bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A013: Sex-dependent hematopoietic stem cell aging and leukemogenic potential
Authors: Chen WenYong 
Published: January 2023

Abstract
Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders. But how HSC aging and sex co-influence leukemogenesis is poorly understood. By examining HSC aging in young, aging (75% lifespan) and longevity (110% lifespan) mice in males vs females, we have discovered that aging males have a significantly higher HSC frequency than females, and that male HSC aging is characterized by an expansion of Lin-CD150+SP HSCs and a decrease of Lin-CD150-SP HSCs, whereas females show opposite HSC changes towards aging and longevity. In line with HSC changes, aging males exhibit an increase of white blood cell counts that is primarily driven by increased myeloid cells, whereas aging females shows a decrease of white blood cell counts that is primarily driven by reduced lymphoid cells. To understand leukemogenic potential of aging HSCs in the true setting of organismal aging, we generated the first aging mouse model of chronic myeloid leukemia (CML) induced by BCR-ABL1 (Oncogene, 2021, 40: 3152-3163). We found that aging male HSCs are significantly more susceptible to BCR-ABL1 transformation and CML induction in aging male mice than aging female HSCs for CML induction in aging female mice. However, in the absence of oncogenic translocation genes, longevity female but not male mice rapidly develop B/myeloid mixed phenotype acute leukemia, a disease of HSC origin, in primary bone marrow transplantation recipients. Leukemias in our aging mouse models phenocopy those of humans in that the incidence of myeloid leukemia is higher in aging men than in women overall, but longevity women have a higher incidence of myeloid leukemia. Using single cell RNA sequencing analysis of HSCs, we found distinct cell clustering patterns and signaling pathways of aging HSCs between male and female mice. The top pathways seen in male HSC aging involve TGFβ and TNFα signaling that have been linked to poor drug response and persistence of human CML stem cells, while those for female HSC aging involve IFNα/γ signaling pathways that have been associated with good drug response of human CML stem cells. Together, our results demonstrate sex-dependent HSC aging and leukemogenic potential and that molecular changes in aging HSCs can inform drug response of leukemia stem cells. Our findings provide novel insight into the etiology of leukemia in males vs females and suggest potential benefit to use sex-based prevention and therapeutic strategies for leukemia in men vs women.
Citation Format: WenYong Chen. Sex-dependent hematopoietic stem cell aging and leukemogenic potential [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 A013.
Abstract A016: Aging-dependent emergent mechanical properties of single epithelial cells exploited for detection of breast cancer susceptibility
Authors: Hinz Stefan , Miyano Masaru , Manousopoulou Antigoni , Sayaman Rosalyn W. , Aguilera Kristina Y. , Todhunter Michael E. , Lopez Jennifer C. , Wang Leo D. , Sohn Lydia L. , LaBarge Mark A. 
Published: January 2023

Abstract
Age is the major risk factor in most carcinomas, yet, little is known about the specific reasons aging increases cancer susceptibility. In the mammary gland, luminal epithelial cells rank high as the putative breast cancer cell of origin. Dysregulation of keratin intermediate filament proteins exemplifies a hallmark age-dependent change in luminal cells, which implicates mechanical states unique to cancer susceptible cells. We implemented mechano-node-pore sensing (mechano-NPS), a multi-parametric single-cell analysis that simultaneously measures cell diameter, resistance to compressive deformation, transverse deformation under constant strain, and recovery time after deformation. We demonstrated that the epithelial lineages, chronological ages, and stages of cancer progression of primary human mammary epithelial cells (HMEC) exhibited discrete mechanical phenotypes. We trained a machine learning model that accurately predicted the chronological age of average risk HMEC cells based exclusively on mechanical properties. Application of the model to cells from women who are germline carriers of high-risk cancer-causing mutations showed that they are mechanically old irrespective of their chronological age, suggesting that mechanical states could be a window into detection and prevention of cancer susceptible states. Indeed, this mechano-age model detected high-risk women with &gt;90% accuracy. Mass spectrometry and cell-based functional assays in mammary epithelia revealed that cytoskeleton related proteins keratin 14 (KRT14) and pseudopodium enriched atypical kinase 1 (PEAK1) were key drivers of age-dependent mechanical signatures. Pharmacological and gene silencing approaches that targeted KRT14 and PEAK1 modulated the mechanical age of HMEC and, in the case of PEAK1 modulation, ablated luminal epithelial cells in an age- and lineage- dependent manner. We define an intersection between mechanical phenotypes and novel age-dependent changes in cytoskeleton-related proteins that we hypothesize can be exploited to assess an individual’s breast cancer susceptibility and provide new targets for cancer-prevention strategies.
Citation Format: Stefan Hinz, Masaru Miyano, Antigoni Manousopoulou, Rosalyn W. Sayaman, Kristina Y. Aguilera, Michael E. Todhunter, Jennifer C. Lopez, Leo D. Wang, Lydia L. Sohn, Mark A. LaBarge. Aging-dependent emergent mechanical properties of single epithelial cells exploited for detection of breast cancer susceptibility [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 A016.
Abstract B019: Aging-induced reprogramming of the cell of origin defines lung cancer evolution
Authors: Zhuang Xueqian , Joost Simon , Wang Qing , Blum Melissa , Ding Selena , Li Zhuxuan , Zhan Yingqian , Koche Richard , Wong Emily , Tammela Tuomas 
Published: January 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR010) of the Conference Proceedings.
Citation Format: Xueqian Zhuang, Simon Joost, Qing Wang, Melissa Blum, Selena Ding, Zhuxuan Li, Yingqian Zhan, Richard Koche, Emily Wong, Tuomas Tammela. Aging-induced reprogramming of the cell of origin defines lung cancer evolution [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 B019.
Abstract B024: Increasing cellular longevity in budding yeast by activating the Anaphase Promoting Complex
Authors: Harris Rachel E. , Harkness Troy A. A. 
Published: January 2023

Abstract
The Anaphase Promoting Complex (APC), a large and highly conserved ubiquitin ligase, is involved in genome stability, resistance to cancer progression, and has an important role in promoting health and lifespan. While best known for its function during the events of the cell cycle, the APC also has important roles outside of mitosis in aging cells. Understanding changes in function of the APC, and how these changes can be optimized, may increase our knowledge of cellular longevity and how it can be enhanced. We hypothesize that the APC loses function with age, and that the introduction of biological activators may aid to rescue these effects, improving the overall health of the cell to extend longevity. The abundance of orthologous genes and pathways between eukaryotes, complemented by the relative ease of genetic manipulation, allows for rapid advancement of research by deciphering gene functions in a yeast model to predict human disease and aging. By extension, increasing cell health in multicellular organisms will ultimately enhance the health of the entire organism. A dual screen was performed in the Harkness Lab on a library of short, random peptides to identify those which reproducibly interact with APC subunits, with particular interest on those which have an affect on function. Current research has found that several of these peptides are effective at extending cellular lifespan and suppressing APC mutant phenotypes, providing a novel means of exploring APC function in aging cells. Utilizing this direct biological activation of the APC, in addition to commercially available activators that function indirectly, I aim to identify potential therapeutic agents that can increase APC activity and extend lifespan utilizing Saccharomyces cerevisiae as a model organism.
Citation Format: Rachel E. Harris, Troy A. A. Harkness. Increasing cellular longevity in budding yeast by activating the Anaphase Promoting Complex [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 B024.
Abstract IA008: Role of race in accelerating progression of colorectal cancer
Authors: Carethers John M. 
Published: January 2023

Abstract
African Americans present earlier in age and have higher incidence and mortality from colorectal cancer (CRC) compared to Whites. Socioeconomic inequality in the US that leads to higher comorbid illness among African Americans is likely a driver. Subsequent biological differences in African Americans include higher risk adenoma precursors that are more often proximally located in the colon, low microstatellite instability prevalence, and deficient immunologic profiles compared to Whites that contribute to cancer progression and outcome. Screening for CRC among African Americans had been recommended by some organizations to commence at age 45 or 40 years due to the observed epidemiology; this was not implemented until the US Preventive Services Task Force recommended CRC screening to commence at age 45 years for all races and ethnicities in 2021.Screening for CRC is one modality of intervention that can eliminate disparities; both colonoscopic and non-invasive screening have been shown to eliminate incidence and mortality differences between African Americans and Whites when using navigation. Recent gains in screening utilization among African Americans compared to Whites might be erased as a result of the COVID-19 pandemic. Navigated non-invasive CRC screening might help the unevenness of preventive services recovery from the pandemic if it can be fully implemented.
Citation Format: John M. Carethers. Role of race in accelerating progression of colorectal cancer [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 IA008.
Abstract IA017: An oncogenic histone reader promotes metaplastic TNBC
Authors: Shah Vrutant V. , Miao Shucheng , Krause Patrick M. , Stratton Sabrina A. , Patel Lalit R. , Barton Michelle C. 
Published: January 2023

Abstract
Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) led to spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2, comprising 70% of all mammary tumors that developed with 40% penetrance. We saw strong correlation of Trim24COE carcinosarcoma tumors with human MpBC tumors and derived a conserved Trim24COE gene signature of Glycolysis, EMT and mTORC1 signaling pathways. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. To assess TRIM24-dependent metabolic alterations, we developed Trim24COE carcinosarcoma spheroid cultures. Tumor-derived Trim24COE carcinosarcoma spheroids exhibit TRIM24-dependent EMT and repressed cellular and mitochondrial ROS levels. We found that TRIM24 expression increased c-myc, NADPH and NRF2 levels to drive ROS repression and TRIM24-dependent cell survival under oxidative stress. TRIM24 mediates NRF2 activation at the level of chromatin structure activation, as shown by ATAC-seq of Trim24COE and shTrim24 carcinosarcoma spheroids. These in vivo and ex vivo models of metaplastic TNBC offer a platform for mechanistic discovery and nomination of potential therapeutic avenues for this highly malignant TNBC subtype.
Citation Format: Vrutant V. Shah, Shucheng Miao, Patrick M. Krause, Sabrina A. Stratton, Lalit R. Patel, Michelle C. Barton. An oncogenic histone reader promotes metaplastic TNBC [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 IA017.
Abstract IA021: Studies of aging, morphology, and cancer in the domestic dog
Authors: Ostrander Elaine A. 
Published: January 2023

Abstract
Each of the nearly 450 domestic dog breeds in existence today has a unique history and genetic profile. Early in the domestication process, dogs were bred to perform specific tasks such as herding, guarding and hunting. Later, fanciers developed hundreds of breeds, often displaying variation in body morphology, including shape and size, in addition to coat color, skull shape, leg length, etc. We are interested in understanding the genetic underpinnings of that variation, and applying those results to studies of growth regulation, normal and abnormal behavior and disease susceptibility. Dogs are a naturally-occurring model for many complex human disorders, including cancer. One in two dogs that live to be ten or older will develop cancer in their lifetimes, with most common human cancers occur spontaneously in dogs. This offers unique opportunities to study cancer susceptibility, progression and treatment response. The high rate of single types of cancer in some breeds, such as histiocytic sarcoma in Bernese Mountain Dogs or invasive bladder cancer in Scottish Terriers offers specific advantages for genetic studies that do not exist in human population studies. As with cancer, domestic dogs present interesting opportunities for studies of aging. Surprisingly, small breeds typically live longer than larger breeds, offering the chance to study the interaction between morphology and lifespan. To take advantage of these opportunities, we have assembled the largest and most diverse dataset of dog breeds and other canines to date, with canines originating from six continents, reflecting the extensive phenotypic variation and heritage that coalesce in modern dogs, and identified over 90 million single nucleotide variants. In this presentation we explore the genetics of cancer and aging in dogs, drawing parallels to the human condition.
Citation Format: Elaine A. Ostrander. Studies of aging, morphology, and cancer in the domestic dog [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 IA021.
Abstract PR003: Apoptotic DNase DFFB mediates stress-induced mutagenesis
Authors: Williams August F. , Gervasio David A.G. , Turkal Claire E. , Hairani Mehrshad , Wang Michael X. , Stuhlfire Anna E. , West Ariel H. , Mauch Brandon E. , Paw Michelle H. , Lathrop Cooper P. , Harris Sophie H. , Page Jennifer L. , Hangauer Matthew J. 
Published: January 2023

Abstract
It was recently discovered that actively proliferating and post-mitotic normal human tissues acquire somatic mutations at the same rate. This indicates that somatic mutagenesis is primarily independent of cell proliferation and therefore cannot be based on DNA replication errors. Furthermore, the mutagenic mechanisms which contribute to ubiquitous mutational signatures such as SBS5 remain unknown. It has been hypothesized that tissues accumulate mutations through unknown physiologic processes which contribute to DNA damage but the molecular details remain unknown. These observations have revealed our lack of understanding of the fundamental processes of mutagenesis. Stress-induced mutagenesis has been previously characterized in bacteria which respond to stress by transiently increasing the rate of mutagenesis to promote the emergence of resistance mutations. This phenomenon was recently discovered in human cancer cells but the mechanism is unknown. Here, we present our discovery that cancer cells under drug stress undergo sublethal apoptotic signaling resulting in activation of apoptotic DNase DFFB. DFFB, which canonically acts to fragment chromosomal DNA during apoptosis, induces DNA strand breaks in surviving cancer cells resulting in error prone repair and mutagenesis. In the context of targeted therapy-treated cancer, we found that DFFB is required for acquired resistance to emerge in multiple tumor types. We also found that CD8 T cells induce a similar process in targeted tumor cells which survive. Therefore, sublethal apoptotic signaling may be a general phenomenon which promotes mutagenesis in human cancer. Based on these observations and prior literature showing sublethal apoptotic signaling occurs in normal cells in response to various stress stimuli, we propose that this mechanism may be a previously unknown fundamental mutagenic process which contributes not only to acquired resistance in cancer but also to tumor initiation, aging and other conditions.
Citation Format: August F. Williams, David A.G. Gervasio, Claire E. Turkal, Mehrshad Hairani, Michael X. Wang, Anna E. Stuhlfire, Ariel H. West, Brandon E. Mauch, Michelle H. Paw, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer. Apoptotic DNase DFFB mediates stress-induced mutagenesis [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 PR003.
Abstract PR009: Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome
Authors: Minteer Christopher J. , Thrush Kyra , Niimi Peter , Rozowsky Joel , Liu Jason , Frank Mor , McCabe Thomas , Hofstatter Erin , Rozenblit Mariya , Pusztai Lajos , Beckman Kenneth , Gerstein Mark , Levine Morgan E. 
Published: January 2023

Abstract
Aging is the leading risk factor for cancer. While some have proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, potentially pushing them towards a more tumorigenic state.
Citation Format: Christopher J. Minteer, Kyra Thrush, Peter Niimi, Joel Rozowsky, Jason Liu, Mor Frank, Thomas McCabe, Erin Hofstatter, Mariya Rozenblit, Lajos Pusztai, Kenneth Beckman, Mark Gerstein, Morgan E. Levine. Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome [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 PR009.
Abstract PR010: Aging-induced reprogramming of the cell of origin defines lung cancer evolution
Authors: Zhuang Xueqian , Joost Simon , Wang Qing , Blum Melissa , Ding Selena , Li Zhuxuan , Zhan Yingqian , Koche Richard , Wong Emily , Tammela Tuomas 
Published: January 2023

Abstract
Aging is one of the most important risk factors for cancer development. However, our understanding of how aging impacts cancer evolution remains at an early stage. We investigated the evolution of lung adenocarcinoma (LUAD) in aged vs. young KrasLSL-G12D/+; Trp53flox/flox (KP) mice. Surprisingly, we found that LUAD initiation and progression were significantly impaired with aging. Using functional in vivo and in vitro assays, we demonstrated that the loss of tumor-initiating potential could be attributed to a loss of stemness in the alveolar type 2 (AT2) cells, which are the predominant cell of origin for LUAD. We next explored the biology of the tumors that formed in aged KP mice using single-cell transcriptomics. We discovered a distinct compositional landscape of cancer cell subsets in aged lung tumors, revealing a delay in the molecular progression of the cancers and an aging-specific gene expression signature. Interestingly, key components of this gene signature could be traced back to specific epigenetic alterations in the AT2 cells. Furthermore, the aged mouse LUAD signature was highly predictive of patient age in human LUAD, indicating conservation of the age-associated changes across species. We hypothesized that the aging-associated changes in gene expression during LUAD tumorigenesis may underpin delayed tumor progression in the aged KP mice. To test this, we performed an in vivo genetic screen in the autochthonous KP model and identified genetic dependencies that were specific to LUAD in aged or young mice. Our results indicate that aging-associated epigenetic changes in the cell of origin are imprinted on evolving tumors, which determines tumor initiation potential, alters trajectory of tumor evolution, and leads to age-dependent vulnerabilities. These findings suggest that the biology of tumors is fundamentally altered by aging, raising new possibilities for cancer treatment and prevention in patients of different ages.
Citation Format: Xueqian Zhuang, Simon Joost, Qing Wang, Melissa Blum, Selena Ding, Zhuxuan Li, Yingqian Zhan, Richard Koche, Emily Wong, Tuomas Tammela. Aging-induced reprogramming of the cell of origin defines lung cancer evolution [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 PR010.