tbuckley/cabot-search huggingface dataset:
Abstract B006: Role of the BAF complex in pancreatic cancer-associated fibroblast function
Authors: Jaye C. Gardiner, Khoa A. Tran, Janusz Franco-Barraza, Edna Cukierman
Journal: Cancer Research (2024)

Abstract Fibroblasts comprise the majority cell type within connective tissue and play an important role in the support and repair of every organ. This homeostatic support occurs via the activation of fibroblasts (e.g. myofibroblasts) that then secrete growth factors, cytokines, and components of the extracellular matrix (ECM) that can further modulate residential cells. It has been demonstrated that cell-derived ECMs (CDMs) alone, generated in vitro, are sufficient to activate or maintain naive fibroblasts depending on the activation status of the fibroblasts that generated the CDM. Using this CDM system, we published that Netrin G1 is a regulator of pancreatic cancer-associated fibroblast (CAF) function that is pathologically expressed, and that its expression is dependent on the ECM. The mechanistic details behind how the ECM regulates fibroblasts’ gene expression to alter its function and activation status, however, is currently unknown. We previously showed that loss of the β5 integrin subunit negatively impacts the ability of pancreatic CAFs to maintain a constitutively activated state and dampens their pro- tumorigenic functions. RNA sequencing of these β5-deficient CAFs showed altered expression of Netrin G1, as well as members of the BAF (BRG/BRM-associated factor) family of chromatin remodelers. The goal of this project is to elucidate the role of the BAF complex in mediating the outside-in signaling from the ECM. To determine the role of the BAF complex on fibroblast activation and function, knockdown (KD) cell lines for the ATP-subunits Brg1 and Brm1 were generated in patient-derived pancreatic CAFs. Akin to β5 KD CAFs, loss of both Brg1 and Brm1 decreased the expression of published TGFβ-dependent markers of pancreatic CAF activation. However, unlike β5 KD CAFs that are unable to generate substantial, aligned CDMs, Brg1 and Brm1 KD CAFs had no effect on matrix deposition or alignment; like Netrin G1 KD CAFs that have decreased pro-tumor functions. Indeed, loss of Brm1 appears to decrease Netrin G1 akin to β5 KD CAFs. Expression levels of Netrin G1 were not restored in β5 nor Brm1 KD CAFs treated with recombinant TGFβ-1 during CDM production, whereas the TGFβ-dependent activation markers were. Collectively, these data begin to suggest that pro-tumorigenic ECM- mediated signaling may alter fibroblast gene expression via the BAF complex in a TGFβ dependent manner, opening the door to epigenetic drug targets as a new therapeutic access point to normalize the tumor-enabling microenvironment in pancreatic cancer patients. Citation Format: Jaye C. Gardiner, Khoa A. Tran, Janusz Franco-Barraza, Edna Cukierman. Role of the BAF complex in pancreatic cancer-associated fibroblast function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B006.
Abstract A007: Emergence of metastasis-initiating cells during lung adenocarcinoma progression
Authors: Jin Suk Park, Yasemin Kaygusuz, Carson Kenum, Mohamed I. Gatie, Lan He, Roshan Sharma, Ronan Chaligné, Abdul G. Khan, Ivo C. Lorenz, Paul J. Balderes, Tuomas Tammela, Anna-Katerina Hadjantonakis, Karuna Ganesh, Charles M. Rudin, Joan Massagué
Journal: Cancer Research (2024)

Abstract Metastatic lung adenocarcinoma (LUAD) is responsible for the most cancer-related deaths worldwide, and only a subset of cells is capable of metastasizing. Our lab has previously shown that these metastasis-initiating cells express the transmembrane glycoprotein called L1CAM and exhibit characteristics of a fetal lung developmental continuum, ranging from early progenitor states to more differentiated states. The exact signal by which progenitor cells with high metastatic potentials are generated remains unknown. Here, we demonstrate that L1CAM facilitates the signaling cascades necessary to initiate and maintain metastasis-initiating cells in LUAD. Mechanistically, L1CAM interacts with the planar cell polarity (PCP) complex and activates the transcription factor c-Jun. Activated c-Jun, as part of the AP-1 complex, binds to enhancer sites of progenitor genes and promotes the emergence of a metastasis-capable progenitor state. Pharmacological ablation of these metastatic progenitor cells by a cytotoxic L1CAM antibody effectively eliminated LUAD metastasis in vivo. Our findings identify a novel L1CAM-mediated mechanism that maintains a progenitor state essential for metastasis and can be targeted therapeutically. Citation Format: Jin Suk Park, Yasemin Kaygusuz, Carson Kenum, Mohamed I. Gatie, Lan He, Roshan Sharma, Ronan Chaligné, Abdul G. Khan, Ivo C. Lorenz, Paul J. Balderes, Tuomas Tammela, Anna-Katerina Hadjantonakis, Karuna Ganesh, Charles M. Rudin, Joan Massagué. Emergence of metastasis-initiating cells during lung adenocarcinoma progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A007.
Abstract A021: HRI inhibition by hemin as a novel targeted therapy for glioblastoma via the integrated stress response
Authors: Xingchuan Ma
Journal: Cancer Research (2024)

Abstract The treatment of glioblastoma (GBM), a highly malignant brain tumor, is critically hindered by the ineffectiveness of current modalities such as surgery, radiation, and chemotherapy. These traditional methods fail to completely remove the tumor mass and lack the ability to discriminate between cancerous and normal brain cells, often resulting in damage to healthy tissue and recurrence of the disease. This underscores an urgent necessity to develop novel therapeutic strategies that can target tumor cells with precision, offering hope for improved survival rates and quality of life for GBM patients. This study investigates targeted therapy, focusing on the Integrated Stress Response (ISR) that cancer cells harness to survive hypoxic stress. Specifically, it demonstrates that EIF2AK1, which encodes Heme-regulated eIF2α kinase (HRI), is activated under hypoxia and co-expressed with the glioma stem cell marker SOX2, which specifically happens in glioma cells, increasing the targeted accuracy of the repurposing drug. This correlation, indicating hypoxia-driven stemness, is confirmed at both the genetic level and through Gene Set Enrichment Analysis (GSEA). Furthermore, GSEA in Spatial Transcriptomics shows hypoxia-induced glycolysis, disrupting the tumor microenvironment and causing necrotic cell death. Stemness phenotype is induced in the peripheral cells due to the unfavorable hypoxic environment. Hemin, an HRI inhibitor, has been repurposed to inhibit ISR and mitigate hypoxia. Treatment with Hemin on the U87 cell line resulted in IC50 values of 23.50 µM and 52.46 µM at 24 and 48 hours, respectively, surpassing Temozolomide's efficacy. A decrease in HRI expression after the Hemin treatment suggests the and ISR activity and, potentially, hypoxia. This would reverse the unfavorable microenvironment so that the stemness phenotype doesn’t spread. Potentially, invasiveness and recurrences of GBM in clinic situation would decrease, thus potentially improving patient prognosis. The therapeutic potential of Hemin is enhanced by its ability to kill glioma cells directly and accurately in the glioma cell in original TME when cells are proliferating with adequate oxygen. Therefore, this study demonstrates the therapeutic potential of repurposing Hemin, an HRI inhibitor, to precisely target hypoxia-induced glioma stem cells in glioblastomas, disrupting the aggressive tumor microenvironment to potentially improve patient prognosis. Citation Format: Xingchuan Ma. HRI inhibition by hemin as a novel targeted therapy for glioblastoma via the integrated stress response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A021.
Abstract A008: Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer
Authors: Charlie Niesen, Nathan Wu, Jonathan Rennhack
Journal: Cancer Research (2024)

Abstract Metastatic disease represents a complex series of interaction between tumors and their surrounding microenvironment. Here we utilize model systems to define organ specific transcriptional signatures present in metastatic seeding. We have identified unique epigenetic programing necessary for the colonization of the liver or the lung by colorectal cancer. We have shown that manipulation of master regulators of these signatures in vitro and in vivo changes the metastatic potential of the tumor. In specific, we have found that native cytokines within the liver and lung are engaged by the metastatic tumor cells to promote this reprograming. In the case of the liver, we have identified hepatocyte released CCL2 acts on metastasizing tumors to promote colonization. Through in vitro and in vivo models, we showed that CCL2 engagement drives upregulation of the transcription factor TCF7 and subsequent enhancer reprograming to promote survival of the metastatic cells in the liver. In the lung, we have identified additional, unique secreted cytokines which lead to the upregulation of other TCF family members. Together this data identifies an important signaling nodes in colorectal cancer. Here we propose a model in which secreted factors by the host organ, such as CCL2, reprogram genes within the tumor cell to promote growth and survival of the metastatic cell in foreign microenvironments such as the lung or liver. Targeting these proteins may kill existing metastatic lesions as well as block new metastases from forming which will be essential in improving the outcomes of patients with oligometastatic and premetastatic disease. Citation Format: Charlie Niesen, Nathan Wu, Jonathan Rennhack. Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A008.
Abstract B020: Lean adipocyte-secreted oxylipin, 9S-HODE, triggers ferroptosis and protects against obesity-accelerated breast cancer
Authors: Meghan Curtin, J. Alan Maschek, Guoying Wang, David Lum, James E. Cox, Keren I Hilgendorf
Journal: Cancer Research (2024)

Abstract Approximately 1 in 8 women will develop breast cancer in their lifetime, and over 40,000 women in the United States die from breast cancer every year. Post-menopausal breast cancer risk and mortality rates are exacerbated by those who are classified as obese, such that a 5-unit increase in body mass index is linked to a 12% increase in risk. The rising rates of obesity make understanding the link between obesity and the incidence, progression, and mortality of breast cancer of high priority. Obesity is marked by an expansion of white adipose tissue, which accounts for 90% of the breast cancer microenvironment. While several studies have identified paracrine factors secreted by obese adipose tissue that promote tumorigenesis, the role that lean adipose tissue plays in breast cancer progression remains underexplored. In this study, I screened the secretome of primary adipocytes isolated from multiple fat pads from both lean and obese mice for the ability to modulate the growth of breast cancer cell lines across multiple different subtypes. I discovered a potent role of lean mammary adipocytes in selectively inhibiting breast cancer cells in vivo and in vitro. This inhibitory function is specific to lean, mammary adipocytes, as the secretomes of obese mammary adipocytes or adipocytes isolated from visceral fat depots do not inhibit breast cancer cell growth. Further, I discovered that the lean mammary adipocytes, but not obese adipocytes, secrete an oxylipin called 9S-HODE, an oxidized metabolite derived from the essential fatty acid linoleic acid. I show that lean adipocytes and 9S- HODE inhibit breast cancer cell growth by triggering ferroptosis. However, normal breast epithelial cells are protected from 9(S)-HODE-induced ferroptosis by transiently growth- arresting and rapidly forming lipid droplets. We propose that lean adipocytes actively inhibit the growth of breast cancer cells by secreting the ferroptosis inducer 9(S)-HODE, and that in patients with obesity, breast cancer is accelerated, at least in part, due to the loss of 9(S)-HODE- mediated tumor suppression. Citation Format: Meghan Curtin, J. Alan Maschek, Guoying Wang, David Lum, James E. Cox, Keren I Hilgendorf. Lean adipocyte-secreted oxylipin, 9S-HODE, triggers ferroptosis and protects against obesity-accelerated breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B020.
Daily or twice daily treatment with topical steroids results in similar responses in eosinophilic esophagitis
Authors: Craig C Reed, Sean S LaFata, Timothy S Gee, Hannah L Thel, Brenderia A Cameron, Angela Z Xue, Akshatha Kiran, Adolfo A Ocampo, Justin McCallen, Christopher J Lee, Stephanie A Borinsky, Walker D Redd, Trevor Barlowe, Rayan N Kaakati, Cary C Cotton, Swathi Eluri, Evan S Dellon
Journal: Clinical Gastroenterology and Hepatology (2024)
Electrospun silk for biomedical applications
Authors: Shufen Dai, Huarun Liang, Mengjia Zhu, Yingying Zhang
Journal: Med-X (2024)

Abstract Electrospinning technology, capable of creating nanofiber-based materials with large specific surface areas and exceptional breathability, has become an important tool in the biomedical field. Silk, as a well-known natural biopolymer, features good biocompatibility, customizable biodegradability, and superior mechanical properties. The conversion of silk into nanofibers via electrospinning allows for the fine-tuning of its properties, thereby enhancing its suitability for a variety of biomedical applications. Electrospun silk not only inherits the natural advantages of silk but also acquires optimized characteristics such as increased surface area, high porosity, and good air permeability. This review article begins by summarizing the latest advances in the rational design and controlled fabrication of electrospun silk. Then, the biomedical applications of electrospun silk in three main areas: health monitoring, regenerative medicine, and personal protection, are reviewed. Lastly, the existing challenges and future perspectives of electrospun silk are discussed. This review aims to highlight the cutting-edge role of electrospun silk in biomedical applications, potentially revolutionizing traditional healthcare into a personalized model. Graphical Abstract
YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix
Authors: Jingchao Bai, Meinan Yan, Yihan Xu, Youhui Wang, Yuan Yao, Peng Jin, Yuhan Zhang, Yang Qu, Liling Niu, Hui Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Tumor-infiltrating regulatory T cells (TI-Tregs) are well-adapted to thrive in the challenging tumor microenvironment (TME) by undergoing metabolic reprogramming, notably shifting from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) for energy production. The extracellular matrix is an important component of the TME, contributing to the regulation of both tumor and immune cell metabolism patterns by activating mechanosensors such as YAP. Whether YAP plays a part in regulating TI-Treg mitochondrial function and the underlying mechanisms are yet to be elucidated. Methods To gain insights into the effect of matrix stiffness on YAP activation in Tregs, alterations in stiffness were performed both in vitro and in vivo . YAP conditional knockout mice were used to determine the role of YAP in TI-Tregs. RNA-seq, quantitative PCR, flow cytometry, lentivirus infection and mitochondrial function assay were employed to uncover the mechanism of YAP modulating mitochondrial function in TI-Tregs. A YAP inhibitor and a low leucine diet were applied to tumor-bearing mice to seek the potential antitumor strategy. Results In this study, we found that YAP, as a mechanotransducer, was activated by matrix stiffness in TI-Tregs. A deficiency in YAP significantly hindered the immunosuppressive capability of TI-Tregs by disrupting mitochondrial function. Mechanically, YAP enhanced mitochondrial OXPHOS by upregulating the transcription of Lars2 (Leucyl-tRNA synthetase 2, mitochondrial), which was essential for mitochondrial protein translation in TI-Tregs. Since Lars2 relied much on its substrate amino acid, leucine, the combination of a low leucine diet and YAP inhibitor synergistically induced mitochondrial dysfunction in TI-Tregs, ultimately restraining tumor growth. Conclusions This finding uncovered a new understanding of how YAP shapes mitochondrial function in TI-Tregs in response to mechanical signals within the TME, making the combined strategy of traditional medicine and diet adjustment a promising approach for tumor therapy.
Inhibition of Cbl-b restores effector functions of human intratumoral NK cells
Authors: Sofia Tundo, Marcel Trefny, Andrijana Rodić, Olivia Grueninger, Nicole Brodmann, Anastasiya Börsch, Clara Serger, Jonas Fürst, Melanie Buchi, Katarzyna Buczak, Alex T Müller, Lisa Sach-Peltason, Leyla Don, Petra Herzig, Didier Lardinois, Viola Heinzelmann-Schwarz, Kirsten D Mertz, Aljaž Hojski, Karin Schaeuble, Heinz Laubli, Marina Natoli, Alberto Toso, Thuy T Luu, Alfred Zippelius, Andrea Romagnani
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background T cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms. However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy. Methods In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types. Results The screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells. Conclusions These findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer.
Uncovering the predictive and immunomodulatory potential of transient receptor potential melastatin family-related CCNE1 in pan-cancer
Authors: Nan Zhang, Hao Zhang, Shuyu Li, Wantao Wu, Peng Luo, Zaoqu Liu, Yu Chen, Zhiwei Xia, Chenshen Huang, Quan Cheng
Journal: Molecular Cancer (2024)

Millions of new cases of cancer are diagnosed worldwide each year, making it a serious public health concern. Developments in customized therapy and early detection have significantly enhanced treatment for and results from cancer. Therefore, it is important to investigate new molecular biomarkers. In this study, we created an efficient transient receptor potential melastatin (TRPM) family members-related TRPM-Score for 17 solid tumors. CCNE1, produced from TRPM-Score, was found to be an exceptional biomarker through several sophisticated machine learning and deep learning computational techniques. TRPM-Score and CCNE1 immunotherapeutic prediction, immunological characteristics, and predictive value were thoroughly assessed. In most cancer types, CCNE1 was a substantially dangerous marker. Additional in vitro tests validated CCNE1's immunomodulatory properties, demonstrating that silencing impeded macrophage movement and decreased PD-L1 expression. Additionally, CCNE1 may accurately predict responses to cancer immunotherapy. These findings indicate that the TRPM family—particularly CCNE1, which is associated with TRPM—is a significant player in the pan-cancer domain and can be utilized as a therapeutic target and prognostic biomarkers, especially in immuno-oncology. The thorough characterization of the TRPM family and the discovery of CCNE1 as a crucial downstream effector mark important developments in our comprehension of pan-cancer biology.
Clinical Presentations and Decreasing Incidence of Melanoma in Pediatric and AYA Patients: 76,108 Cases from a Nationally Representative Cohort
Authors: Bianca E Ituarte, Mitchell A Taylor, Sierra I Thomas, Divya Sharma, Kaeli Samson, Mollie Oudenhoven, Nicole Harter, Erin X Wei, Ashley Wysong
Journal: Journal of the American Academy of Dermatology (2024)
3D‐Printed In Situ Growth of Bilayer MOF Hydrogels for Accelerated Osteochondral Defect Repair
Authors: Kaiqi Qin, Xinyue Huang, Shengfeng Wang, Jiachen Liang, Zengjie Fan
Journal: Advanced Healthcare Materials (2024)

Abstract Repairing osteochondral (OC) defect presents a significant challenge due to the intricate structural requirements and the unpredictable differentiation pathways of bone marrow mesenchymal stem cells (BMSCs). To address this challenge, a novel biomimetic OC hydrogel scaffold is developed that features a structure of soft and hard components. This scaffold incorporates bilayer metal–organic frameworks (MOFs), specifically ZIF‐67 in the upper layer and ZIF‐8 in the lower layer, achieved through an in situ printing process. This configuration enables the spatial and temporal modulation of BMSC differentiation by controlling the release of Co 2 ⁺ and Zn 2 ⁺. The results demonstrate that the bilayer MOF hydrogels significantly outperform hydrogels that either lack MOFs or contain a single type of MOF in enhancing repair outcomes in rabbit models of knee OC defects. The improved regenerative efficacy is attributed to the distinct chondrogenic and osteogenic differentiation cues provided by the bilayer MOFs, effectively guiding BMSCs toward enhanced tissue regeneration. This customizable biomimetic OC hydrogel scaffold not only opens new avenues for innovative therapeutic strategies but also holds great promise for widespread clinical applications.