bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C043: Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs
Authors: Reavis Hunter D. , Tisdale Arwen A. , Maraszek Kathryn E. , Feigin Michael E.
Published: November 2024

The present study sets out to determine how commonly prescribed triazolobenzodiazepines (triazoloBZDs) modulate the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC), and how this can be leveraged therapeutically to improve patient outcomes. PDAC is one of the most lethal cancer subtypes with a 5-year survival rate of ∼13%. The poor prognosis of this disease is, in part, attributable to the dense, fibrotic tumor microenvironment (TME), and lack of durable responses to standard-of-care treatment options. A recent study from our lab reported that over 40% of PDAC patients at Roswell Park are prescribed benzodiazepines (BZDs) to manage anxiety, nausea, and other disease-related side effects. Importantly, survival outcomes in these patients varied in a compound-specific manner, as the usage of the n-unsubstituted BZD lorazepam was associated with poorer outcomes, while usage of the n-substituted triazoloBZD alprazolam was associated with improved progression-free survival. In vitro and in vivo data from the aforementioned study suggested that these findings may be a result of BZD-specific regulation of interleukin-6 (IL6), a proinflammatory cytokine with a known role in PDAC pathogenesis. More specifically, alprazolam-treated cancer-associated fibroblasts (CAFs) exhibited a potent reduction in IL6 transcription and secretion, while lorazepam treatment increased IL6 production. Based on these data, we hypothesized that triazoloBZDs may uniquely reduce intratumoral inflammation to alleviate immunosuppression in PDAC. We now find that triazoloBZDs such as alprazolam suppress the secretion of several proinflammatory cytokines (IL6, CCL2, CXCL12, IL8) by CAFs, the stromal components of the PDAC TME responsible for fibrosis and exclusion of immune infiltrates. Furthermore, we have observed that this phenotype is likely a result of triazoloBZD-mediated inhibition of the platelet- activating factor (PTAFR) signaling cascade. Investigations are currently underway to determine the impact of triazoloBZDs on regulating the immune landscape of the PDAC TME in vivo. Altogether, these findings provide a basis to inform clinical selection of BZDs for symptom management and present a novel therapeutic opportunity to repurpose FDA-approved compounds for treatment of PDAC.

Citation Format: Hunter D. Reavis, Arwen A. Tisdale, Kathryn E. Maraszek, Michael E. Feigin. Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs [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 C043.
Abstract C046: PARP inhibitors as immune modulators in metastatic ovarian cancer treatment
Authors: Vosahlikova Sarka , Holicek Peter , Moserova Irena , Hensler Michal , Mikyskova Romana , Kasikova Lenka , Pasuvka Josef , Drozenova Jana , Mojzisova Katerina , Kovar Marek , McNiesh Iain , Halaska Michael , Rob Lukas , Orsulic Sandra , Reinis Milan , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka Palich
Published: November 2024

Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes.

Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [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 C046.
Abstract C051: Epigenetic reprogramming of brain-infiltrating myeloid cells deters brain metastasis outgrowth
Authors: Yang Shao-Ping , Duan Yimin , Yuan Xiangliang , Zhang Lin , Liu Wendao , Yao Jun , Zhang Patrick , Huse Jason T , Zhao Zhongming , Yu Dihua
Published: November 2024

The unique brain immune microenvironment (BrIME) co-evolves with brain metastasis (BrM) and is marked by immune suppression, posing a significant therapeutic challenge. BrIME is dominated by myeloid cells, with monocyte-derived macrophages (MDMs) comprising nearly half of the tumor-infiltrating leukocytes. Targeting MDMs remains challenging due to their inherent heterogeneity and high plasticity, which are regulated by epigenetic modifiers, including histone deacetylases (HDACs). Yet, the impact of HDAC inhibition in BrIME and its implications for BrM immunotherapy remains unclear. Here, we establish BrM syngenetic model by intracarotid artery (ICA) injection. Immune profiling by mass cytometry (CyTOF) analysis shows that selective class I HDAC inhibitor (HDACi) Entinostat (ENT) significantly enriches inflammatory MDMs in E0771 murine mammary tumor BrM model. Additionally, functional assay with bone marrow-derived macrophages (BMDMs) shows that ENT significantly enhances tumor cell phagocytosis and antigen presentation, increasing the proliferation of antigen-specific T cells in vitro. To test whether HDAC inhibition enhances antitumoral response in the BrIME, we designed a novel sequential treatment: with (1) ENT pre-conditioning the BrIME, (2) low- dose whole brain radiotherapy (LD-WBRT) to release tumor antigen followed by (3) anti-PD1 immune checkpoint therapy (ICT) to reinvigorate tumor-infiltrating. Our result shows that sequential triple treatment demonstrates significant BrM deterrence and induce a specific interferon-responsive MDM subset with robust type I interferon response in single-cell RNA sequencing, correlating with improved ICT clinical outcomes. Our data show that selective HDACi treatment reprograms the suppressive BrIME by steering the BrM-infiltrating MDMs toward immuno-stimulatory status. Sequential triple combinatorial therapy impedes BrM by activating innate and adaptive immunity simultaneously and is well tolerated in the animal model. Our findings highlight the potential of HDACi-mediated epigenetic reprogramming of the BrIME to enhance therapeutic efficacy in treating BrM.

Citation Format: Shao-Ping Yang, Yimin Duan, Xiangliang Yuan, Lin Zhang, Wendao Liu, Jun Yao, Patrick Zhang, Jason T Huse, Zhongming Zhao, Dihua Yu. Epigenetic reprogramming of brain-infiltrating myeloid cells deters brain metastasis outgrowth [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 C051.
Abstract IA009: Modulating amino acid cross talk between cancer and the host to improve diagnosis and therapy
Authors: Erez Ayelet
Published: November 2024

Metabolic rewiring is a significant driver of cancer metastasis and presents a persistent challenge for therapy. Previously, we demonstrated that a high pyrimidine-to-purine ratio promotes tumor proliferation while enhancing the response to immunotherapy. Through a computational screen, we identified PDE5A as a target whose inhibition increases cGMP levels and, hence, could reduce GMP purine levels. We discovered that in addition to affecting the pyrimidine-to-purine ratio in cancers with high PDE5A expression, the PDE5A inhibitor Sildenafil (Viagra) induces the expression of cholesterol biosynthesis genes and metabolites across diverse cancer models. These metabolic shifts in cholesterol metabolism are associated with the accumulation of lipid droplets in the lysosomes and decreased cholesterol availability. Similarly, genetic inhibition of PDE5A using shPDE5A results in lysosomal cholesterol trafficking defects resembling Niemann-Pick disease type C (NPC1). Phenotypically, restricting PDE5A activity significantly inhibits cancer cell migration, invasion, proliferation, and colony formation. Moreover, Sildenafil restricts metastasis in mice and significantly increases survival rates in cancer patients compared to common antidepressants. Our findings position Sildenafil as a potent modulator of cholesterol metabolism in cancer, underscoring its potential use as an anti-cancer therapy. Furthermore, our results highlight the potential therapeutic opportunity in utilizing the host macroenvironment to indirectly rewire cancer metabolism.

Citation Format: Ayelet Erez. Modulating amino acid cross talk between cancer and the host to improve diagnosis and therapy [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 IA009.
Abstract IA013: Stromal and immune plasticity shape the metastatic microenvironment
Authors: Erez Neta
Published: November 2024

Mortality from cancer is almost exclusively due to metastasis to distant organs. Therefore, understanding the biology of tumor metastasis is the most significant challenge in cancer research today. The tumor microenvironment is central in supporting tumor growth. However, the role of the metastatic microenvironment in the multistage process of metastasis is largely unresolved. Since each metastatic microenvironment exerts specific functions that support or oppose colonization by disseminated tumor, understanding distinct organ-specific mechanisms that enable metastatic growth is of crucial importance. Utilizing mouse models of breast cancer metastasis to lungs, brain and bone, combined with clinical data from patients with metastatic disease, we uncover the mechanisms that underlie the early events of metastasis to provide the mechanistic basis for therapeutic targeting to reduce metastatic relapse. Our findings reveal organ-specific co-evolution of stromal and immune cells at distinct metastatic niches, that lead to the formation of an immunosuppressive microenvironment, permissive to metastatic growth. Analysis of human metastasis reveal that these pathways are also operative in human disease. We show that genetic and/or pharmacological targeting of specific nodes in the interactions between stromal and immune cells results in attenuated metastasis and improved survival. Our findings imply that combinatorial therapeutic strategies to target the crosstalk between stromal and immune cells at the metastatic microenvironment may be a promising treatment strategy to inhibit metastatic relapse.

Citation Format: Neta Erez. Stromal and immune plasticity shape the metastatic microenvironment [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 IA013.
Abstract IA014: Unraveling pancreatic tumor defenses: inside the stromal orchestra with the HOST-factor
Authors: Cukierman Edna
Published: November 2024

Dive into how members of the Cukierman lab and their collaborators explore desmoplasia, the dense “shield” around tumors. Discover their groundbreaking 3D model that reveals the intricate “symphony” of fibroblasts and the interstitial extracellular matrix they produce. Learn how these elements impact cancer cells, as well as the function of immune and other tumor microenvironment cells. Central to the lab’s research is the HOST-Factor (Harmonic Output of Stromal Traits), a new tool to measure and eventually modify the microenvironment’s influence on tumors. Don’t miss this opportunity to see how the team is transforming our understanding of pancreatic cancer’s onset, progression, and treatment responses.

Citation Format: Edna Cukierman. Unraveling pancreatic tumor defenses: inside the stromal orchestra with the HOST-factor [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 IA014.
Abstract IA018: Determinants of B cell fate and function in cancer
Authors: Pylayeva-Gupta Yuliya
Published: November 2024

Effector B cell responses in solid malignancies are associated with favorable response to immunotherapy. B cells can amplify anti-tumor immune responses via antibody production, antigen presentation, and pro-inflammatory cytokine release; yet B cells in cancer patients and tumor-bearing mice often fail to support these functions. We have evaluated the contribution of either systemic inflammatory cues or antigenic quality to B cell differentiation and function in cancer. First, we identify dysregulated transcriptional programs activated in pancreatic cancer-associated B cells that promote differentiation of naïve into immunosuppressive B cells and inhibit differentiation of anti-tumor plasma cells. Second, we find that systemic exposure to STING agonists potentiates expansion of immunosuppressive regulatory human and mouse IL35+ B lymphocytes. Finally, using a system where a B cell neoantigen is either soluble or tethered to the surface of cancer cells, we demonstrate that membrane-tethered antigen is sufficient to elicit activation of anti-tumor immunity and reduce tumor growth in a NK cell-dependent manner. Thus, inflammation and quality of antigen impact basic mechanisms governing B cell differentiation and the resulting immune response to solid malignancy with implications for vaccine engineering.

Citation Format: Yuliya Pylayeva-Gupta. Determinants of B cell fate and function in 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 IA018.
Abstract IA019: Regulation of EMT tumor states by stromal cells
Authors: Blanpain Cédric
Published: November 2024

Epithelial-to-mesenchymal transition (EMT) is a reversible process during which epithelial cells lose their epithelial characteristics and acquire mesenchymal features, that are important for tumor initiation, progression, stemness, metastasis, and therapy resistance. Different EMT states, each with distinct functional properties, have been identified across various tumor models. These EMT states reside within specific physical niches, characterized by unique stromal cell populations. Understanding the cellular interactions within the tumor microenvironment (TME) and their influence on EMT could lead to novel therapeutic strategies. To understand how the TME regulates the distinct tumor states, we performed single-cell RNA sequencing of the tumor cells and their TME in mouse cancer models presenting EMT. We identified distinct subsets of cancer-associated fibroblasts (CAFs), macrophages, neutrophils, endothelial cells, pericytes, adipocytes, dendritic cells, mast cells, Schwann cells, and T cells in different tumor types. To unravel how TME-tumor cell interactions regulates EMT, we used different bioinformatic approaches to identify ligand-receptor pairs that are likely to organize the tumor niche and to regulate tumor transition states. In vitro treatment of tumor cells with some of these ligands demonstrated their EMT-promoting effects. These findings provide novel mechanistic insights on the crosstalk between tumor cells and the surrounding TME, that may have important implications for anti-cancer therapy.

Citation Format: Cédric Blanpain. Regulation of EMT tumor states by stromal cells [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 IA019.
Abstract IA027: Age-related stromal changes drive breast cancer tumor progression
Authors: Stewart Sheila A.
Published: November 2024

Age is the single largest risk factor for the development of cancer, but how age impacts the molecular mechanisms that drive cancer remain poorly understood. While it is clear that age-related accumulation of cell autonomous mutations contributes to tumorigenesis, the central role age-related changes in the tumor microenvironment play in the transformation process is becoming more fully appreciated. Underscoring the importance of an aged microenvironment in cancer development are findings that senescent fibroblasts, which accumulate with age, directly stimulate preneoplastic and neoplastic cell growth and tumor progression. Investigations into how senescent fibroblasts promote tumorigenesis revealed that they express a plethora of growth factors, extracellular matrix remodeling enzymes, chemokines, and cytokines collectively referred to as the senescence associated secretory phenotype (SASP). Chemotherapy induces similar changes that can negatively impact a patient’s quality of life. We will discuss how these changes impact tumor progression and therapy-induced bone loss.

Citation Format: Sheila A. Stewart. Age-related stromal changes drive breast cancer tumor 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 IA027.
Abstract PR004: Age-induced chronic accumulation of glucocorticoids drives therapy resistance in lung cancer
Authors: Raizada Devesh , Lazure Felicia , Drapela Stanislav , Sarigul Nadir , Tejero Joanne , Ilter Didem , Da Silva Gomes Ana
Published: November 2024

Non-small cell lung cancer (NSCLC), a highly aggressive cancer, is the leading cause of cancer- related deaths in the U.S. While chemotherapy and targeted therapy are the main treatment modalities in the clinic, many patients do not respond to these treatments. Strikingly, the median age for lung cancer diagnosis is 71. Yet, preclinical and clinical research have largely been skewed towards young mice and patients. Here, we address this gap in knowledge and evaluate if old age affects the response to standard of care NSCLC therapies in KRAS-driven NSCLC. Using human sera from young and old healthy subjects to treat NSCLC cell lines, we show that age-driven circulatory changes are sufficient to drive a state of profound resistance to both chemotherapies as well as KRASG12C targeted therapies. We confirmed the relevance of our findings in vivo, by transplanting cancer cells derived from the K-rasLSL-G12D/+; p53fl/fl genetically engineered mouse model of lung cancer into young and old C57BL/6 mice. Using this model we showed that unlike young lung tumor-bearing mice on chemotherapy, old tumor-bearing mice do not respond to treatment and have a poor prognosis. Mechanistically, we found that old age drives a transcriptional reprogramming that favors drug resistance and identified the glucocorticoid receptor as a major driver of these transcriptional changes. We traced this to an age-induced chronic accumulation of glucocorticoids in circulation and within the tumor interstitial fluid. Chronic treatment with age-relevant concentrations of cortisol alone was sufficient to drive glucocorticoid receptor activation and induce resistance to therapies mirroring the effects of old age. Further supporting a driving role for glucocorticoids in driving age- induced drug resistance, blocking the glucocorticoid receptor genetically or pharmacologically rescues the drug resistance state imposed by old age in NSCLC cells. Lastly, using TCGA patient data we show an inverse correlation between glucocorticoid receptor activation (GR score) and progression-free survival of lung cancer patients. Together, our work demonstrates a role for age-induced glucocorticoids in circulation in promoting therapy-resistance in NSCLC patients and supports the use of therapeutic agents that block the glucocorticoid receptor as a strategy to increase therapy efficacy in NSCLC patients.

Citation Format: Devesh Raizada, Felicia Lazure, Stanislav Drapela, Nadir Sarigul, Joanne Tejero, Didem Ilter, Ana Da Silva Gomes. Age-induced chronic accumulation of glucocorticoids drives therapy resistance in lung 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 PR004.
Abstract PR005: Adiponectin inhibits high-fat diet feeding-induced tumor growth through restoration of anti-tumor activity of exhausted-CD8+ T cells
Authors: Nguyen Kem Thi , Park Hoon Pil
Published: November 2024

There is a growing appreciation that obesity is one of the significant risk factors for the development of various types of cancers. Obesity has been shown to dysregulate the immune system, including alteration of immune population in tumor microenvironments (TME) and dysfunction of immune cells. Recent studies have also indicated that obesity induces dysregulation of hormones and cytokines production by adipose tissue, collectively called adipokines. Among them, downregulation of adiponectin is implicated in various types of diseases related to obesity. In this study, we examined the effect of adiporon, an adiponectin receptor agonist, on high-fat diet (HFD) feeding-induced breast tumor growth, and population and function of immune cells in the tumor microenvironment (TME) of obese mice. Adiporon significantly inhibits HFD-acceleration of breast tumor growth and restores the dysregulation of immune population in TME. In following experiments to elucidate the underlying mechanisms, we also found that treatment with adiporon protects CD8+ T lymphocyte from apoptosis induced by treatment with cancer cell culture media (CM) and palmitic acid (PA), while reducing various features of exhausted T cell, such as downregulation of PD-1 and Tim-3 expression and restoration of cytokine-production in CD8+ T cell. Treatment with globular adiponectin generates essentially similar effects, collectively indicating the positive effects of adiponectin on survival and function of exhausted CD8+ T cells. In addition, we found that stimulation with adiporon increased mitochondrial biogenesis and modulates mitophagy in CD8 + T cell exposed to CM and PA. In summary, adiponectin signaling restores the survival and anti-tumor activity of exhausted CD8+ T cells through modulation of mitochondrial homeostasis.

Citation Format: Kem Thi Nguyen, Hoon Pil Park. Adiponectin inhibits high-fat diet feeding-induced tumor growth through restoration of anti-tumor activity of exhausted-CD8+ T cells [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 PR005.
Abstract PR009: FMRP upregulation in cancer: Implicating FMRP-expressing cancer-associated fibroblasts in immune evasion
Authors: Yucel Simge , Fournier Nadine , Gomez Mireia Blanco , Hanahan Douglas
Published: November 2024

Our research has uncovered a novel and significant role for Fragile-X-mental-retardation-protein (FMRP) in cancer biology, extending its well-established functions beyond neuronal development. In a recent Science publication (Zeng et al., 2022), we demonstrated that elevated FMRP levels drive immune evasion in various murine and human tumors by modulating immune cell subsets, particularly through the suppression of effector T-cells. To further elucidate the mechanisms of FMRP-mediated immune evasion, we investigated its influence on the stromal component of the tumor microenvironment. Single-cell RNA sequencing of pancreatic ductal adenocarcinoma (PDAC) tumors revealed cancer-associated fibroblasts (CAFs) as the primary stromal cell subtype expressing FMRP. Given the crucial roles that CAFs play in tumor progression and therapeutic resistance, we explored whether FMRP expression contributes to the immunosuppressive characteristics of CAFs in PDAC and breast tumors. Our findings reveal that FMRP expression is markedly upregulated in CAFs from both breast and PDAC tumors, in contrast to its absence in naïve fibroblasts from healthy tissues. Knockdown of FMRP in CAFs resulted in substantial changes in their myofibroblastic and inflammatory properties, while overexpression of FMRP in naïve fibroblasts was sufficient to induce a CAF-like phenotype. Notably, FMRP overexpression led to significantly elevated inflammatory CAF (iCAF) and myofibroblastic CAF (myCAF) signatures, highlighting its role as a key pan-CAF regulator that influences both extracellular matrix (ECM) modulation and the secretory phenotype of CAFs. We utilized the full-body knockout (KO) mice model of the Fmr1 gene, which encodes FMRP, to further delineate the functional importance of FMRP expression in CAFs in stimulating an immunosuppressive program in vivo. Through bulk RNA sequencing, we developed an FMRP- associated gene signature for CAFs and applied it to human datasets, where we observed a pronounced increase in FMRP signatures in CAFs from human PDAC and breast tumors, highlighting its translational relevance. In conclusion, our research underscores the pivotal role of FMRP in cancer biology, impacting both the immune and stromal components of the tumor microenvironment. Targeting FMRP, particularly within CAFs, emerges as a promising therapeutic strategy to improve cancer treatment outcomes.

Citation Format: Simge Yucel, Nadine Fournier, Mireia Blanco Gomez, Douglas Hanahan. FMRP upregulation in cancer: Implicating FMRP-expressing cancer-associated fibroblasts in immune evasion [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 PR009.
Abstract PR011: Efferocytic macrophage promotes pancreatic cancer liver metastasis
Authors: Astuti Yuliana , Raymant Meirion , Quaranta Valeria , Clarke Kim , Abudula Maidinaimu , Smith Olivia , Bellomo Gaia , Chandran-Gorner Vatshala , Nourse Craig , Halloran Christopher , Ghaneh Paula , Palmer Daniel , Jones Robert , Campbell Fiona , Pollard Jeffrey , Morton Jennifer , Mielgo Ainhoa , Schmid Michael
Published: November 2024

Pancreatic ductal adenocarcinoma (PDAC) presents a major therapeutic challenge due to its aggressive metastatic behavior. In the liver metastasis microenvironment of PDAC, macrophages are key drivers of tumor progression. Targeting these pro-tumorigenic macrophages requires a deep understanding of the various macrophage populations and the factors influencing their phenotypes. Our study has revealed a distinct subset of macrophages with a pro-tumorigenic phenotype that emerges early in PDAC liver metastasis. We found that the establishment of hepatic metastases triggers local tissue damage, which, through efferocytosis, reprograms macrophages into an immunosuppressive state, thereby facilitating metastasis. Inhibiting efferocytosis pharmacologically prevented the conversion of macrophages, enhanced CD8+ T cell responses, and reduced liver metastasis. These results highlight the role of macrophages in tissue repair processes that promote liver metastasis in PDAC and suggest potential therapeutic targets to hinder its progression.

Citation Format: Yuliana Astuti, Meirion Raymant, Valeria Quaranta, Kim Clarke, Maidinaimu Abudula, Olivia Smith, Gaia Bellomo, Vatshala Chandran-Gorner, Craig Nourse, Christopher Halloran, Paula Ghaneh, Daniel Palmer, Robert Jones, Fiona Campbell, Jeffrey Pollard, Jennifer Morton, Ainhoa Mielgo, Michael Schmid. Efferocytic macrophage promotes pancreatic cancer liver metastasis [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 PR011.
Abstract PR012: KRAS mutation-specific effects on the tumor immune microenvironment drive tumor progression in pancreatic cancer
Authors: Wenger Andrew , Baron Tal , Hissong Erika , Chandiwani Rohit , Dow Lukas , Siolas Despina , Bacchi Katherine , Sun Huanhuan , Hissong Erika , Vega Adrian , Sisso Whitney , Abdilleh Kawther
Published: November 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available and real-world human PDAC datasets and enrichment of dendritic cells and other immune related cell types in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to a unique immunogenic role.

Citation Format: Andrew Wenger, Tal Baron, Erika Hissong, Rohit Chandiwani, Lukas Dow, Despina Siolas, Katherine Bacchi, Huanhuan Sun, Erika Hissong, Adrian Vega, Whitney Sisso, and Kawther Abdilleh. KRAS mutation-specific effects on the tumor immune microenvironment drive tumor progression in pancreatic 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 PR012.
Abstract PR014: DNA associated with EVs is uniquely chromatinized and prevents metastasis by enhancing anti-tumor immunity
Authors: Wortzel Inbal , Kim Han-Sang , Lyden David C.
Published: November 2024

Cells release extracellular vesicles (EVs) loaded with functional biomolecules that facilitate intercellular communication in health and disease. These EVs contain DNA (EV-DNA), mirroring the mutational profile of parental cells, yet the mechanism of DNA packaging onto EVs and its role in diseases like cancer remain unclear. Using advanced imaging and biochemical techniques, we discovered that EV-DNA predominantly resides on the vesicle surface, bound to modified histones. Through genome-wide CRISPR knockout screens in cancer cell lines, we identified immune-related pathways and genes crucial for EV-DNA loading, such as APAF1 and NCF1. In several cancer models, loss of APAF1 reduced EV-DNA packaging, and enhancing metastasis, thus implicating EV-DNA in immune surveillance against cancer spread. We demonstrated that EV-DNA uptake by liver macrophages triggers DNA damage response, altering cytokine production and promoting immune activation in pre-metastatic sites. Moreover, quantifying EV-DNA in colorectal cancer biopsies revealed its potential as a predictive metastatic risk biomarker. Our findings shed light on EV-DNA packaging mechanisms and its significance, suggesting that elevated levels of tumor-derived EV-DNA bolster anti-tumor immunity and inhibit metastasis.

Citation Format: Inbal Wortzel, Han-Sang Kim, David C. Lyden. DNA associated with EVs is uniquely chromatinized and prevents metastasis by enhancing anti-tumor immunity [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 PR014.
Diálogos intermidiáticos em Terra Vermelha: a mediação cultural como ponte criativa intercultural
Authors: Souza Izabela Fernandes de
Published: November 2024

Neste artigo nos aproximamos do processo criativo da peça Terra Vermelha, a partir da proposição de mediação cultural de Diana Pereira (2023), como categoria analítica e prática. Objetivamos compreender o fazer cênico como uma atitude mediadora. Para tanto, faremos uso da análise interpretativa e dos estudos performáticos, coloniais, de gênero, raça e suas intersecções, tendo como referencial as noções de Diana Taylor (2013), que considera as potencialidades práticas e epistemológicas da cultura incorporada e a noção de aquilombamento de Beatriz Nascimento (Ratts, 2006) para pensar o corpo feminino e negro em movimento. O estudo revela que a mediação cultural é uma forma criativa de lidar com a alteridade e contrariar assimetrias sociais.
A empatia e o contágio: as impregnações dos encontros
Authors: Santos Mariana Rosa e Silva
Published: November 2024

Este artigo visa abordar o fenômeno da empatia para atores e espectadores, em diálogo com a ciência, para explicá-la e entender seus mecanismos. Trataremos da empatia cinestésica como contágio gravitacional, apontada por Hubert Godard, gerenciada por músculos que criam um efeito de transporte. Relacionaremos essa empatia com as noções de intercorporeidade propostas por Maurice Merleau-Ponty e faremos reflexões a partir de textos de José Gil a respeito de outro tipo de contágio, que faz a comunicação de inconscientes por meio de corpos espectrais, iniciando ponderações sobre o obsidiar da obra para o artista.
Mediação teatral e a formação da pessoa licenciada em teatro: discussões sobre o caráter ético e sensível do espaço entre cena e público
Authors: Gomes Sidmar Silveira
Published: November 2024

Este texto aborda el tema de la mediación teatral en el contexto de la formación de los licenciados en Teatro. Inicialmente, se esboza una revisión bibliográfica, contextualizando las nociones de mediación teatral a partir de autores como Desgranges, Pupo, Diéguez, entre otros. Posteriormente, con miras a profundizar en el tema en discusión, se plantea un acercamiento a algunos aspectos del pensamiento de Michel Foucault. Vinculado a las reflexiones anteriores, se reporta un proceso artístico-pedagógico en el ámbito de la formación en teatro mediante la propuesta de procesos de mediación teatral. Finalmente, se presenta que las justificaciones de la importancia de abordar la mediación teatral en el camino formativo de los licenciados en Teatro se basan en el campo de su actividad profesional y la importancia de los aspectos éticos y sensibles vinculados a esta función.
A dança dos Orixás: enlaces da performance do sagrado nas artes da cena
Authors: Viecili Raqueli Biscayno , Vieira Marcílio de Souza
Published: November 2024

En las Artes Escénicas, algunos artistas brasileños interpretan la danza de los Orixás, ya sea en la danza, teatro, o en la música o performance, sin trascender el carácter religioso del ritual. Este estudio tiene como objetivo explicar los estudios y probables dualidades de la danza de los Orixás en su forma ritual cuando se realiza en terreiros, y en la forma artística y performativa cuando se realiza con fines artísticos y estéticos. Se abordan combinaciones de significados, percepciones, historias, experiencias, recuerdos de la artista brasileña Juliana D Passos, particularmente en la obra Macumbaria, con conocimientos artísticos provenientes de la Antropología Teatral y los estudios de performance. Se destaca que en las artes rituales y escénicas las bases de la convivencia singular y colectiva son una gran libertad de expresión e interpretación transmitida a través de espectáculos de artes escénicas, como Macumbaria.
Interrogações a quatro mãos
Authors: Pupo Maria Lucia de Souza Barros , Cangussu Ana Beatriz
Published: November 2024

Dos autoras, una estudiante recién graduada y su profesora de Artes Escénicas presentan y discuten experiencias de mediación artística en la 35.ª Bienal de São Paulo. Marcadas por el debate identitario que surge de la exposición, diferentes modalidades de mediación traen a colación desafíos de carácter educativo y estético. Se destacan como temas las expectativas de los mediadores, la relación entre la visita a la Bienal y el aprendizaje escolar, y los intentos dirigidos a la implicación corporal de los visitantes con relación a las obras.
The Psychodidae (Diptera) of Fernando de Noronha, Brazil, with a records overview of volcanic islands fauna
Authors: VIEIRA GABRIEL SANTOS , BRAVO FREDDY , LIMEIRA-DE-OLIVEIRA FRANCISCO , RAFAEL JOSÉ ALBERTINO
Published: November 2024

The family Psychodidae (Diptera) is recorded for the oceanic archipelago of Fernando de Noronha, represented by two genera and three species: Clogmia albipunctata Williston, Psychoda buxoides Quate, P. savaiiensis Edwards, as well as an undetermined species belonging to the tribe Pericomaini. The fauna of Psychodidae in Fernando de Noronha is remarkably inferior to the Brazilian continental fauna, including species known as cosmopolitan due to the introduction into the most varied environments by human action. An identification key for the Psychodidae of Fernando de Noronha is given, and an overview of the records of Psychodidae for volcanic islands worldwide is also provided.
The genus Toyoides Matsumura (Hemiptera: Auchenorrhyncha: Delphacidae): new combination and lectotype designations
Authors: PARK JAEKOOK , JUNG SUNGHOON
Published: November 2024

In this study, we revised the planthopper genus Toyoides Matsumura (Hemiptera: Auchenorrhyncha: Delphacidae) to include three species. The genus Epunka Matsumura be synonymized with Toyoides based on habitus and genital characteristics. The lectotype specimens have been designated for both T. albipennis and T. bilineata comb. n. Morphological information on T. bilineata comb. n. is presented, with photographs of the habitus and male genitalia provided. We have also provided the keys for the identification of related genera and species.
A new species of Cis Latreille (Coleoptera: Ciidae) widespread in Brazil but with similarities to the African fauna
Authors: ROSA-OLIVEIRA AYESSA , BORLINI PAULA VIEIRA , LOPES-ANDRADE CRISTIANO
Published: November 2024

Cis caramelo sp. nov. is described based on specimens collected in the North, Northeast, and Southeast Regions of Brazil. It stands out for being more similar to the species of Cis Latreille from Africa than South America. Cis caramelo sp. nov. fits into the Cis neserorum species-group, being morphologically similar to Cis aster Souza-Gonçalves & Lopes-Andrade, but differing in the presence of a sex patch on the first abdominal ventrite of males and in the morphology of the aedeagus, with a wide tegmen lacking acute tips on the sides and a penis wide and sclerotized at its basal portion, abruptly narrowed and membranous apically. Brief descriptions and images of immatures of C. caramelo sp. nov. are also provided.
Description of a new species of the Loxerebia saxicola (Oberthür, 1876)-complex from Guizhou, Southwest China (Lepidoptera: Nymphalidae: Satyrinae)
Authors: WANG XUE-JIAN , LANG SONG-YUN
Published: November 2024

In this paper, a new species of the Loxerebia saxicola (Oberthür, 1876)-complex, viz. L. zangkena Lang & Wang sp. nov., is described from Guizhou province, Southwest China.
Mutated LRRK2 induces a reactive phenotype and alters migration in human iPSC-derived pericyte-like cells
Authors: Peltonen Sanni , Sonninen Tuuli-Maria , Niskanen Jonna , Koistinaho Jari , Ruponen Marika , Lehtonen Šárka
Published: November 2024

Background

Pericytes play a crucial role in controlling inflammation and vascular functions in the central nervous system, which are disrupted in Parkinson’s disease (PD). Still, there is a lack of studies on the impact of pericytes on neurodegenerative diseases, and their involvement in the pathology of PD is unclear. Our objective was to investigate the molecular and functional differences between healthy pericytes and pericytes with the LRRK2 G2019S mutation, which is one of the most common mutations associated with PD.

Methods

Our study employed pericyte-like cells obtained from induced pluripotent stem cells produced from PD patients with the LRRK2 G2019S mutation as well as from healthy individuals. We examined the gene expression profiles of the cells and analyzed how the alterations reflect on their functionality.

Results

We have shown differences in the expression of genes related to inflammation and angiogenesis. Furthermore, we observe modified migration speed in PD pericyte-like cells as well as enhanced secretion of inflammatory mediators, such as soluble VCAM-1 and MCP-1, in these pericyte-like cells following exposure to proinflammatory stimuli.

Conclusions

In summary, our findings support the notion that pericytes play a role in the inflammatory and vascular changes observed in PD. Further investigation of pericytes could provide valuable insight into understanding the pathogenesis of PD.
Automated image registration of RGB, hyperspectral and chlorophyll fluorescence imaging data
Authors: Bethge Hans Lukas , Weisheit Inga , Dortmund Mauritz Sandro , Landes Timm , Zabic Miroslav , Linde Marcus , Debener Thomas , Heinemann Dag
Published: November 2024

Background

The early and specific detection of abiotic and biotic stresses, particularly their combinations, is a major challenge for maintaining and increasing plant productivity in sustainable agriculture under changing environmental conditions. Optical imaging techniques enable cost-efficient and non-destructive quantification of plant stress states. Monomodal detection of certain stressors is usually based on non-specific/indirect features and therefore is commonly limited in their cross-specificity to other stressors. The fusion of multi-domain sensor systems can provide more potentially discriminative features for machine learning models and potentially provide synergistic information to increase cross-specificity in plant disease detection when image data are fused at the pixel level.

Results

In this study, we demonstrate successful multi-modal image registration of RGB, hyperspectral (HSI) and chlorophyll fluorescence (ChlF) kinetics data at the pixel level for high-throughput phenotyping ofA. thalianagrown in Multi-well plates and an assay with detached leaf discs ofRosa × hybridainoculated with the black spot disease-inducing fungusDiplocarpon rosae. Here, we showcase the effects of (i) selection of reference image selection, (ii) different registrations methods and (iii) frame selection on the performance of image registration via affine transform. In addition, we developed a combined approach for registration methods through NCC-based selection for each file, resulting in a robust and accurate approach that sacrifices computational time. Since image data encompass multiple objects, the initial coarse image registration using a global transformation matrix exhibited heterogeneity across different image regions. By employing an additional fine registration on the object-separated image data, we achieved a high overlap ratio. Specifically, for theA. thalianatest set, the overlap ratios (ORConvex) were 98.0 ± 2.3% for RGB-to-ChlF and 96.6 ± 4.2% for HSI-to-ChlF. For theRosa × hybridatest set, the values were 98.9 ± 0.5% for RGB-to-ChlF and 98.3 ± 1.3% for HSI-to-ChlF.

Conclusion

The presented multi-modal imaging pipeline enables high-throughput, high-dimensional phenotyping of different plant species with respect to various biotic or abiotic stressors. This paves the way for in-depth studies investigating the correlative relationships of the multi-domain data or the performance enhancement of machine learning models via multi modal image fusion.