bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B026: SIWA318H, a novel advanced glycation end product (AGE) specific antibody, targets cancer and senescent cells in the tumor microenvironment and exhibits potent antitumor activity in a humanized mouse model for pancreatic cancer. [R]
Authors: Rossi Gabriela , Gruber Lewis , Gruber Misty , Han Haiyong 
Published: January 2023

Abstract
The aging-related and cancer cell derived oxidatively stressed tumor microenvironment drives cell senescence. Senescent cells (SCs), in turn, promote immune suppression, tumor progression, and metastasis. Hence, targeting SCs presents an attractive approach for cancer therapy. SIWA318H is a monoclonal antibody that selectively targets an advanced glycation end product biomarker on the surface of dysfunctional cells exhibiting both (a) aerobic glycolysis and (b) oxidative stress. The SIWA318H biomarker is associated with cancer cells, SCs, oxidatively damaged cells, and infected cells. SIWA318H has been shown to bind to an ADCC inducing human IgG FcγR3 receptor as a mechanism of action. SIWA318H exhibits strong binding to pancreatic cancer patient derived xenograft tumors as demonstrated by immunohistochemistry. In an in vivo study using a humanized mouse xenograft model for pancreatic cancer, we showed that treatment with SIWA318H (both high and low dose groups) statistically significantly reduced tumor growth compared to the isotype antibody control group (P &lt; 0.0001). In addition, there was a significantly higher number of mice had complete remission in the treated groups compared to the isotype control group: 37.5% in high dose group (P = 0.0325) and 43.8% in low dose group (P = 0.0143). Moreover, mice treated with 318H had a median overall survival of &gt; 45 days compared to 26 days for the isotype control mice. There was no difference in animal body weight between the SIWA318H-treated mice and the isotype control mice. Immunohistochemical analysis of tumor tissues taken from the in vivo study showed that SIWA318H treatment significantly reduced (a) tumor fibrosis as measured by the area of αSMA+ staining and (b) the number of senescent cells in the tumor stroma as measured by the number of p16INK4a positive cells in αSMA+ areas. In summary, our results demonstrate that SIWA318H is a novel senolytic antibody that exhibits potent preclinical antitumor activity against pancreatic cancer. SWA318H is currently under development for a first in human clinical trial.
Citation Format: Gabriela Rossi, Lewis Gruber, Misty Gruber, Haiyong Han. SIWA318H, a novel advanced glycation end product (AGE) specific antibody, targets cancer and senescent cells in the tumor microenvironment and exhibits potent antitumor activity in a humanized mouse model for pancreatic cancer. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B026.
Abstract IA003: Neuronal Genome Stability and Plasticity
Authors: Nussenzweig Andre 
Published: January 2023

Abstract
The DNA of neurons is continually damaged due to lifelong, high-level metabolic and transcriptional activity. In addition, recent studies have demonstrated extensive “programmed” DNA damage and somatic mutation in differentiating post-mitotic neurons. Here, we identify these endogenous lesions as single strand break intermediates of thymine DNA glycosylase (TDG)-mediated removal of oxidized methylcytosines during active DNA demethylation. Interrupting active DNA demethylation using anti-neoplastic cytosine analogs triggers TDG-dependent neuronal cell death. This suggests that the well-known neurotoxic side effects of certain chemotherapies, also called “chemobrain,” could be linked to DNA repair processes intrinsic to normal neuronal differentiation. In this presentation, we discuss the implications of these findings to neurodegeneration and cancer.
Citation Format: Andre Nussenzweig. Neuronal Genome Stability and Plasticity [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA003.
Abstract IA005: From hematopoiesis to immunity: Delineating the impact of aging on B-cell acute lymphoblastic leukemia progression
Authors: Henry Curtis J. 
Published: January 2023

Abstract
The world’s aging population, those 65 and older, is projected to increase from 703 million people to 1.5 billion people by 2050. This great accomplishment comes with the added obligation of providing adequate healthcare for this vulnerable population given the number of diseases that manifest with age, including cancer. Chronic inflammation is a well-established hallmark of aging, and we have demonstrated that this state compromises hematopoiesis, notably the function of B-progenitor cells. Furthermore, we have shown that aging-associated functional declines in B-progenitor cells can be rescued with the anti-inflammatory cytokine interleukin-37, which also reduces the expression of checkpoint proteins on aged innate immune cells and augments the function of aged lymphocytes. Importantly, interleukin-37-mediated improvements in hematopoiesis and immunity suppress B-cell acute lymphoblastic leukemia (B-ALL) progression and enhance the protective capacity of aged chimeric antigen receptor (CAR) T-cells in murine models of B-ALL. Our results highlight the therapeutic potential of anti-inflammatory agents in treating hematological malignancies and suggest that combining anti-inflammatory cytokine treatment with immunotherapy strategies may represent a novel approach for treating aging-associated blood cancers.
Citation Format: Curtis J. Henry. From hematopoiesis to immunity: Delineating the impact of aging on B-cell acute lymphoblastic leukemia progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA005.
Abstract IA006: Measuring the microbiome: Improving the predictive power of microbiome analysis in cancer outcomes
Authors: Bhatt Ami S. 
Published: January 2023

Abstract
More than 1,000 species of bacteria, archaea, viruses and fungi live in the human gut. Far from being passive passengers, these organisms strongly interact with one another and with their host’s metabolism and immune system. Compelling early experiments have demonstrated associations between the intestinal microbiome composition and obesity, cardiovascular diseases, and certain cancer chemotherapies’ efficacy. Yet teasing apart the mechanisms by which microbes impact host health has been challenging. To accelerate an otherwise challenging, slow and tedious process and to deconstruct mechanisms, we must critically examine our existing “tool kit” for studying the microbiome, and mature our measurement tools to meet these challenges. Our translational laboratory builds and designs observational and interventional clinical cohorts to study. We have also steadfastly worked to develop genomic tools to study strain level dynamics of the microbiome, how microbial genomes change over time and how microbes use hidden “microproteins” to communicate with each other and their human hosts. In this presentation, I will speak about three recent developments in our lab: (1) I will introduce the importance of absolute quantification in microbiome research, and our efforts toward that. This will form the basis of revised estimates of the number of microbial cells in a human body. (2) I will give an overview of a new computational workflow called “Phanta”, which enables simultaneous taxonomic profiling of eukaryotes, bacteria and viruses in a human gut metagenomic sample. (3) I will share unpublished work on how antibiotic exposure negatively impacts cancer outcomes in patients with triple-negative breast cancer.
Citation Format: Ami S. Bhatt. Measuring the microbiome: Improving the predictive power of microbiome analysis in cancer outcomes [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA006.
Abstract PR011: TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation
Authors: Hao Xue , Zhao Bo , Towers Martina , Liao Liping , Tang Hsin Yao , Havas Aaron , Kossenkov Andrew V. , Berger Shelley , Adams Peter D. , Speicher David W. , Zhang Rugang 
Published: January 2023

Abstract
Cellular senescence regulates cancer and tissue aging in part through the secretion of proinflammatory factors known as the senescence-associated secretory phenotype (SASP). For example, sterile inflammation or ‘inflammaging’ is a hallmark of tissue aging. Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and is often upregulated in human cancers. TXNRD1’s role in regulating tissue aging and cancer has been attributed to its enzymatic role in regulating cellular redox. Here we show that TXNRD1 drives the SASP and inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments (CCF) and interacts with cGAS in a senescence status dependent manner, which is required for the SASP. Biochemically, TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune-surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse tumor models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not an inhibitor of its enzymatic activity alone, downregulated inflammaging in several tissues. In summary, our results report TXNRD1 promotes inflammation via activating the innate immune response in a manner depending on its interaction with cGAS but not its enzymatic activity. Our findings have important implications for both tissue aging and cancer.
Citation Format: Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Hsin Yao Tang, Aaron Havas, Andrew V. Kossenkov, Shelley Berger, Peter D. Adams, David W. Speicher, Rugang Zhang. TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR011.
Abstract PR013: BH3 profiling of senescent cancer cells to identify mechanisms of resistance to ABT-263
Authors: Jochems Fleur , MacDonald Julie A. , Baltira Chrysiida , Daniels Veerle , Gooijer Mark de , Tellingen Olaf Van , Letai Anthony , Bernards René 
Published: January 2023

Abstract
Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents. ABT-263 is a broad acting senolytic that targets anti-apoptotic proteins BCL-2, BCL-xL and BCL-W. Our group has shown that ABT-263 has a senolytic effect in most cancer cell lines, but not in all. This raised the question why certain senescent cancer cells undergo into apoptosis after treatment with ABT-263, while others remain refractory. To investigate this, we performed BH3 profiling, a technique that measures apoptotic priming (readiness to undergo into apoptosis) and apoptotic dependencies. We found that BH3 profiling in senescent cells requires specific optimization, and it determines that senescent ABT-263 sensitive cells highly depend on specific anti-apoptotic signaling, while ABT-263 resistant cells did not. Moreover, we found that ABT-263 sensitive cells were more primed to apoptosis compared to resistant cells. Intriguingly, this correlation was already apparent in the parental state. Nevertheless, we found that senescent cells were less primed to apoptosis than their parental counterparts, which was in contrast to what we expected. In conclusion, whether senescent cells will respond to ABT-263 is already determined in the parental state, and they become dependent on anti-apoptotic signaling for their survival. The observation that senescent cells were less primed to apoptosis was surprising, and we intend to further understand how it is possible that senescent cells are less primed to apoptosis, but still sensitive to ABT-263.
Citation Format: Fleur Jochems, Julie A. MacDonald, Chrysiida Baltira, Veerle Daniels, Mark de Gooijer, Olaf Van Tellingen, Anthony Letai, René Bernards. BH3 profiling of senescent cancer cells to identify mechanisms of resistance to ABT-263 [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR013.
Abstract A006: The NALCN channel regulates metastasis and non-malignant cell dissemination
Authors: Rahrmann Eric , Shorthouse David , Jassim Amir , Hu Linda , Ortiz Mariaestela , Mahler-Araujo Betania , Vogel Peter , Paez-Ribes Marta , Fatemi Atefeh , Hannon Gregory , Iyer Radhika , Blundon Jay , Lourenço Filipe , Kay Jonathan , Nazarian Rosaylnn , Hall Benjamin , Zakharenko Stanislav , Winton Douglas , Zhu Liqin , Gilbertson Richard 
Published: January 2023

Abstract
We identify the Sodium Leak Channel Non-Selective Protein (NALCN) as a key regulator of cancer metastasis and non-malignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric (Prom1CreERT2/LacZ;KrasG12D;Trp53Flx/Flx; n=269), intestinal (Villin1-CreERT2;KrasG12D;Trp53Flx/Flx; n=141) or pancreatic adenocarcinomas (Pdx1-Cre;KrasG12D;Trp53Flx/+; n=55) in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice (Villin1-CreERT2;KrasG12D;Trp53Flx/Flx; n=28) with gadolinium–an imaging contrast agent and NALCN channel blocker–similarly increased CTCs and metastasis. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer(Prom1CreERT2/LacZ; n=174), caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumor-bearing animals. These cells trafficked to distant organs to form normal structures including lung epithelium and kidney glomeruli and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer, divorcing this process from tumorigenesis and unmasking a potential new target for anti-metastatic therapies.
Citation Format: Eric Rahrmann, David Shorthouse, Amir Jassim, Linda Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory Hannon, Radhika Iyer, Jay Blundon, Filipe Lourenço, Jonathan Kay, Rosaylnn Nazarian, Benjamin Hall, Stanislav Zakharenko, Douglas Winton, Liqin Zhu, Richard Gilbertson. The NALCN channel regulates metastasis and non-malignant cell dissemination [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A006.
Abstract A013: Loss of MLL3 epigenetic regulator drives metastasis by promoting a hybrid epithelial-mesenchymal transition state
Authors: Cui Jihong , Zhang Chi , Lee Ji-Eun , Bartholdy Boris , Yang Dapeng , Liu Yu , Erler Piril , Galbo Phillip , Hodge Dayle Q. , Huangfu Danwei , Zheng Deyou , Ge Kai , Guo Wenjun 
Published: January 2023

Abstract
Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. However, the mechanisms controlling the induction of hybrid EMT remain poorly defined. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and mesenchymal-epithelial transition, respectively, distinct from other known EMT regulators mediating unidirectional changes. Consequently, MLL3 deletion greatly increased metastasis by enhancing metastatic colonization. MLL3 loss led to increased IFNg signaling, which is required for the induction of hybrid EMT cells and the enhanced metastatic capacity. Mechanically, MLL3 loss enhanced IFNg signaling by increasing H3K27ac intensity in the enhancers of a subset of IFNg response genes in both epithelial and mesenchymal tumor cells. We further showed that MLL3-deficient cells were sensitive to BET inhibition, which effectively suppressed the growth of MLL3-mutant primary tumors and metastases. These results uncovered a key driver of the hybrid EMT state in breast cancer that could be targeted therapeutically.
Citation Format: Jihong Cui, Chi Zhang, Ji-Eun Lee, Boris Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip Galbo, Dayle Q. Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo. Loss of MLL3 epigenetic regulator drives metastasis by promoting a hybrid epithelial-mesenchymal transition state [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A013.
Abstract A018: Phosphorylated nuclear DICER1 promotes open chromatin state and lineage plasticity of lung adenocarcinomas
Authors: Reyes-Castro Raisa A. , Chen Shin-Yu , Seemann Jacob , Arur Swathi 
Published: January 2023

Abstract
DICER1 controls micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) to regulate tumorigenesis of lung adenocarcinomas (LUADs). We discovered that DICER1 is phosphorylated by ERK and nuclear translocated and phospho-DICER1 contributes to tumorigenesis. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. We show that phospho-nuclear DICER1 associates with invasive human LUADs with oncogenic KRAS mutations and promotes late-stage tumor progression in mice with oncogenic Kras mutations. Surprisingly, phosphomimetic DICER1 regulates LUAD progression independent of miRNAs and EMT. Integrating single-cell RNA sequencing, fluorescent in situ RNA hybridization, immunofluorescence, and ATAC-sequencing, in mice,we discovered that phosphomimetic DICER1 generates an open chromatin state in the lung tumor alveolar cells leading to expression of gastrointestinal genes and altered AT2 cell identity. Strikingly, we also observe the gastric gene signature in human LUADs with phospho-DICER1 and KRAS mutations. We propose that phosphorylated nuclear DICER1 regulates chromatin remodeling leading to tumor cell reprogramming which drives lung cancer progression.
Citation Format: Raisa A. Reyes-Castro, Shin-Yu Chen, Jacob Seemann, Swathi Arur. Phosphorylated nuclear DICER1 promotes open chromatin state and lineage plasticity of lung adenocarcinomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A018.
Abstract A036: Juxtacrine signaling between macrophage and cancer cell inhibits radiation-induced ferroptosis in syngeneic colon cancer
Authors: Kim Sang Wha , Chung Hyewon , Seok Seung Hyeok 
Published: January 2023

Abstract
Although radiotherapy (RT) is one of the most common modalities for cancer treatment, radioresistance remains an intractable challenge. RT induces intratumoral infiltration of macrophages for the clearance of injury debris, but rather tumor-associated macrophages confer fitness advantages to cancer cells after RT. Here, we report that tumor-associated macrophage instigates radioresistance by inhibiting RT-induced cell death in a contact-dependent manner. Mechanistically, RT increases receptor tyrosine kinases (RTKs) expression in cancer cells to enable direct interaction with macrophages, resulting in reduced cancer cell ferroptosis triggered by RT. Unbiased RNA-seq analysis of RTK-dependent juxtacrine signaling in macrophages further reveals a profound remodeling of the irradiated tumor microenvironment (TME) via regulation of macrophage polarization and cytotoxic T cell-mediated antitumor responses. Using a syngeneic colon cancer model, we found that ablation of RTK-induced juxtacrine signaling sensitized tumor to RT through increasing cancer cell ferroptosis and impairing macrophages-mediated TME. Collectively, our study supports the RTKs as a new radiosensitizing target via attenuation of the interaction between cancer cells and macrophages during RT.
Citation Format: Sang Wha Kim, Hyewon Chung, Seung Hyeok Seok. Juxtacrine signaling between macrophage and cancer cell inhibits radiation-induced ferroptosis in syngeneic colon cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A036.
Abstract A042: Differences in gain-of-function and inhibitory effects amongst p53 mutants in vivo
Authors: Xiong Shunbin , Chachad Dhruv , Zhang Yun , Gencel-Augusto Jovanka , Sirito Mario , Pant Vinod , Yang Peirong , Sun Chang , Lozano Guillermina 
Published: January 2023

Abstract
The majority of p53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis in vivo, we generated a novel germline p53R245W allele (contact mutation) and compared it to existing p53R172H (structural mutation) and p53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed all three hot-spot mutations exhibited similar inhibitory effects on wild type p53 transcription in vivo and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of p53R245W/+ and p53R270H/+ mice, but not p53R172H/+ mice, was significantly shorter than that of p53+/- mice, demonstrating p53 mutation-specific GOF contributions to tumor development. Furthermore, p53R245W/+ and p53R270H/+ mice had more osteosarcoma metastases than p53R172H/+ mice, indicating that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Omics analyses using RNA-sequencing data from p53R172H/+, p53R245W/+, and p53R270H/+ primary osteosarcomas in comparison to p53+/- indicated GOF was mediated by distinct pathways among the three mutations. Thus, both the inhibitory effect of mutant over WT p53, and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcomas.
Citation Format: Shunbin Xiong, Dhruv Chachad, Yun Zhang, Jovanka Gencel-Augusto, Mario Sirito, Vinod Pant, Peirong Yang, Chang Sun, Guillermina Lozano. Differences in gain-of-function and inhibitory effects amongst p53 mutants in vivo [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A042.