 and HCT116 cells have been treated with 1 ug/mL PFOS and proliferation was measured at 1, 2, and 3 months using the Presto Blue Cell Viability Reagent fluorescence assay. Proliferation markers were assessed by qPCR and Western blot. Control and PFOS exposed cells were treated with sulforaphane, a nuclear factor erythroid 2-related factor 2 (Nrf-2) inducer, at concentration 5, 10 and 20 uM for 72 hours. Results: We show that chronic, low-dose PFOS exposure promotes proliferation of SW480 and HCT116 cell lines starting at 3 months since the first exposure. The increase in proliferation is associated with upregulation of Cyclin D, pAkt and FASN. We also show that sulforaphane significantly decreases proliferation of HCT116 and SW480 cells, and its efficacy is significantly higher in PFOS exposed CRC cells. The current studies show no effect on sulforaphane on normal colon epithelium cells. Conclusion: Our studies suggest that chronic PFOS exposure promotes proliferation of CRC cells by increasing pro-carcinogenic gene expression and signaling. Furthermore, our findings suggest that supplementation of diet sulforaphane can potentially mitigate the harmful effects from PFOS exposure. Our studies warrant further investigation of the mechanisms behind the effect of PFOS exposure on cancer progression that would guide development of effective intervention strategies to mitigate the harmful effects of the exposure to “forever chemicals”. Citation Format: Jerika Durham, Josiane Weber Tessmann, Bernhard Hennig, Yekaterina Zaytseva. Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal 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 1478.
Abstract 4725: Phenotypic single-cell analysis of nuclear stress responses in drug-treated prostate cancer cells
Authors: Enkhzaya Batnasan, Minttu Kärkkäinen, Sonja Koivukoski, Pekka Ruusuvuori, Leena Latonen
Journal: Cancer Research (2024)

Abstract Chemotherapy with anti-cancer drugs aims to stop the growth of cancer cells either by killing them or by stopping them from dividing. The different specificities in inducing cellular damage responses are incompletely understood currently and may underlie the preferential effectiveness of anti-cancer drugs against different types of cancer cells. Better understanding and tools to measure drug-induced phenotypes in vitro may aid in assessing cellular heterogeneity of responses, determining potential effectiveness, estimating amount and types of adverse effects, and predicting likelihood of surviving populations for residual disease. To measure the types and extent of nuclear stress responses to cancer drugs, we studied nuclear organelle, namely nucleolar and Cajal body, phenotypes to drug-induced stress in prostate cancer cells. We utilized organelle-specific markers NPM, Fibrillarin, Coilin, and SMN1 in immunofluorescence staining to determine suitable markers for nuclear organelle stress. We used three different prostate cancer cells lines representing different biological types of advanced prostate cancer (AR positive, AR negative, and expressing AR transcript variant). Based on initial assessments, NPM and coilin immunostaining were selected for automated phenotypic analysis screening for drug effects. Using AI-assisted nuclear segmentation and feature-based single-cell phenotypic analysis, we demonstrated quantitative effects on nuclear morphology, nucleoli, and Cajal bodies with drug treatments. A proof-of-principle study with platinum-based chemotherapeutic agents in clinical use demonstrated heterologous responses to the platinum drugs that are associated with prostate cancer cell types with different AR status. Further, we have defined the corresponding quantitative responses for androgen deprivation therapy (ADT) drugs enzalutamide and bicalutamide in AR-positive prostate cancer cells. Our findings evidence variability of prostate cancer cells’ response to chemotherapy and have implications in future therapy regimen considerations. Furthermore, we have developed a fluorescence light microscopy-based method to assess nuclear stress response phenotypes in prostate cancer cells that can be used for high throughput drug screening. Citation Format: Enkhzaya Batnasan, Minttu Kärkkäinen, Sonja Koivukoski, Pekka Ruusuvuori, Leena Latonen. Phenotypic single-cell analysis of nuclear stress responses in drug-treated 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 4725.
Abstract 3181: Immune modulatory activity of radio-sensitizing gold nanoparticle
Authors: Tanmay Kulkarni, Shamit Dutta, Hazel Parent, Karington Perry, Yuri Mackeyev, Santanu Bhattacharya
Journal: Cancer Research (2024)

Abstract Radiation therapy (RT) is frequently used in the neoadjuvant setting in borderline resectable and some resectable pancreatic ductal adenocarcinoma (PDAC) and in the definitive setting in locally advanced PDACs which is third leading cause of cancer associated death. Higher doses of RT improve overall treatment outcomes but increasing the dose significantly above 50Gy in standard 2Gy fractions risks profound gastrointestinal (GI) toxicity. Additionally, genotoxic stress such as RT, can induce CXCL12 secretion by cancer associated fibroblast (CAFs) and overexpression of CXC motif chemokine receptor 4 (CXCR4) in cancer cells. CXCL12-CXCR4 downstream signaling results in immune suppression and consequent enhanced tumor growth and metastasis and poor prognosis in PDAC. To overcome these clinical challenges, we have developed multimodal gold nanoparticle constructs (GNPs) by functionalizing the CXCR4 antagonists to (i) bind to CXCR4 and mediate GNP internalization, (ii) abolish the feedback immune inhibitory signals mediated by CXCR4 overexpression, and (iii) enhance therapeutic benefit of radiation. To achieve these multimodal activities, we have covalently attached the CXCR4 antagonist, AMD070, to thiol-terminated polyethylene glycol (PEG) to synthesize AMD-PEG which was then conjugated with GNPs to produce AMD-PEG-GNP. In our experiment AMD-PEG-GNP has successfully inhibited CXCL12-CXCR4 downstream signalling such as reduction of ERK phosphorylation in PDAC cells. To analyze the radiosensitization role of GNP nanoconjugates, PDAC cells were incubated with AMD-PEG, PEG-GNP and AMD-PEG-GNPs for 4 hours and then treated with increasing doses of radiated, from 1-4Gy. AMD-PEG-GNP demonstrated a systematic enhancement on reactive oxygen species (ROS) production and downregulation of a colony formation. Collectively, the results from in vitro study with PDAC cells confirm that the nanoconjugate with AMD070 enhances radio-cytotoxicity and impair CXCL12-CXCR4 downstream signaling. Hence AMD-PEG-GNP has strong merit to enhance radiation dose locally and simultaneously restrict RT induced immunosuppression in PDAC. Citation Format: Tanmay Kulkarni, Shamit Dutta, Hazel Parent, Karington Perry, Yuri Mackeyev, Santanu Bhattacharya. Immune modulatory activity of radio-sensitizing gold nanoparticle [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 3181.
Abstract 512: Cell-cycle inhibition may influence differences in 2D vs 3D tumor sensitivity profiles
Authors: Jahanvi Kumar, Chiara Maestri, Rajeshwar Nitiyanandan, Ivan Trus, Ricardo J. Parker, Brigitte Apfel, Christian Apfel
Journal: Cancer Research (2024)

Abstract Background: Traditional cell culture methods involve growing cells on flat surfaces, which do not fully replicate the human physiological conditions. In contrast, 3D cell cultures accurately reproduce aspects of the in-vitro malignant and non-malignant cell behavior. However, differences in tumor sensitivity platforms between 2D vs. 3D models might be relevant for some, but not for other drugs. Methods: The colorectal cancer cell line HCT-116 was cultured and plated in flat bottom well plates for the 2D condition and in Ultra Low Attachment round-bottom plates for the 3D condition. After plating, cells were treated with chemotherapies and targeted therapies for four days; cellular sensitivity was assessed through a viability assay. Four-parameter logistic (4PL) dose response curves were generated and IC50s were quantified to understand the differences in responses between 2D and 3D cellular environments. Results: HCT-116 exhibited similar responses to platinum drugs, taxanes, and several other tested drugs in both platforms, with the exception of gemcitabine (2D IC50 0.04 mcM; 3D IC50 12.8 mcM), lapatinib (2D IC50 23; 3D IC50 418), tucatinib (2D IC50 23.3; 3D IC50 79.3), and palbociclib (2D IC50 7.0; 3D IC50 24.0). Interestingly, these drugs share a common mechanism of action, which is the inhibition of cell cycle progression from G1 to S phase. Hence, we hypothesize that this shared mechanism may account for the observed differences in drug efficacy between the two environments. Conclusions: Similar dose responses have been observed with various drugs on both platforms, yet drugs that inhibit cell cycle progression from G1 to S phase, revealed higher sensitivity in 2D and more resistance in the 3D platform. Confirmatory cell-cycle results analyses are in progress. Further research is needed to understand if this applies to patient samples. Citation Format: Jahanvi Kumar, Chiara Maestri, Rajeshwar Nitiyanandan, Ivan Trus, Ricardo J. Parker, Brigitte Apfel, Christian Apfel. Cell-cycle inhibition may influence differences in 2D vs 3D tumor sensitivity profiles [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 512.
Abstract 511: Cell cycle inhibitors exhibit anti-tumor immunomodulatory roles through the HIF-1-DDX41 cytosolic DNA sensing pathway in HCC
Authors: Cerise Yuen Ki Chan, Po Yee Wong, Helen Do Gai Xue, Chi Ching Goh, Jacinth Wing Sum Cheu, Aki Pui Wah Tse, Misty Shuo Zhang, Carmen Chak Lui Wong
Journal: Cancer Research (2024)

Abstract Cell cycle inhibitors have a long history as anti-cancer therapeutics in clinical applications. Uncontrolled and infinite cell cycles are hallmarks of cancer, which enable them to proliferate rapidly and survive. To target these key features of cancer cells, cell cycle inhibitors are used to arrest their active cell cycle and induce cell death. In this study, beyond the known primary effect on cell cycle control, we identified that an expected and a secondary effect in immune modulation by the cell cycle inhibitors. Anti-mitotic agents including Paclitaxel (microtubule stabilizer), Palbociclib (CDK4/6 inhibitor) and AZD1152 and GSK1070916 (Aurora Kinase B inhibitors) can also eliminate cancer cells via an alternative mechanism - the activation of STING signaling. Our results demonstrated that these anti-mitotic agents caused DNA damage and cytosolic DNA accumulation. The cytosolic DNA was captured by a cytosolic DNA sensor DDX41,which triggered STING-TBK1-IRF3/7 pathway to upregulate secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors in cancer cells. In addition, we revealed that transcription of DDX41 was mediated by the transcription factor known ashypoxia-inducible factor (HIF). In HCC, hypoxia induced DDX41 expression through HIF-1,thus hypoxic HCC cells were more prone to STING activation and SASP production under mitotic stress induced by cell cycle inhibitors. In the tumor microenvironment, the SASP enhanced infiltration of immune cells into the tumor core to eliminate cancer cells. We also observed the additive effects of cell cycles inhibitors (Paclitaxel, Palbociclib, and AZD1152)with anti-PD-1 mAb to arrest growth of HCC in mouse models. In summary, this study exhibited the novel immune-mediated aspect of cell cycle inhibitors in suppressing tumor growth. Our data suggested the potential combination regimen of cell cycle inhibitors and currently available immunotherapy with promising result. Citation Format: Cerise Yuen Ki Chan, Po Yee Wong, Helen Do Gai Xue, Chi Ching Goh, Jacinth Wing Sum Cheu, Aki Pui Wah Tse, Misty Shuo Zhang, Carmen Chak Lui Wong. Cell cycle inhibitors exhibit anti-tumor immunomodulatory roles through the HIF-1-DDX41 cytosolic DNA sensing pathway in HCC [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 511.
Abstract 5265: Targeting mtDNA dynamics enhances immunogenicity and sensitizes <i>KRAS</i> mutant cancers to PD-1 blockade
Authors: Kosuke Tanaka, Yasuki Adachi, Miyuki Yoshiya, Takuya Owari, Tomoko Yamamori-Morita, Akihiro Ohashi, Susumu Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa
Journal: Cancer Research (2024)

Abstract Mitochondrial DNA (mtDNA) can stimulate an innate immune response that potentiates the efficacy of cancer immunotherapy. However, mtDNA-targeting therapy has not been developed to enhance this innate immune system in specific cancer subtypes efficiently. Here we discover that mtDNA is enriched in KRAS mutant tumors where the DNA sensor machinery cGAS-STING signaling is primed for innate immune activation. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate the cGAS-STING signaling, which in turn induces PRKN-mediated mitophagy in response to mitochondrial stress in KRAS mutant cancer cells. During the process of mitophagy, PRKN, as an E3 ubiquitin ligase, degrades BAX protein and attenuates mitochondrial pore formation, which is essential for mtDNA efflux upon MEK inhibition. Combined MEK and mitophagy inhibitors efficiently stimulate type I IFNs in both mtDNA- and STING-dependent manners, and this combination enhances the efficacy of PD-1 blockade in Kras mutant murine syngeneic tumors. In the clinic, PRKN is associated with a ‘cold tumor’ phenotype among KRAS mutant tumors. Together, targeting mtDNA dynamics by co-inhibition of MEK and mitophagy represents a promising strategy to convert ‘cold to hot tumor’ in mtDNA-enriched KRAS mutant cancers. Citation Format: Kosuke Tanaka, Yasuki Adachi, Miyuki Yoshiya, Takuya Owari, Tomoko Yamamori-Morita, Akihiro Ohashi, Susumu Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa. Targeting mtDNA dynamics enhances immunogenicity and sensitizes KRAS mutant cancers to PD-1 blockade [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 5265.