tbuckley/cabot-search huggingface dataset:
Targeting the cell cycle to enhance chemotherapy efficacy in glioblastoma
Authors: Matthew McCord, Pouya Jamshidi
Journal: Neuro-Oncology (2024)

Journal Article Accepted manuscript Targeting the cell cycle to enhance chemotherapy efficacy in glioblastoma Get access Matthew McCord, Matthew McCord Department of Pathology, Northwestern University Feinberg School of Medicine Corresponding Author: Matthew McCord, MD, Advanced Training and Research Fellow, Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Superior Street, Chicago, IL, 60611, 312-503-4209, matthew.mccord@northwestern.edu https://orcid.org/0000-0001-7673-4463 Search for other works by this author on: Oxford Academic PubMed Google Scholar Pouya Jamshidi Pouya Jamshidi Department of Pathology, Northwestern University Feinberg School of Medicine Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noae062, https://doi.org/10.1093/neuonc/noae062 Published: 22 March 2024 Article history Received: 08 March 2024 Published: 22 March 2024
Abstract 2880: Radiation induces myofibroblast differentiation of pericytes
Authors: Tomoko Yamazaki, Kelley R. Jordan, Marka R. Crittenden, Michael J. Gough, Kristina H. Young
Journal: Cancer Research (2024)

Abstract Radiation not only kills cancer cells directly through DNA damage, but also indirectly by inducing vascular changes. Endothelial cells (ECs) in small blood vessels and capillaries connect with pericytes, a type of mural cells which are important for vascular stability and structure. Effects of radiation on tumor vasculature are critical for the therapeutic efficacy, however, its impacts on pericytes remain largely unknown. In this study, we focused on the effect of radiation on pericytes and sought to elucidate the mechanism by which radiation affects pericytes. We show 20Gy for C3H10T1/2 (10T1/2) mouse embryonic mesenchymal pericyte precursor cells and 10Gy for human pericytes from placenta (hPC-PL) cells induces pericyte differentiation and activation of adhesion molecules. Radiation enhanced lymphocyte adhesion and decreased permeability in co-culture of ECs and pericytes primarily through endothelial cells, not via pericytes. Furthermore, radiation promoted transdifferentiation of pericytes into myofibroblasts. Supernatant from irradiated cells in combination with a TGFβ inhibitor showed that TGFβ signaling is involved in pericyte differentiation by radiation but not all pericyte marker genes are regulated by TGFβ. Therefore, we performed phospho-kinase array analysis and revealed Akt signaling pathway activation 10 minutes following radiation, which was verified by the phosphorylation of GSK3β and PRAS40. Along with this, generation of intracellular reactive oxygen species (ROS) occurs as early as 5 min following radiation. Inhibitors of Akt and ROS suppress the expression of myofibroblast markers increased by radiation. To investigate whether radiation induces pericyte differentiation into myofibroblast in tumors, we employed NG2DsRedBAC (NG2DsRed) transgenic mice where DsRed is expressed under the control of NG2 promoter to trace pericytes. The endogenous expression of DsRed was detected in pericytes in the tumors implanted to NG2DsRed mice. Flow cytometry analysis of tumors harvested 7 days after radiation shows radiation increased vimentin+ cells and decreased DsRed+ cells, which indicates radiation induced pericyte differentiation into myofibroblast. In conclusion, radiation promotes pericyte maturation and transdifferentiation into myofibroblast via Akt signaling. Further study using Akt inhibitor with radiation to tumor-bearing N2DsRed mice will be warranted. Citation Format: Tomoko Yamazaki, Kelley R. Jordan, Marka R. Crittenden, Michael J. Gough, Kristina H. Young. Radiation induces myofibroblast differentiation of pericytes [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 2880.
Abstract 393: RAS and PI3K activation promote glioblastoma progression and ischemia-associated tumor cell death
Authors: Soo Yeon Kim, Miaolu Tang, Stephen Chih, Jessica Thorpe, Tong Lu, Hong-Gang Wang, Wei Li
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults. Despite the association of tumor necrosis and a poor prognosis in GBM, the mechanisms underlying tumor necrosis formation remain unclear, likely due to the lack of appropriate experimental models to examine the development of tumor necrosis. In our study, we developed mouse models with tumor necrosis by intracranially injecting human GBM cells expressing KRAS or PI3K active mutants into immunodeficient mice. Surprisingly, despite all tumors displayed similar sizes, the control tumors expressing an empty vector (EV) did not exhibit tumor necrosis. This intriguing observation led us to explore the potential role of KRAS and PI3K in promoting cell death within the tumor microenvironment. Ischemia, which is characterized by insufficient nutrients and hypoxia, is often found in GBM. Under an in vitro ischemia mimetic condition, we found that the KRAS or PI3K activated GBM cells showed more cell death compared to EV cells. Mechanistically, ischemia activates the p38 MAPK-MK2 pathway to induce cell death, a process further enhanced by KRAS or PI3K. Notably, we observed elevated expression of p-MK2 in the peri-necrotic areas of GBMs harboring KRAS or PI3K mutants compared to the cellular tumor zones. Moreover, we revealed that ischemia induces the unfolded protein response (UPR) pathway. Among UPR-related molecules, KRAS and PI3K upregulate ERN1, which encodes the transmembrane protein kinase IRE1, in ischemic conditions. Inhibition of ERN1 not only prevented ischemia-induced cell death but also inhibited the p38 MAPK-MK2 pathway. Furthermore, we observed an increase in the expression of pro-inflammatory cytokine IL-8 under ischemic conditions, a response that was prevented by inhibitors of p38 MAPK or MK2. Lastly, we found that ischemia induces ATP release and calreticulin exposure, indicating the cell death possessing certain immunogenic cell death features. In summary, our findings revealed a pivotal role of KRAS and PI3K in inducing cell death in the ischemic GBM tumor microenvironment through activating the IRE1-p38 MAPK-MK2 pathway. The cell death under this circumstance displays pro-inflammatory and immunogenic properties. Therefore, the IRE1-p38 MAPK-MK2 pathway may be exploited for the treatment of GBM in which RAS or PI3K is activated. Citation Format: Soo Yeon Kim, Miaolu Tang, Stephen Chih, Jessica Thorpe, Tong Lu, Hong-Gang Wang, Wei Li. RAS and PI3K activation promote glioblastoma progression and ischemia-associated tumor cell death [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 393.
Abstract 3155: Metabolic stress induces an intrinsic inflammatory CAF phenotype that regulates stromal architecture in pancreatic cancer
Authors: Yijuan Zhang, Swetha Maganti, Jennifer Hope, Li Lin, Cheska Marie Galapate, Florent Carrette, Linda Bradley, Cosimo Commisso
Journal: Cancer Research (2024)

Abstract Macropinocytosis is a critical amino acid supply pathway that fuels the metabolism of tumor cells and cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC). PDAC tumors are deficient in glutamine, a critical amino acid that tumor cells and CAFs use to sustain their cellular fitness. We have previously shown that both PDAC cells and CAFs stimulate macropinocytosis as an adaptive response to glutamine depletion. How these linked metabolic mechanisms might co-operate to control stromal architecture remains elusive. In this study, we employed glutamine starvation and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), a selective inhibitor of macropinocytosis, to investigate how metabolic stress impacts the tumor microenvironment. We find that concomitant suppression of glutamine metabolism and macropinocytosis synergizes to drive an intrinsic inflammatory CAF phenotype that requires metabolic stress-induced ERK/MAPK signaling. Utilizing immunocompetent syngeneic mouse models of PDAC, we find that blocking macropinocytosis in these glutamine-depleted tumors diminishes tumor growth and reorganizes the tumor stroma by decreasing collagen deposition, increasing vasculature expansion and enhancing the infiltration of both CD8+ and CD4+ T cells. Alterations in the stromal landscape under these conditions are linked to the enhancement of CAFs that display an inflammatory signature while simultaneously suppressing more myofibroblastic identities within the tumor. Interestingly, we find that these effects on the tumor microenvironment can be harnessed to improve therapeutic responses. We determine that combining macropinocytosis inhibition with immune checkpoint blockade reduces PDAC tumor burden and significantly inhibits metastasis. We also find that macropinocytosis inhibition enhances drug delivery, thereby improving the efficacy of gemcitabine chemotherapy. Our findings demonstrate that intratumoral metabolic stress plays a critical part in preserving and modulating the tumor stroma. Citation Format: Yijuan Zhang, Swetha Maganti, Jennifer Hope, Li Lin, Cheska Marie Galapate, Florent Carrette, Linda Bradley, Cosimo Commisso. Metabolic stress induces an intrinsic inflammatory CAF phenotype that regulates stromal architecture in 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 3155.
Abstract 3257: Unleashing immune power: How mRNA-encoded modulators suppress tumor growth
Authors: Dong Wang, zhixiang zhang, peili wang, binbin duan, xiangnan qiang, qingyang gu
Journal: Cancer Research (2024)

Abstract Subsequent to the emergence of the COVID-19 pandemic, an increased number of nucleic acid-based therapeutics have secured clinical endorsement. Unlike conventional protein-targeted therapies, nucleic acid therapeutics provide the potential for long-lasting effects and can be further categorized into oligonucleotides, single-guide RNA (sgRNA), and messenger RNA (mRNA). In this study, we aim to explore the anti-tumor properties of mRNA-encoded CD3-EpCAM Bispecific Antibody (BsAb) and mRNA-encoded IL-12 protein. We conducted qPCR, flow cytometry, and ELISA analysis to assess the dynamic concentration of mRNA-encoded CD3-EpCAM BsAb and mRNA-encoded IL-12 protein within tumor cells post-transfection. We then accessed their effects on anti-tumor and immune activation in vitro via flow cytometry and ELISA. Furthermore, using in vivo imaging system (IVIS), we were able to determine the biodistribution of mRNA-encoded BsAb in vivo. Efficacy was evaluated in subcutaneous tumor xenograft models with mRNA content in tumors examined via qPCR. Moreover, we analyzed the activation of tumor-infiltrating immune cells post mRNA-encoded IL-12 treatment. Finally, to ascertain the preliminary safety of mRNA-encoded BsAb and mRNA-encoded IL-12 protein, we conducted serum biochemistry analysis and histopathological examination of various organs. In this comprehensive preclinical evaluation, we found that both mRNA-encoded BsAb and mRNA-encoded IL-12 promoted the activation and cytotoxicity of human T cells, exhibiting significant inhibitory effects on tumor growth in vivo while maintaining a favorable safety profile. Our findings provide compelling evidence that mRNA therapeutics hold significant research value and exhibit promising potential for clinical applications. Citation Format: Dong Wang, zhixiang zhang, peili wang, binbin duan, xiangnan qiang, qingyang gu. Unleashing immune power: How mRNA-encoded modulators suppress tumor growth [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 3257.
Abstract 5569: Mechano-chemical control of secretory cues regulating immune tolerance, survival and invasion in oral squamous cell carcinomas
Authors: Bethany R. Bareham, Matthew Dibble, Leila Mouhib, Aitor Bermejo Arteagabeitia, Subhankar Mukhopadhyay, Maddy Parsons
Journal: Cancer Research (2024)

Abstract Tissue fibrosis and extracellular matrix (ECM) stiffening have been shown to promote tumor cell proliferation, metastasis, and chemoresistance in a range of cancers. Stiffness of the ECM can lead to changes in cancer cell behavior, including enhanced proliferation, activation of mechano-sensitive signaling pathways, and potential genomic damage, with implications for cancer progression and immune responses. Recent research suggests stiff matrix may also induce the release of tumor-derived small extracellular vesicles (sEVs) that promote tumor growth. Tumor-derived sEVs carry bioactive cargo, such as micro-RNAs (miRNAs) and DNA fragments, and function as a unique form of intracellular communication promoting cell survival, growth, and metastasis. Understanding these mechano-sensing mechanisms is essential for identifying potential targets in precision medicine for solid tumor treatment. However, the influence of tumor stiffness on secretory cues, and their subsequent role in immunomodulation and/or chemo-resistance has not been extensively studied. This project aims to explore how tumor stiffness can alter cell responses to genotoxic stress and how these responses can perpetuate feedback to the immune system through the release of secretory cues such as sEVs. Here, we outline the isolation and characterization of tumor-derived sEVs obtained from culture media of oral squamous cell carcinoma (OSCC) spheroids, cultured at varying stiffness (0.2kPa-1.5kPa). In this project, we use OSCC lines that are either sensitive or resistant to cisplatin (HSC-3 and HN-5, respectively). To explore the immunomodulatory effects of these tumor-derived sEVs, we first established a consistent supply of CD206+ve macrophages differentiated from human induced pluripotent stem cells (iMacs), following the established protocol of Douthwaite et al (2021). iMacs were then treated with sEVs with their resulting immunophenotype, and activation assessed. These preliminary experiments provide a step towards understanding how the biophysical environment influences tumor cell resistance to therapy and how sEVs can modulate the relationship between cancer cells and macrophages. Citation Format: Bethany R. Bareham, Matthew Dibble, Leila Mouhib, Aitor Bermejo Arteagabeitia, Subhankar Mukhopadhyay, Maddy Parsons. Mechano-chemical control of secretory cues regulating immune tolerance, survival and invasion in oral squamous cell carcinomas [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 5569.
Abstract 4052: Neutrophil recruitment and activation promotes cutaneous adverse effects with T cell immunotherapies
Authors: Daniel Hirschhorn, Lukas Kraehenbuehl, Sadna Budhu, Valeria Estrada Navarro, Levi Mark B Mangarin, Yacine Marouf, Jacob Ricca, Billel Gasmi, Olivier De Henau, Yanyun Li, Czrina Cortez, Hamadene Linda, Isabell Schulze, Cailian Liu, Katherine Panageas, Mario Lacuoture, Gabrielle A. Rizzuto, Mikala Egeblad, Jedd D. Wolchok, Taha Merghoub Merghoub
Journal: Cancer Research (2024)

Abstract Immune-based therapies that induce tumor regression are often accompanied by immune-related adverse events (irAEs) which can occasionally present with severe and lethal symptoms. Currently, there are no well-defined preventative approaches to uncouple anti-tumor immunity from irAEs. Currently approved immunotherapies include agents that activate T cell responses, such as antibodies blocking immune checkpoints and infusion of tumor-derived, T cell receptor-transgenic or chimeric antigen receptor-modified T cells. While the beneficial and toxic effects of T cell-based therapies in the clinic are being extensively explored, the precise mechanisms underlying their activity remain the subject of investigation. In this study, we treated preclinical models of established melanomas with tumor-specific adoptive CD4+ T cell transfer in combination with T cell co-stimulation via OX40 agonism or CTLA-4 blockade. We found that, despite adequate T cell stimulation, acute local inflammation plays an important role in tumor elimination and the manifestation of irAEs. While stimulated T cells are necessary for initiating a therapeutic response, activation of endogenous neutrophils constitutes an important and necessary effector mechanism for both tumor destruction and the development of irAEs. Extensive neutrophil extracellular traps (NETs) were associated with irAEs. Furthermore, melanoma patients treated with immune checkpoint blockade with skin rashes equivalent to irAEs found in mice showed increased survival and NETs in biopsies from both rashes and tumors. Our results bring forward a novel paradigm where T cells prime an anti-tumor immune response that is followed by an inflammatory effector mechanism provided by the innate immune system, resulting in both curative and undesirable side effects in mice and patients. Citation Format: Daniel Hirschhorn, Lukas Kraehenbuehl, Sadna Budhu, Valeria Estrada Navarro, Levi Mark B Mangarin, Yacine Marouf, Jacob Ricca, Billel Gasmi, Olivier De Henau, Yanyun Li, Czrina Cortez, Hamadene Linda, Isabell Schulze, Cailian Liu, Katherine Panageas, Mario Lacuoture, Gabrielle A. Rizzuto, Mikala Egeblad, Jedd D. Wolchok, Taha Merghoub Merghoub. Neutrophil recruitment and activation promotes cutaneous adverse effects with T cell immunotherapies [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 4052.
Abstract 3710: Determining the efficacy of blood filtration in patients diagnosed with pancreatic cancer through the liquid biopsy
Authors: Divya D. Suresh, George Courcoubetis, Emmeline Lin, Jeremy Mason, Nicholas Nissen, Srinivas Gaddam, Simon Lo, Stephen Pandol, Peter Kuhn, Stephanie Shishido
Journal: Cancer Research (2024)

Abstract Cancer becomes lethal as it spreads from the primary site to the rest of the body. Circulating tumor cells (CTCs) are considered a marker of disease progression and have been associated with decreased overall survival. Blood filtration is one such method of removing cancer cells from circulation to improve patient prognosis. This study utilizes the liquid biopsy to assess the efficacy of a proprietary filtration device on the blood of patients with pancreatic ductal adenocarcinoma (PDAC) using the third generation high-definition single cell assay (HDSCA3.0) workflow. Blood samples were collected and analyzed to characterize the CTCs and other rare cells present before and after filtration. Examination of 6 paired portal (PoVB) samples demonstrated a statistically significant decrease in total rare cells, total CK+ cells, and epi.CTCs across all patients due to filtration of the blood. Furthermore, analysis of 2 paired peripheral blood (PB) samples showed a decrease in total rare cells, total CK+ cells, and specific phenotypes of rare cells upon filtration. These preliminary results demonstrate initial proof of concept that this filtration device can remove CTCs from the circulation, which may be used as a potential therapeutic device for PDAC patient care. Citation Format: Divya D. Suresh, George Courcoubetis, Emmeline Lin, Jeremy Mason, Nicholas Nissen, Srinivas Gaddam, Simon Lo, Stephen Pandol, Peter Kuhn, Stephanie Shishido. Determining the efficacy of blood filtration in patients diagnosed with pancreatic cancer through the liquid biopsy [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 3710.
Abstract 5756: Silver graphene quantum dots as drug delivery platforms for anti-cancer application
Authors: Rafael A. Villanueva, Tori Cole, Nataniel Medina, Dr. Gerardo Morell, Brad Weiner
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) stands as the most frequently diagnosed cancer and the third leading cause of cancer-related deaths among men in the United States (2019). Various cancer treatments, including Rehabilitation therapy, Immunotherapy, Hormone therapy, Stem Cell Therapy, and Chemotherapy, are available. However, chemotherapy has notable limitations due to its tendency to harm healthy cells, resulting in side effects such as nausea, vomiting, alopecia, diarrhea, anemia, bleeding, and sterility. In response to these challenges, we developed nanoparticle (NP) drug delivery platforms for cancer treatment. These platforms utilize silver graphene quantum dots nanocomposites (AgGQD), known for their ability to enhance drug therapies. Silver nanoparticles (AgNPs) exhibit toxicity towards both normal and cancer cells by impacting mitochondrial function, reactive oxygen species (ROS) production, lactate dehydrogenase (LDH) release, cell cycle dysregulation, induction of apoptotic genes like Bax, micronucleus formation, chromosome aberration, and DNA damage. Additionally, AgNPs demonstrate antiangiogenic and antiproliferative properties by inhibiting PI3K phosphorylation of Akt, disrupting the signaling pathway, ultimately halting angiogenesis, depriving cells of oxygen, and causing tumor cell death. To mitigate the toxicity of AgNPs in healthy cells and enhance their performance as drug delivery platforms, graphene quantum dots (GQDs) were introduced in this study. Moreover, GQDs may contribute to improving the solubility of drugs with low water solubility. The NPs were synthesized using graphene quantum dots as reducing agents. The study involved identifying the IC50 value, conducting validation tests on AgGQD and AgGQD doped, and comparing their toxicity on cells. Confocal microscopy was employed to identify the intracellular location of the drug. Citation Format: Rafael A. Villanueva, Tori Cole, Nataniel Medina, Dr. Gerardo Morell, Brad Weiner. Silver graphene quantum dots as drug delivery platforms for anti-cancer application [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 5756.