bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C026: TGF-β induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis
Authors: Wang Zhenghan , Elbanna Yassmin , Godet Inês , Peters Lila , Lampe George , Chen Yanyan , Xavier Joao , Huse Morgan , Massagué Joan 
Published: November 2024

Abstract
Epithelial-to-mesenchymal transition (EMT) plays important roles during development, injury repair, cancer invasion and metastasis. The heterogeneity of EMT programs is manifest in the diverse EMT-like phenotypes occurring during tumor progression. However, little is known about the mechanistic basis and functional role of specific forms of EMT in cancer. Here we address this question in lung adenocarcinoma (LUAD) cells that enter a dormancy period in response to TGF-β upon disseminating to distant sites. Through in vivo selection, we established dormant metastasis models from human and mouse early-stage LUAD cell lines. LUAD cells with the capacity to enter dormancy are characterized by expression of SOX2 and NKX2-1 primitive progenitor markers, whereas cells derived from overt metastases express high level of the late-stage progenitor marker Sox9. Using a TGF-β signaling reporter, we showed that in the primitive progenitors, TGF-β induces growth inhibition accompanied by a classic EMT response that subsequently transitions into an atypical mesenchymal state of round morphology as the disseminated cells establish dormancy. Prolonged treatment with TGF-β in vitro recapitulates this transition in these primitive progenitors, but not in the late-stage progenitors. Given this dramatic morphological change, we focused on actin-cytoskeleton regulators and found that TGF-β induces this transition by driving the expression of the actin-depolymerizing factor gelsolin, which changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors, protecting them from killing by mechanosensitive cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Inhibiting this actin depolymerization process clears tissues of dormant metastatic cells. Thus, LUAD primitive progenitors undergo an atypical EMT as part of a strategy to evade immune-mediated elimination during dormancy. Our results provide a mechanistic basis and functional role of this atypical EMT response of LUAD metastatic progenitors and further illuminate the role of TGF-β as a crucial driver of immune evasive metastatic dormancy.
Citation Format: Zhenghan Wang, Yassmin Elbanna, Inês Godet, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué. TGF-β induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant 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 C026.
Abstract C038: Harnessing NK cells to improve targeted therapy therapeutic efficacy in BRAF- mutant melanoma
Authors: Hsu Chia-Hsin , White Andrew C. 
Published: November 2024

Abstract
Malignant melanoma is the most lethal form of skin cancer, with BRAFV600E as the most common driver mutation. Despite the success of BRAF/MEK inhibitors (BRAF/MEKi) as a standard-of-care, drug resistance occurs at high frequency and remains a concern to be overcome. In addition to suppressing cancer cell proliferation and survival, BRAF/MEKi treatment alters the tumor microenvironment to favor anti-tumor immunity, with extensive previous studies focusing on the T cell compartment. Investigating other immune components, such as natural killer (NK) cells, may offer new insights into improving the overall effectiveness of BRAF/MEKi. NK cells are innate immune cells that provide activating signals to cytotoxic T cells, in addition to their critical roles in tumor surveillance and metastasis. However, the role of NK cells as a component of the BRAF/MEKi response in melanoma remains largely unknown. To investigate the role of NK cells in BRAF/MEKi-mediated tumor control, we depleted NK cells in melanoma-bearing mice. We found that the tumors developed full resistance faster in the NK cell-depleted group than in controls. Moreover, quantification of tumor-infiltrating NK cells in different melanoma phases, including off-therapy growth, therapy-induced regression, drug- tolerant residual disease, and on-therapy regrowth and resistance, revealed a positive correlation between NK cell infiltration and the tumor response to BRAF/MEKi. We further increased NK cell infiltration during drug-tolerant residual disease by inhibiting Ptpn22, a potential negative regulator of activity in NK and other immune cell populations, resulting in a delayed onset of therapy resistance. These results demonstrate the indispensable role of NK cells in the BRAF/MEKi tumor response and their potential to improve the therapeutic efficacy of BRAF/MEKi.
Citation Format: Chia-Hsin Hsu, Andrew C. White. Harnessing NK cells to improve targeted therapy therapeutic efficacy in BRAF- mutant melanoma [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 C038.
Abstract C041: MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer
Authors: Murphy Katherine 
Published: November 2024

Abstract
Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8+ T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signaling in vivo led to CD8+ T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC.
Citation Format: Katherine Murphy. MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate 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 C041.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.