tbuckley/cabot-search huggingface dataset:
Abstract 858: A functional atlas of cancer mutation-rewired protein interactome networks
Authors: Anjali Agrawal, Daniel McGrail, Nidhi Sahni, S. Stephen Yi
Journal: Cancer Research (2024)

Abstract Somatic mutations in cancer can exert effects on protein-protein interactions (PPIs), leaving some wild-type (WT) interactions perturbed while others unperturbed. The type of PPI perturbations can be used to link the mutation to its phenotypic effects. Here, we apply a technique known as functional variomics to characterize PPI profile changes for around 1,000 cancer missense mutations. Remarkably, our results reveal 5 distinct classes (edgotypes) of mutations: mutations losing PPIs compared to WT (edgetic), gaining PPIs (gain), gaining &amp; losing PPIs (gain/loss), losing all PPIs (quasi-null), and those that do not perturb PPIs (quasi-WT). Notably, gastroenterological cancers have a greater proportion of edgetic mutations, whereas reproductive cancers have a greater proportion of gain edgotype mutations, demonstrating the link between edgotype and cancer type. We further show that more severe cancer stages are associated with interaction-perturbing mutation edgotypes, and the gain/loss edgotype is the most deleterious of all. In addition, pathway enrichment analysis suggests that the edgotypes are predictive of biological effects. For example, mutation edgotypes with loss of interactions are involved in apoptotic process and DNA damage repair, consistent with the expected loss of such functions in cancer. Meanwhile, gain edgotype is linked with cell division and G2/M transition. To our knowledge, this represents the first attempt to perform systematic interactome profiling for cancer mutations. As our results can reveal specific phenotypic attributes and biological functions that are altered for different PPI profiles, our functional platform is important for cancer precision medicine. Our study strengthens the link between genotypes and phenotypes while illustrating the significance of edgotypes in complex disease modeling. Citation Format: Anjali Agrawal, Daniel McGrail, Nidhi Sahni, S. Stephen Yi. A functional atlas of cancer mutation-rewired protein interactome networks [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 858.
Abstract 6797: CCR5/CCL4 axis in lung cancer clinicopathological significance and its therapeutic application
Authors: Santosh K. Singh, Rajesh Singh
Journal: Cancer Research (2024)

Abstract Lung cancer (LC) is the most prevalent type of cancer globally and the leading cause of cancer-related deaths. Based on the histology and type of treatments, LC is divided into small-cells and non-small cell lung cancer (NSCLC) carcinomas, which are more aggressive and less responsive to chemotherapy. Since LC is known to be a highly heterogeneous cell population, treatment is challenging. It has been observed that chemokine receptor-ligand interaction is essential for cancer cells homing to distant sites. Most malignancies, including LC, have established disease status indicators concerning elevated levels of CCL4, a structurally unique chemokine, and its receptor (CCR5). Therefore, treatment strategies that inhibit the LC cell's tumor environment may improve patients' quality of life. However, the CCR5/CCL4 interface in LC invasion and metastasis is poorly understood. In this study, we examined the expression and function of the CCR5/CCL4 axis in the development and invasiveness of LC patient's clinical tissues and cell lines. We conducted immunohistochemistry (IHC) dual staining of CCR5/CCL4 antibodies in LC tissues. Our findings demonstrated significantly (p &amp;lt; 0.001) higher expression of CCR5 and CCL4 in advanced-stage malignant tissues than in normal tissues. The in-vitro analysis of the human LC cell lines NCI-H1437, NCI-H1573, and NCI-H1975 revealed CCL4 activation expressing higher CCR5, determined by immunofluorescence, western blots, flow cytometry, 3D-invasion assay, and RT-qPCR methods. Further, a calcium mobilization assay confirmed the direct interaction between CCR5 and CCL4. However, treating with Maraviroc, a small molecule inhibitor of CCR5, to LC cells blocks their ability to proliferate, demonstrating the crucial role that CCR5-CCL4 chemotaxis plays in LC metastasis. Our findings show both the biological and clinical significance of CCR5 and CCL4 expression, which may serve as potential indicators for metastatic LC. Therefore, inhibiting the CCR5/CCL4 interaction may offer a more effective therapeutic approach for managing the progression of LC. Citation Format: Santosh K. Singh, Rajesh Singh. CCR5/CCL4 axis in lung cancer clinicopathological significance and its therapeutic 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 6797.
Abstract 4267: Inflammation mediated expression of integrin αvβ3 potentiates KRAS driven PDAC oncogenesis
Authors: Ryan M. Shepard, Alejandro D. Campos, Zachary M. Ortega, Hiromi I. Wettersten, Tami Von Schalscha, Sara M. Weis, David A. Cheresh
Journal: Cancer Research (2024)

Abstract Understanding how pancreatic epithelial cells respond to inflammation and why some become tumorigenic and aggressive could identify new methods of early detection and novel therapeutic targets to control disease progression. Here, we leveraged an in vivo model in which mice with pancreas-specific expression of mutant Kras progress from pre-malignant intraepithelial neoplasias (PanINs) to pancreatic ductal adenocarcinoma (PDAC) following caerulein-induced chronic pancreatitis. During the transition from PanINs to PDAC, we observe two classes of neoplastic lesions: classically-described PanIN tubular structures that are highly organized and previously uncharacterized atypical highly disorganized lesions that are marked by robust integrin αvβ3 expression, observations which are consistent with human pancreatitis and PDAC. In vitro, we report that immune-, stroma-, and tumor cell-derived inflammatory cytokines induce β3 expression in a STAT3-dependent manner leading to increased integrin αvβ3. Considering that we previously established αvβ3 as a driver of cancer cell stress tolerance, drug resistance, and a stem-like phenotype, the acquisition of αvβ3 during chronic inflammation may promote tumorigenesis. Indeed, using the spontaneous tumor mouse model and xenograft models of human PDAC, we find that cells with an inability to upregulate β3 during tumor initiation fail to form tumors. These findings implicate integrin αvβ3 as a critical driver of inflammation-mediated pancreatic tumorigenesis. Citation Format: Ryan M. Shepard, Alejandro D. Campos, Zachary M. Ortega, Hiromi I. Wettersten, Tami Von Schalscha, Sara M. Weis, David A. Cheresh. Inflammation mediated expression of integrin αvβ3 potentiates KRAS driven PDAC oncogenesis [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 4267.
Abstract 3199: Nano gelasomes: Novel lamellar metal-protein suprastructures for nucleic acid delivery
Authors: Agasthya Suresh Babu, Dhananjay Suresh, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan
Journal: Cancer Research (2024)

Abstract There is considerable interest in the development of self-assembled charged nanocarriers that form organized, predictable structures to enhance stable packaging and delivery of nucleic acid materials in vivo. However, the synthesis of stably-charged, organized nanostructures is highly challenging, requiring a controlled balance of nanomaterial components, stabilizers, and hydrophobic forces. Herein, we report a significant step forward in the controlled lamellar assembly of a charged complex between ultra-small 2 nm gold nanoparticles and a lipidoid within an organic matrix to form Gelasomes. These spherical suprastructures feature an intricate 3D concentric arrangement with a constant interlayer distance (4nm). The cationic lipidoid within this arrangement aids in the highly efficient packaging of nucleic acid materials in the nanoparticle. To demonstrate the potential biomedical applications of Gelasomes, we have loaded siRNA (AXL or YAP), mRNA (EGFP), or CRISPR components (Cas9 mRNA and guide RNA) and validated their functionality by in vitro or in vivo studies. Gelasomes with AXL siRNA (~20 bp) demonstrated rapid uptake (&amp;lt;2 hrs), successful endosomal escape, remarkable transfection efficiency (99.87 ± 0.04 %), gene downregulation (97 ± 2.8 %), and disassembly within the cell (&amp;lt;24 hrs). In vivo downregulation studies in Lung Cancer PDX (Gelasomes with AXL siRNA) and CDX (Gelasomes with YAP siRNA) models confirm the gene-silencing capability (91% or 38 % respectively) of Gelasomes underscoring their potential in advancing nanomedicine. Similarly, Gelasome loaded with EGFP mRNA (1 kb) showed 47 ± 8.54 % expression efficiency within 48 h of treatment in vitro. We also show the packaging of larger nucleic acids such as CRISPR Cas9 mRNA (5 kb) along with the guide RNA (100 bp) in vitro for generating knockouts, that achieved an editing efficiency of ~6%. Together, the results from this study pave the way for the development of adaptable, biodegradable, and functionally versatile supraparticles for medical applications. Citation Format: Agasthya Suresh Babu, Dhananjay Suresh, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan. Nano gelasomes: Novel lamellar metal-protein suprastructures for nucleic acid delivery [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 3199.
Abstract 3182: Role of Frizzled 7 in melanoma development and metastasis
Authors: Minakshi Nihal, Sheikh A. Umar, An-Bo A. Chang, Nihal Ahmad, Hao Chang
Journal: Cancer Research (2024)

Abstract The frizzled (Fzd) family of proteins are 7-transmembrane G-protein coupled receptors (GPCRs) that transduce signals mainly for Wnt ligands. There are 10 Fzds identified in mammals, and they are involved in multiple cellular and biological functions via signaling through the canonical Wnt/beta-catenin, planar cell polarity, and calcium signaling pathways. Our previous work revealed a pro-metastasis role of Fzd6 in melanoma. This project focuses on Fzd7, a homolog of Fzd6, in melanoma. We found that FZD7 is highly expressed in multiple melanoma cell lines. siRNA knockdown of FZD7 does not affect cell proliferation but significantly reduces cell invasion in A375, Hs294T, and SK-MEL28 cells in vitro. To determine the in vivo role of Fzd7 in melanoma, we generated Fzd7 knockout YUMM1.7 cell lines for xenograft experiments using CRISPR. All three Fzd7 knockout clones showed a significant reduction in primary tumor growth when xenografted in C57BL/6 mice. To determine the potential mechanism of Fzd7 in melanoma growth and invasion, we performed bulk RNA-Seq on the YUMM1.7 knockout cell lines and identified 215 downregulated and 31 upregulated genes (with a fold change of 2, p&amp;lt;0.05). We are in the process of confirming these transcriptional profile changes. Further functional analysis will be performed using gain- and loss-of-function approaches to determine the downstream mechanisms of Fzd7 in melanoma growth and invasion. Citation Format: Minakshi Nihal, Sheikh A. Umar, An-Bo A. Chang, Nihal Ahmad, Hao Chang. Role of Frizzled 7 in melanoma development and metastasis [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 3182.
Abstract 1485: Hallmarks of APOBEC3 mutagenesis in normal, pre-leukemic, and myeloproliferative neoplasm cell populations
Authors: Jane Marie Isquith, Thomas Whisenant, Jessica Pham, Ludmil Alexandrov, Catriona Jamieson
Journal: Cancer Research (2024)

Abstract Changes in gene expression and subsequent editing patterns of APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like) cytosine deaminases have been shown to be present in solid tumor cancer evolution, however, the context specificity and mechanisms by which APOBEC3 enzymes promote cancer initiation and progression require further elucidation, especially in the hematopoietic niche. Building on advanced sequencing data of healthy, pre-leukemic, and myeloproliferative neoplasm patient samples, we seek to uncover normal and malignant patterns of APOBEC3C overexpression in hematopoietic cells. Overexpression of lentiviral APOBEC3C and an editase-mutated APOBEC3C in normal cord blood, healthy bone marrow, and MPN patient hematopoietic stem/progenitor cells (HSPCs) allows us to study the effects of deaminase dysregulation in hematopoietic cells. In addition to APOBEC3, we are exploring the upregulation of adenosine deaminase acting on RNA1 (ADAR1), as we have previously shown that these two innate immune deaminases are synchronously upregulated in the high-risk myelofibrosis (MF) stem cell population compared to normal aged bone marrow. These overexpression studies show novel differential gene expression changes, RNA hyper-editing sites, and DNA mutation signatures induced by APOBEC3 mutagenesis, which can be cross-referenced to gene expression and mutation signatures seen in hematopoietic malignancies and solid tumor cancers. In addition to mutation patterns, the regulation of LINE-1 elements has been shown to be another important function of APOBEC3 enzymes. In these studies, we examine the effects of APOBEC3 overexpression on repetitive element expression in hematopoietic cell populations and have found that there are strong cell type and context patterns across the APOBEC3 family and between cell types within the hematopoietic system. We will use this comprehensive study of APOBEC3 deregulation to uncover predictive biomarkers of malignant transformation. Citation Format: Jane Marie Isquith, Thomas Whisenant, Jessica Pham, Ludmil Alexandrov, Catriona Jamieson. Hallmarks of APOBEC3 mutagenesis in normal, pre-leukemic, and myeloproliferative neoplasm cell populations [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 1485.
Abstract 5941: Small molecule NSC59984 synergizes with PARP inhibitors in BRCA1 wild type ovarian cancer
Authors: Shengliang Zhang, Lanlan Zhou, Leiqing Zhang, Maximilian Pinho-Schwermann, Benedito Carneiro, John Sedivy, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract PARP inhibitors (PARPi) targeting poly (ADP-ribose) polymerase are the first clinically approved drugs designed to apply synthetic lethality in BRCA1 mutant/deficient cancer. However, the treatment can cause reversion of BRCA mutation which results in drug resistance. To explore new strategies to improve antitumor efficacy of PARPi, we applied PARPi in combination with a small molecule NSC59984 for cancer therapy. NSC59984 is a small molecular targeting mutant p53 degradation and activating p73 via ROS-ERK2-MDM2 pathway. The treatments with radiation or hydrogen peroxide showed that NSC59984 enhanced DNA comet tails and gamma-H2AX, correlated to reduction of rad51 foci in cancer cells. These results suggest that NSC59984 impairs DNA damage repair via abrogation of homologous recombination (HR). We further applied the combinational treatment of NSC59984 and PARPi in BRCA1 wild-type ovarian cancer cells and found that NSC59984 synergized with PARPi to reduce cell viability, inhibit colony formation, and increase cell death. The combination treatment enhanced DNA damage and correlated with reduction of BRCA1 at the protein level. These results, taken together, suggest that the induction of BRCAness causes a synthetical lethality with PARPi in BRCA1 wild-type cancer cells. Cell cycle profiling showed that the cells were arrested at the G2/M phase in response to combinational treatment. At the G2 phase arrest, the high doses of the combinational drugs led to cell death via mitotic catastrophe, and the intermediate doses induced cellular senescence defined by senescence phenotypic hallmarks including senescence-associated beta-gal staining and a secretome consistent with senescence-associated secretory phenotype (SASP). Therapy-induced senescence (TIS) in cancer cells is considered as one of the mechanisms of tumor recurrence and drug resistance. To reduce the risk of TIS in treatment, we applied senolytic treatment to target senescent cells in the combinational treatment. The senolytic drug ABT263 treatment eliminated the senescent cancer cells from the combinational treatment. ABT263, NSC59984 + PARPi combinational treatment further reduced cell viability. Our study provides a rationale for small molecular compounds targeting HR deficiency in combination with PARPi to treat BRCA1wild-type ovarian cancer cells, and additional senolytic treatment may be required to limit resistance by removal of the TIS. Citation Format: Shengliang Zhang, Lanlan Zhou, Leiqing Zhang, Maximilian Pinho-Schwermann, Benedito Carneiro, John Sedivy, Wafik S. El-Deiry. Small molecule NSC59984 synergizes with PARP inhibitors in BRCA1 wild type ovarian 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 5941.
Abstract 2014: Tumor glycosylation impacts the efficacy of HER2 targeting therapies
Authors: Ana Ruiz-Saenz, Roos Vincken, Denise Wolf, Veronica Steri, Laura van't Veer, John Martens, Danny Huylebroeck, Mark M. Moasser
Journal: Cancer Research (2024)

Abstract Cancer progression remains a major obstacle to the successful treatment of cancer. In HER2+ breast cancer, targeting therapies against HER2 have revolutionized the treatment landscape. However, predictive factors for response are largely unknown and a significant number of patients develop resistance. An extensive body of work has revealed a plethora of mechanisms of resistance. However, a key aspect of cancer cells has been largely overlooked: their aberrant glycosylation profile. Aberrant glycosylation of proteins is a hallmark in cancer and has been linked to multiple processes such as invasion, angiogenesis and modulation of the immune response. Yet the influence of altered glycosylation on the efficacy of HER2-targeted therapies remains unknown. Therefore, here, we address this question using clinical data, 3D co-culture systems and advanced live microscopy. Bioinformatics analysis of SPY-2 clinical trial data reveals an association of specific glycogenes with response to HER2-targeting therapies in breast cancer patients. We validated these findings in resistance cell models generated in-vitro and in-vivo using gain and loss of function assays. Furthermore, to provide a more relevant cell model system, we implement the use of 3D co-cultures of cancer spheroids and immune cells. Thus, our research addresses a largely unexplored area in cancer biology combining clinical data from tumor biopsies, trastuzumab-resistant cancer cell models and, live imaging of 3D heterotypic cultures. This work holds the potential to identify new markers of response to therapies and highlights the importance of the interplay of cancer cells and their microenvironment on the efficacy of current treatments. Citation Format: Ana Ruiz-Saenz, Roos Vincken, Denise Wolf, Veronica Steri, Laura van't Veer, John Martens, Danny Huylebroeck, Mark M. Moasser. Tumor glycosylation impacts the efficacy of HER2 targeting therapies [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 2014.
Abstract 2696: Tumor organoid and immune cells co-cultures to study myeloid cells-targeting immunotherapy
Authors: Lorenzo Spagnuolo, Francisco Morales-Rodriguez, Alessandra Merenda, Cesar Oyarce, Farzin Pourfarzad, Robert G. Vries, Sylvia F. Boj
Journal: Cancer Research (2024)

Abstract Cancer immunotherapy is one of the main pillars of oncology treatment due to the clinical success of approaches that enhance anti-tumoral T cell responses. Nonetheless, many patients do not benefit from these approaches, highlighting the need to develop novel immunomodulatory strategies. Exploiting the anti-tumor capacity of innate immune cells is a promising approach that can overcome specific limitations of T cell-targeting therapies and complement existing immunotherapies. Still, promising therapeutic developments face hurdles in translating preclinical findings into treatment since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures. Patient-specific organoids are generated from healthy and disease tissues and recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity and morphological and functional traits. To assess the efficacy of therapies that engage innate immune cells, we developed an assay in which organoids derived from colorectal (CRC) or breast cancer patients are co-cultured with PBMC-derived macrophages or monocytes to evaluate the cytotoxic potential of exogenously activated myeloid cells. We tested the ability of macrophages to phagocyte human CRC organoid cells in response to anti-CD47 antibody. The pro-phagocytic function of anti-CD47 was detected by several methods (i.e., flow cytometry, imaging), indicating the platform's suitability to evaluate ADCP-modulating compounds. Moreover, to assess whether our PBMC-organoids co-culture platform is suited to detect monocyte-mediated effects, Lipopolysaccharide (LPS) plus IFN-γ were used to activate monocytes in the co-culture assays. We observed an increase in cytokines secretion (i.e., CXCL10), immune cell activation and organoid killing, indicating that our assay allows the detection of monocyte activation through different types of readouts. In summary, our organoid-immune cell co-culture platform allows to study the response of tumor organoids to innate immune cells, holding significant value for the preclinical development of immunotherapies based on innate immune cells. Citation Format: Lorenzo Spagnuolo, Francisco Morales-Rodriguez, Alessandra Merenda, Cesar Oyarce, Farzin Pourfarzad, Robert G. Vries, Sylvia F. Boj. Tumor organoid and immune cells co-cultures to study myeloid cells-targeting immunotherapy [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 2696.