bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C036: Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses
Authors: Fan Jiawei , Qi Sumeng , Shih Ie-Ming , Wang Tian-Li 
Published: November 2024

Abstract
As a critical component of innate and adaptive immunity, macrophages play an important role in shaping the tumor microenvironment (TME), which affects tumor initiation, progression, and response to treatment. Tumor-associated macrophages can display anti-tumor or pro-tumor activity, a cell fate attributed to macrophage polarization that depends on metabolomic regulation. Targeting macrophage metabolism could be a promising approach for cancer treatment by converting a pro-tumor TME into an anti-tumor TME. To examine in vivo mechanisms behind glutamine metabolism on macrophages, we treated immunocompetent murine ovarian cancer models with a clinical-grade glutamine prodrug, JHU083, and performed single-cell RNA sequencing (scRNAseq). In addition to the significant anti-tumor efficacy of JHU083, we found that JHU083 specifically suppressed the M2-like tumor macrophages while sparing M1-like macrophages. To better understand the molecular mechanism of how JHU083 causes macrophage polarization shift, we cultured an M1-like macrophage cell line with DON (6-Diazo-5-oxo-L-norleucine), the active component of JHU083, and performed bulk RNA sequencing. Using bulk RNAseq and scRNAseq transcriptome analyses on M1-like macrophages, glutamine inhibitor treatment significantly enhanced MHC class II genes, including CD74, H2-Aa, H2-Eb1, H2-Ea, H2-Ab1, and TNF family genes including Tnfsf12, and Tnfrsf14 which may promote T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Moreover, DON-treated bone marrow-derived M1 macrophages promoted CD4+ T cell expansion. On the other hand, DON treatment significantly suppressed bone marrow-derived M2 macrophages. In conclusion, our findings suggest that glutamine metabolism reprogramming can promote anti-tumor functions in tumor macrophages. Therefore, targeting glutamine metabolism to regulate macrophage function and polarization can be a promising direction for future cancer therapy.
Citation Format: Jiawei Fan, Sumeng Qi, Ie-Ming Shih, Tian-Li Wang. Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses [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 C036.
Abstract C052: Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents
Authors: Yang Yang 
Published: November 2024

Abstract
High-grade serous ovarian carcinoma (HGSOC) is a very aggressive form of ovarian cancer, contributing to most ovarian cancer deaths. Paclitaxel is one of the major components of the first line treatment for HGSOC, but the development of chemoresistance to paclitaxel leads to the frequent relapse of the disease and poor prognosis in HGSOC patients. However, the mechanism underlying the chemoresistance has not been well established nor have the strategies to overcome the resistance been developed, which was investigated in the present study using three representative HGSOC cell lines (i.e. Kuramochi, OVCAR4, and OVCAR3 cells) in vitro. The results from our study show that induction of senescence contributes to paclitaxel-induced chemoresistance in HGSOC cells. More importantly, we found that senescent HGSOC cells induced by paclitaxel became highly dependent on BCL-xL for survival and thus were very sensitive to BCL-xL targeting agents, particularly to DT2216 (a BCL-xL specific proteolysis targeting chimera or PROTAC) and 753b (a BCL-xL and BCL-2 dual PROTAC). Because these PROTACs are more potent against senescent HGSOC cells but less toxic to platelets than ABT263 (a BCL-xL and BCL-2 dual inhibitor), they have the potential to be developed as new senolytics to overcome HGSOC chemoresistance to paclitaxel without causing the on-target and dose-limiting thrombocytopenia associated with ABT263 treatment.
Citation Format: Yang Yang. Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents [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 C052.
Abstract IA016: Vascular control of metastasis
Authors: Augustin Hellmut G. 
Published: November 2024

Abstract
The molecular analysis of tumor vessel interactions during tumor progression and metastasis has primarily focused on the study of tumor cell-derived angiogenic and lymphangiogenic signals with the purpose to exploit such factors as therapeutic targets. Angiogenic factors activate endothelial cells in nearby blood and lymphatic capillaries to sprout towards the tumor. Tumor angiogenesis thereby not only nourishes the growing tumor, but access to the blood and lymphatic vasculatures enables cells from the primary tumor to enter the circulation to eventually form metastases at distant sites. The complex cellular interactions between tumor cells and endothelial cells have in this context mostly been studied from a tumor cell-centric perspective, i.e., the tumor cells send signals to which endothelial cells merely respond. Yet, the past decade has witnessed a fundamental change of paradigm with the discovery that the vascular endothelium does not just respond to exogenous cytokines but exerts active ’angiocrine’ gatekeeper roles controlling their microenvironment in an instructive manner. We have applied the concepts of angiocrine signaling towards the study of tumor progression and metastasis. Employing novel surgical preclinical metastasis models that better mimic tumor progression and the response to therapy as it occurs in humans, we have molecularly dissected vascular endothelial cells in progressing primary tumors as well as in the pre-metastatic and metastatic niches. These experiments were on the one hand aimed at establishing the systems map of endothelial transcriptomic changes during tumor progression and metastasis and on the other hand to identify and validate novel therapeutic targets. This presentation will review recent advances in the field of tumor microenvironment research and present novel angiocrine signaling mechanisms as promising targets of future mechanism-driven anti-metastatic therapy.
Citation Format: Hellmut G. Augustin. Vascular control of 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 IA016.
Abstract IA025: Targeting the gut microbiome for cancer immunotherapy
Authors: Trinchieri Giorgio 
Published: November 2024

Abstract
Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The impaired response to immunotherapy in patients treated with antibiotics supports this role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analyzed the underlying mechanisms. Gut microbial communities (microbiotypes) with non-uniform geographic distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts Now, a better understanding of the taxonomy of the species involved and of their mechanisms of action has been achieved. Defined bacterial species have been shown to promote a response to immune checkpoint inhibitors through the production of different products or metabolites, although a suppressive effect of Gram(-) bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on patients’ microbiota composition can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, the interest in modulating the microbiota composition to improve patients’ responsiveness to therapy has been mounting. Our data of a fecal microbiota transfer clinical trial in anti-PD1 refractory melanoma patients has provided clinical proof of concept of the possibility to target the gut microbiota composition in cancer therapy. Also, both in clinical studies and in experimental animals, diets rich in fibers improve the response to immunotherapy by modifying the gut microbiome suggesting the possibility of dietary approaches to target the microbiota composition in cancer therapy. However, while many early clinical studies have analyzed the association of the microbiota composition with the response to anti-PD-1 in cancer patients, emerging evidence suggests that the association may be context dependent and different types of mono or combination immunotherapies may be differentially regulated by the microbiota, Thus, a more personalized approach depending original gut microbiota composition of the patients and the type of immunotherapy protocol selected may be necessary for optimal clinical results.
Citation Format: Giorgio Trinchieri. Targeting the gut microbiome for cancer immunotherapy [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 IA025.
Abstract PR001: An immunomodulatory crosstalk between cancer cells and the hepatic microenvironment underlies mutant estrogen receptor-driven breast cancer-to-liver metastasis
Authors: Das Sunny , Donaher Joana Liu , Verhoeven Lisa , Mishra Ranjan , Reinhardt Ferenc , Gupta Sumeet , Li Zheqi , Polyak Kornelia , Weinberg Robert A. 
Published: November 2024

Abstract
While major advancements have been made in treatment of primary tumors in estrogen receptor-positive (ER+) breast cancer, reducing mortality from metastatic breast cancer (mBC) in treated patients who develop endocrine resistance to first line therapies remains an unmet clinical need. Wild-type ER activity or availability of its cognate ligand 17-beta estradiol (E2) are major factors in primary tumor progression, which are lost/reduced due to endocrine treatments, such as use of selective estrogen degraders (SERDs) and aromatase inhibitors (AIs), respectively. Over time, this leads to selection of rare cancer cells bearing point mutations in ESR1, the gene encoding ER-alpha, which become the dominant population at metastatic sites, and such mutations are now recognized as a frequent driver of endocrine resistance and metastasis, especially in patients with advanced ER+ breast cancer who have been heavily pre-treated with AIs. Analyses of clinical samples have shown a statistically significant association enrichment of ESR1 mutations in liver metastases, compared to the primary tumor. Other distant tissues commonly colonized by breast cancer cells, such as bones, lungs, or brain, although prevalent, do not display this strong association. While this might be due to ease of biopsy sampling in the liver compared to other sites, an alternate and intriguing hypothesis is that the liver offers a fertile soil for metastatic colonization by mutant ER-expressing cells, compared to other distant sites, such as lungs. Using a combination of pre-clinical models, we assessed if mutant ER could drive metastatic colonization at distant sites, such as the liver. We have uncovered a novel link between cancer cell-intrinsic immunomodulatory signaling pathways that are specifically upregulated in mutant ER-expressing breast cancer cells, which represents at least one major molecular mechanism underlying the observed liver tropism of mutant ER-associated, endocrine resistant ER+ breast cancer. We show that disseminated, mutant ER-expressing BC cells engage in crosstalk with the liver stromal and immune populations post-extravasation to further fuel metastatic outgrowth.
Citation Format: Sunny Das, Joana Liu Donaher, Lisa Verhoeven, Ranjan Mishra, Ferenc Reinhardt, Sumeet Gupta, Zheqi Li, Kornelia Polyak, Robert A. Weinberg. An immunomodulatory crosstalk between cancer cells and the hepatic microenvironment underlies mutant estrogen receptor-driven breast cancer-to-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 PR001.
Abstract PR003: Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses
Authors: Chhabra Yash , Weeraratna Ashani T. 
Published: November 2024

Abstract
There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear; while biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Dermal fibroblasts are known to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in these fibroblasts can alter the course of melanoma tumor growth, visceral metastasis, and responses to therapy. We find that skin fibroblasts undergo age-mediated sex-differential changes in their proliferation, senescence, ROS production and stress response. We find that aged male fibroblasts drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging promotes sex- dimorphic BMP2 secretion exclusively by aged male fibroblasts, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. Our data provide an integrated view of how host factors such as advancing age and biological sex alter the tumor microenvironment and contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare.
Citation Format: Yash Chhabra, Ashani T. Weeraratna. Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses [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 PR003.
Abstract PR018: Inflammation-induced mechanotransduction is necessary and sufficient to create pre-cancerous squamous lung metaplasias and necessary to drive progression to dysplasia
Authors: Tisty Thea D. , Pan Deng , Gascard Philippe , Caruso Joseph , Ferri Lorenzo , Chen-Tanyolac Chira 
Published: November 2024

Abstract
Chronic exposure to tobacco smoke triggers chronic inflammation, fostering a fibrotic microenvironment and promoting the focal replacement of columnar human bronchial epithelial cells (hBECs) with cells exhibiting squamous morphology, termed metaplasia. How squamous metaplasia progresses to squamous dysplasia and, ultimately, squamous lung carcinoma is under intense investigation. Using human bronchial tissues, we demonstrate that, both in vitro and in vivo, cellular stress associated with chronic inflammation (e.g., oxidative stress, DNA damage) enhances TGF-β signaling and creates a fibroblast state exhibiting upregulated HSP47 expression, driving increased collagen fiber alignment, elevated tissue stiffness, and subsequent activation of YAP-dependent mechanotransduction in adjacent hBECs. These Stress/Tension-producing Instructive Fibroblasts (STIFs) alone were sufficient to induce hBECs to squamous metaplasia, precursors to tumor formation. Furthermore, when tumor suppressor function was compromised in hBECs, STIFs induced dysplastic phenotypes. Mechanistically, STIFs act in a dominant manner modulating epithelial cell identity and malignant phenotypes via extracellular matrix (ECM)-dependent mechanotransduction. Inhibition of HSP47-dependent collagen processing effectively prevented fibroblast-induced squamous metaplasia and dysplasia and was capable of reversing fibroblast-induced metaplasia, restoring bronchial epithelial cell identity.
Citation Format: Thea D. Tisty, Deng Pan, Philippe Gascard, Joseph Caruso, Lorenzo Ferri, Chira Chen-Tanyolac. Inflammation-induced mechanotransduction is necessary and sufficient to create pre-cancerous squamous lung metaplasias and necessary to drive progression to dysplasia [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 PR018.
Figure 3 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells
Authors: Schaaf Zachary A. , Ning Shu , Leslie Amy R. , Sharifi Masuda , Gao Richard Y. , Maine James P. , Lou Wei , Lombard Alan P. , Liu Chengfei , Yu Ai-Ming , Mitsiades Nicholas , Gao Allen C. 
Published: November 2024

<p>Mitochondrial live stain and ETC functional test demonstrate higher function in 2B-OlapR cells. <b>A,</b> Left, MitoTracker staining counterstained with nuclear-specific DAPI reveals higher amounts of relative mitochondrial mass in 2B-OlapR cells over C42B. 10× images shown, with 20× crops within. Right, TCF ratio of MitoTracker to DAPI displaying quantification of relative increased active mitochondria in the resistant cell subline. <b>B,</b> Left, ETCC1 kit assay results express a higher rate of ETCC1 activity in 2B-OlapR cells. Right, Reported rate of change in NAD+ associated absorbance between 300 and 2,000 seconds show significant increased ETCC1 rate in 2B-OlapR cells. <math><mo>*</mo><mo>*</mo><mo>*</mo><mo>,</mo><mo> </mo><mi>P</mi><mo>≤</mo><mn>0</mn><mo>.</mo><mn>001</mn><mo>;</mo><mo> </mo><mo>*</mo><mo>*</mo><mo>*</mo><mo>*</mo><mo>,</mo><mo> </mo><mi>P</mi><mo>≤</mo><mn>0</mn><mo>.</mo><mn>0001</mn></math>.</p>
Refugee Education: Aligning Access, Learning & Opportunity
Authors: Dryden-Peterson Sarah 
Published: November 2024

Abstract
Access, learning, and opportunity are usually conceptualized in a sequential and linear way: with access to school comes learning and with learning comes opportunity. But for most refugee students-and for most marginalized students globally-this model simply does not hold. In settings where students’ mobility and their social, economic, and political rights have massive restrictions, access to school does not translate into learning, and learning does not translate into opportunities. Creating education that enables refugee young people to feel a sense of belonging and prepares them to help build more peaceful and equitable futures requires us to address these misalignments, which are rooted across the ecosystem, from macrolevel geopolitical arrangements to micro-level interactions in classrooms. I pose three questions as central in understanding these misalignments: Who is allowed to be where and for how long? Who is responsible for refugee education? And who can feel a sense of belonging? Answering these questions informs how we might work, through policy and practice, toward alignment.
Educational Equity in Schools in India: Perils & Possibilities
Authors: Joshee Reva 
Published: November 2024

Abstract
India is one of the most diverse nation-states in the world. After gaining independence from Britain in 1947, it adopted a constitution that was based on pluralism, secularism, and egalitarianism. This constitutional vision guided the national education policies until very recently. The current moment in all areas of public policy is being defined by the ruling party's agenda of Hindutva, or Hindu nationalism. In education, the hallmarks of this move have been a rewriting of history to glorify a mythohistoric version of the Hindu past and a call to engage with ancient Indian knowledge systems and traditions. Unfortunately, Hindu nationalism is creating growing rifts between the majority Hindu population and other groups, including Muslims, Christians, and Dalits (formerly known as “untouchables” or “outcastes”). The aim of this essay is to understand what is happening in Indian education and to consider ways to return to an engagement with the constitutional principles of pluralism, secularism, and egalitarianism.
Constructing Effective Civic Education for Noncitizen Students
Authors: Banks Angela M. 
Published: November 2024

Abstract
Primary and secondary education is essential because it not only provides students with critical literacy and numeracy skills, but also, for many students, it begins their civic education. The goals of civic education vary by country, but a consistent goal is to provide students with the knowledge and skills necessary to be productive members of society. Globally, approximately thirty-six million children are living outside of their country of nationality. With the growing number of migrant children, states are facing two challenges to effective civic education. The first is access to schools, and the second is creating a civic education curriculum that effectively prepares all students to participate in society in ways that align with democratic principles and goals. This essay focuses on unauthorized migrant children's access to public schools and argues for civic education to incorporate the exploration of membership boundaries so that students, citizen and noncitizen alike, can study unauthorized migrants' participation in society within the context of membership status. This exploration offers students the opportunity to consider how to better align unauthorized migrants' lived realities with their legal status-and to better realize democracy's promise.
Extricating Sexual Corruption from the Shadow of Anti-Corruption Law: The Imperative for a New Approach
Authors: Williams Sope 
Published: November 2024

Abstract
Sexual corruption is a gendered crime, in which especially women and girls are coerced into providing sexual acts in exchange for access to public services or public opportunities. It has not received sufficient legislative attention, is often partially and inadequately criminalised through a patchwork of laws that ignore the different dimensions of the offence, and its impact on women and girls. This paper examines the legal framework against sexual corruption in South Africa and in several other countries, examining the approaches taken to criminalize sexual corruption and the challenges inherent in these approaches. The paper suggests a new way of defining sexual corruption and proposes a framework for addressing sexual corruption through a dedicated sexual corruption offence and victim-centred reporting infrastructure.