bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B005: Exploring breast cancer heterogeneity in the context of metastatic tumour microenvironments and therapy resistance
Authors: Gadipally Sreeja Reddy , Berthelet Jean , Lee Samuel C. , Bhuva Dharmesh D. , Roach Michael , El-Saafin Farrah , Bell Caroline , Wu Yunjian , Baloyan David , Ginestier Christphe , Emmanuelle Charafe Jauffret , Davis Melissa , Anderson Robin L. , Martelotto Luciano , Yeo Belinda , Merino Delphine 
Published: November 2024

Abstract
Breast tumors comprise several sub-populations of cells, so-called “clones”, with specific cellular and molecular characteristics. Some cancer clones can be more ‘aggressive’ than others in particular tumor microenvironments (TMEs), contributing to metastatic progression and drug resistance. Understanding the specific genes/pathways deregulated in these aggressive cancer cells is essential for developing new tailored treatment strategies. To accomplish this, we optimized the use of a lentiviral-based barcoding technique (Berthelet, J., et.al., Sci Adv 2021, Serrano, A., et.al., Nat Rev Cancer 2022) where cancer cells from cell lines and patient-derived xenografts are tagged with optical barcodes and transplanted into the mammary fat pads of immunodeficient mice. Upon resection of tumors and collection of metastatic organs at the experimental endpoint, we analyzed clonal fate and fitness using flow cytometry and imaging. The subsequent molecular characterization of individual clones was determined by bulk and single-cell RNA sequencing. We also leverage the use of these barcoded models to investigate the mechanisms of innate and acquired resistance to Sacituzumab Govitecan (SG), a drug recently approved for the treatment of patients with advanced breast cancer. Our studies revealed unique gene signatures and pathways associated with preferential organ tropism (in the lungs, liver and brain TMEs) and SG resistance. This comprehensive analysis, currently validated using autopsy samples and patient databases, will support the design of new predictive markers and targeted therapies for metastatic breast cancer.
Citation Format: Sreeja Reddy Gadipally, Jean Berthelet, Samuel C. Lee, Dharmesh D. Bhuva, Michael Roach, Farrah El-Saafin, Caroline Bell, Yunjian Wu, David Baloyan, Christphe Ginestier, Charafe Jauffret Emmanuelle, Melissa Davis, Robin L. Anderson, Luciano Martelotto, Belinda Yeo, Delphine Merino. Exploring breast cancer heterogeneity in the context of metastatic tumour microenvironments and therapy resistance [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 B005.
Abstract B006: Role of the BAF complex in pancreatic cancer-associated fibroblast function
Authors: Gardiner Jaye C. , Tran Khoa A. , Franco-Barraza Janusz , Cukierman Edna 
Published: November 2024

Abstract
Fibroblasts comprise the majority cell type within connective tissue and play an important role in the support and repair of every organ. This homeostatic support occurs via the activation of fibroblasts (e.g. myofibroblasts) that then secrete growth factors, cytokines, and components of the extracellular matrix (ECM) that can further modulate residential cells. It has been demonstrated that cell-derived ECMs (CDMs) alone, generated in vitro, are sufficient to activate or maintain naive fibroblasts depending on the activation status of the fibroblasts that generated the CDM. Using this CDM system, we published that Netrin G1 is a regulator of pancreatic cancer-associated fibroblast (CAF) function that is pathologically expressed, and that its expression is dependent on the ECM. The mechanistic details behind how the ECM regulates fibroblasts’ gene expression to alter its function and activation status, however, is currently unknown. We previously showed that loss of the β5 integrin subunit negatively impacts the ability of pancreatic CAFs to maintain a constitutively activated state and dampens their pro- tumorigenic functions. RNA sequencing of these β5-deficient CAFs showed altered expression of Netrin G1, as well as members of the BAF (BRG/BRM-associated factor) family of chromatin remodelers. The goal of this project is to elucidate the role of the BAF complex in mediating the outside-in signaling from the ECM. To determine the role of the BAF complex on fibroblast activation and function, knockdown (KD) cell lines for the ATP-subunits Brg1 and Brm1 were generated in patient-derived pancreatic CAFs. Akin to β5 KD CAFs, loss of both Brg1 and Brm1 decreased the expression of published TGFβ-dependent markers of pancreatic CAF activation. However, unlike β5 KD CAFs that are unable to generate substantial, aligned CDMs, Brg1 and Brm1 KD CAFs had no effect on matrix deposition or alignment; like Netrin G1 KD CAFs that have decreased pro-tumor functions. Indeed, loss of Brm1 appears to decrease Netrin G1 akin to β5 KD CAFs. Expression levels of Netrin G1 were not restored in β5 nor Brm1 KD CAFs treated with recombinant TGFβ-1 during CDM production, whereas the TGFβ-dependent activation markers were. Collectively, these data begin to suggest that pro-tumorigenic ECM- mediated signaling may alter fibroblast gene expression via the BAF complex in a TGFβ dependent manner, opening the door to epigenetic drug targets as a new therapeutic access point to normalize the tumor-enabling microenvironment in pancreatic cancer patients.
Citation Format: Jaye C. Gardiner, Khoa A. Tran, Janusz Franco-Barraza, Edna Cukierman. Role of the BAF complex in pancreatic cancer-associated fibroblast function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B006.
Abstract B011: Sensory neurons regulate intracellular and intercellular mitochondrial dynamics in breast cancer cells
Authors: Tiwari Ankit , Wu Yue , Borniger Jeremy C. 
Published: November 2024

Abstract
Crosstalk between cancer and the nervous system regulates tumor progression. These interactions occur at both the local (i.e., within the tumor parenchyma) and systemic (e.g., endocrine signaling) levels. More recent work has determined that cancer cells not only interact with their local environment via secreted molecules, but in some cases, via acquiring proteins or organelles from other cells within the tumor microenvironment (TME). Here, we demonstrate that breast cancer cells acquire mitochondria from neurons. Breast cancer cells with higher metastatic potential acquire more mitochondria in NGF dependent manner compared to the cell line with lower metastatic potential. These results suggest that in addition to their known roles in electrochemical and paracrine signaling, tumor-innervating nerves can also enhance cancer cell fitness via transfer of mitochondria. We are now characterizing the mechanisms underlying this transfer, determining the fate of transferred mitochondria in recipient cells, and defining how transferred mitochondria drive cancer development, progression, and metastasis. Further, sensory neurons at the tumor microenvironment dictate the intracellular mitochondria dynamics affecting morphology and function. The change in mitochondria dynamics enhances cancer cell survival and metastasis, we are uncovering how sensory neuron induced mitochondria dynamics drives tumor progression.
Citation Format: Ankit Tiwari, Yue Wu, Jeremy C. Borniger. Sensory neurons regulate intracellular and intercellular mitochondrial dynamics in breast cancer 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 B011.
Abstract B014: NRF2 regulation of the immune microenvironment in breast cancer
Authors: Ozdemir Yasemin Ceyhan , Alvarez James V. 
Published: November 2024

Abstract
Immune checkpoint inhibitors (ICIs) have emerged as a significant advance in the treatment of various cancer types, including breast cancer, though their efficacy varies widely depending on the cancer subtype and the stage of the disease. Following their initial approval in metastatic triple-negative breast cancer (TNBC), ICIs have shown promising results in other contexts, including early-stage cancers and ER+ and HER2+ subtypes. However, even in advanced TNBC the objective response rate to monotherapy ICI is only ∼20%. These results highlight the need to better understand determinants of ICI response in breast cancer. A detailed, high-resolution definition of the tumor immune microenvironment (TIME) will be critical for predicting and engineering effective responses to ICIs. In previously published work, we and others found that the antioxidant transcription factor NRF2 is constitutively active in breast cancer and is associated with tumor recurrence, metastasis, and poor prognosis. However, the mechanisms through which NRF2 promotes breast cancer progression remain unclear. In the current study, we explore the role of NRF2 in reshaping the TIME and its impact on breast cancer progression using preclinical models, flow cytometry, and transcriptomic analyses. We find that NRF2 is constitutively activated in a subset of human and mouse breast cancers where it functions to suppress inflammatory gene expression. In models of recurrent and metastatic mammary tumors, NRF2 knockdown results in a marked reduction in tumor growth rates. Furthermore, the NRF2 inhibition significantly alters the composition of innate and adaptive immune cell populations within the tumor microenvironment. Cytokine profiling revealed that these immune alterations are associated with increased levels of inflammatory cytokines in NRF2-deficient tumor cells compared to controls. RNA sequencing of tumor cells further supports the observed shifts in the immune landscape associated with NRF2 deficiency. Collectively, our findings demonstrate that the loss of NRF2 impairs tumor growth in part through remodeling the TIME and suggest that NRF2 may be a promising therapeutic target for sensitizing breast cancers to ICIs.
Citation Format: Yasemin Ceyhan Ozdemir, James V. Alvarez. NRF2 regulation of the immune microenvironment in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B014.
Abstract B021: Aneuploidy-associated cohesin RAD21 gains promote immune evasion in prostate cancers
Authors: DeArment Elise G. , Wang Ruoxi W. , Lu Kate , Su Xiaofeng A. , Elliott Andrew , Zorko Nicholas A. , Hwang Justin H. , Su Xiaofeng A. 
Published: November 2024

Abstract
Aneuploidy, characterized by imbalanced chromosome numbers, is a hallmark of cancer and is strongly correlated with lethal progression in prostate cancer. Our recent work identified that gains of chromosome 8q, the most frequently gained chromosome in aneuploidy prostate cancers, drive cancer progression, partially through the cohesin RAD21 gene located on the chr8q24 region. We demonstrated that increased RAD21 expression accelerates lethal progression and oncogenesis in both prostate cancer and Ewing sarcoma by alleviating oncogenic stress during early-stage oncogenesis in both cell line and organoid models. Therefore, we hypothesize that elevated RAD21 levels could enable cancer cells to evade immune surveillance by mitigating oncogenic stress and DNA damage. In this study, we developed isogenic prostate and breast cancer cell culture models with varying levels of RAD21. Using a natural killer (NK) cell co-culture assay, we observed that cells with elevated RAD21 expression were significantly less susceptible to NK-mediated cytotoxicity and exhibited increased survivorship when co-cultured with NK cells. These findings align with publicly available data showing that tumors with high RAD21 levels have reduced NK cell infiltration in prostate cancer. Our results suggest that increased RAD21 expression, commonly associated with chr8q gains, facilitates immune evasion in cancer cells, thereby promoting early-stage oncogenesis. Understanding the role of RAD21 in immune evasion could reveal novel therapeutic strategies targeting immune surveillance mechanisms in prostate cancer.
Citation Format: Elise G. DeArment, Ruoxi W. Wang, Kate Lu, Xiaofeng A. Su, Andrew Elliott, Nicholas A. Zorko, Justin H. Hwang, Xiaofeng A. Su. Aneuploidy-associated cohesin RAD21 gains promote immune evasion in prostate cancers [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 B021.
Abstract B027: ISG15 modulate cancer cell mechanics and metastasis in breast cancer
Authors: Haloul Mohamed , Shah Priya , Pai Vinay , Hossen Faruk , Lee James James , Er Ekrem Emrah 
Published: November 2024

Abstract
Metastasis in breast cancer is a major challenge for prognosis and effective treatment, primarily because cancer cells can create an immune-suppressive microenvironment that supports their progression and spread. The physical properties of cancer cells significantly influence their metastatic potential and their interaction with the environment. Identifying targets that impact both the physical characteristics of cancer cells, and their microenvironment is crucial for tackling metastatic disease. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, is often overexpressed in breast cancer tissues and is associated with poor prognosis, higher tumor grade, and increased invasiveness. Despite these associations, the precise role of ISG15 and its post-translational modification, ISGylation, in cancer cell behavior and interactions with their microenvironment remains unclear. To explore this, we interrogated the biophysical role of ISG15 by using mouse modeling and in vitro loss of function approaches. We utilized whole- body ISG15-deficient mice and conducted a series of experiments to assess the impact of ISG15 on cancer cell properties and their surrounding environment. Our preliminary results indicate that cells lacking ISG15 exhibit altered physical traits, such as increased stiffness and size, which may influence their metastatic behavior. Additionally, targeting ISG15 or disrupting ISGylation enhances the susceptibility of cancer cells to immune cell-mediated destruction. In ISG15- deficient mice, we observed significantly reduced tumor growth and metastasis compared to wild-type controls. These findings suggest that ISG15 modulates critical aspects of cancer cell behavior and their interactions with the microenvironment, contributing to immune evasion and metastatic spread. Our research highlights ISG15 as a promising therapeutic target and provides a foundation for developing new strategies to prevent and treat metastatic cancer
Citation Format: Mohamed Haloul, Priya Shah, Vinay Pai, Faruk Hossen, James James Lee, Ekrem Emrah Er. ISG15 modulate cancer cell mechanics and metastasis in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B027.
Abstract B030: Productive T-cell-mediated immunoediting of developing sarcomas by distinct mechanisms
Authors: Hunt Brian G , Cheung Julie F. , Venkatesan Srividhya , Loza Jennifer L. , Connolly Kelli A. , Wahed Shudipto , Cheng Elaine , Bansal Ishan , Borr Emily , Wei Wei , William Ivana , Fitzgerald Brittany , Joshi Nikhil 
Published: November 2024

Abstract
Immunoediting is the process where developing tumors are shaped by cells of the immune system. Tumors with low immunogenicity are likely to emerge after neoantigen-specific T cells eliminate the most immunogenic cell populations. However, direct interrogation of mechanisms by which this occurs has not possible due to the pre-emergent nature before the disease is verifiably established. By modifying a mouse model of soft-tissue sarcoma where emergent tumors are consistently edited, we developed a system to examine mechanisms underlying how T cells interact with pre-emergent tumor cell populations to suppress tumor emergence. This system involves production of neoantigen-expressing autochthonous tumors with a fluorescent reporter to define neoantigen-expression status of individual cells. Tumors emerge with lower penetrance and delayed onset in T cell-sufficient mice, while every tumor from T cell-deficient mice contain a significant fraction of neoantigen-negative tumor cells. Yet, ∼53% of T cell-sufficient mice never developed, which suggests that neoantigen silencing was necessary, but not sufficient for tumor emergence. Consistent with this, genetic removal of the neoantigen after malignant transformation shows that tumor development is only rescued when neoantigen loss occurs prior to the peak T cell response, occurring around 8 days post transformation. Moreover, clonality studies reveal the presence of T cells reduces the number clones that contribute to tumor emergence down to 1-2 clones per emerged tumor. Mechanistically, blockade of the T cell effector cytokine, IFNgamma, rescues the neoantigen-negative, but not neoantigen-expressing tumor cells, demonstrating that T cells control early tumors via at least two distinct mechanisms: IFNgamma-dependent suppression of neoantigen-negative tumors cells and IFNgamma-independent suppression of neoantigen-expressing cells. Thus, our findings support that neoantigen-negative cells are subjected to cytokine-mediated suppression from T cells responding to the neoantigen-positive population in the pre-emergent tumor microenvironment. This bystander suppression can prevent tumor emergence despite non-homogeneity in neoantigen expression.
Citation Format: Brian G Hunt, Julie F. Cheung, Srividhya Venkatesan, Jennifer L. Loza, Kelli A. Connolly, Shudipto Wahed, Elaine Cheng, Ishan Bansal, Emily Borr, Wei Wei, Ivana William, Brittany Fitzgerald, Nikhil Joshi. Productive T-cell-mediated immunoediting of developing sarcomas by distinct mechanisms [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 B030.
Abstract B036: WEE1 confers resistance to PD-1 blockade via hyperactivation of the AKT signaling pathway
Authors: Lee Hyo-Jung , Kim Suyeon , Cho Eunho , Kim Tae Woo 
Published: November 2024

Abstract
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but resistance limits its clinical effectiveness. Therefore, understanding immune resistance mechanisms and identifying predictive markers are essential. Our transcriptomic analysis of PD-1 blockade-treated patients and non-responsive tumor models identifies WEE1 as a key resistance factor, promoting cancer stem cell (CSC)-like traits and immune resistance phenotypes including low T cell infiltrated into tumor and anti-apoptotic properties to cytotoxic T cells (CTLs). WEE1 drives AKT hyperactivation, enhancing expression of resistance factors such as CYCLIN A which contributes to CSC-like properties, and the anti-apoptotic molecule MCL-1, while also reducing T cell infiltration via CXCL10 downregulation. This signaling axis is conserved across various cancers. Notably, WEE1 inhibition sensitizes tumors to ICB by disrupting these refractory properties and reinvigorating antitumor immunity. These findings underscore the novel role of WEE1 in driving immune resistance and CSC-like characteristics, supporting the use of WEE1 inhibitors as a strategy to overcome resistance to anti-PD-1 therapy.
Citation Format: Hyo-Jung Lee, Suyeon Kim, Eunho Cho, Tae Woo Kim. WEE1 confers resistance to PD-1 blockade via hyperactivation of the AKT signaling pathway [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 B036.
Abstract B047: Understanding the role of cancer-associated adipocytes in breast tumor microenvironment to delineate the relationship between obesity and cancer
Authors: Song Yaechan , Na Hee Ju , Lee Han Woong 
Published: November 2024

Abstract
Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Our results reveal that the activation of YAP/TAZ signaling in CAAs induces adipocyte dedifferentiation and the formation of a malignant TME. The additional deletion of YAP/TAZ significantly led to tumor regression by mitigating adipokine secretion such as Lipocalin2 and TNFα. Furthermore, mice fed a high- fat diet exhibit increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression, highlighting its efficacy against mice with metabolic dysregulation. These findings provide insights into the key mediators of CAA transformation and their significance in developing a TME. Our study extends to the impact of maladaptive adipocytes as a TME component. We gather multi-omics results including single-nucleus RNA sequencing and spatial transcriptomics (Xenium) to identify the CAA population in the peritumoral region. CAAs are found to modulate the TME via interacting with multiple immune cells, especially macrophages. Xenium result visualizes the proximity between CAAs and macrophages, indicating their cellular interaction. Additionally, our in-vitro co- culture system shows that CAAs recruit macrophages more effectively compared to normal adipocytes. Overall, we strive to understand the importance of adipocyte quality in forming a malignant TME and ultimately introduce therapeutic strategies targeting the tumor microenvironment, especially adipocytes.
Citation Format: Yaechan Song, Hee Ju Na, Han Woong Lee. Understanding the role of cancer-associated adipocytes in breast tumor microenvironment to delineate the relationship between obesity and 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 B047.