bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A013: Sex-dependent hematopoietic stem cell aging and leukemogenic potential
Authors: Chen WenYong
Published: January 2023

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

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 >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

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

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

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

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

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

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

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

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.
Abstract A014: Transcriptional regulation of basal leader cell identity during collective breast cancer invasion
Authors: Doak Andrea E. , Qu Rose , Cheung Kevin J.
Published: January 2023

An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. Studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers. The presence of these K14+ cells promote metastasis and predict poor prognosis. The molecular mechanisms regulating K14+ leader cell identity and the methods for targeted depletion of these cells remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified, and through correlation with K14 expression and invasive strand formation we classified one of the states as leader cells. Having confirmed the leader cell cluster markers spatially localize to the invasive front, we next asked which transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. Three different shRNAs targeting ten genes were systematically evaluated for their effects on collective invasion and keratin-14 transcription. Each transcription factor was designated as either an invasion promoter or invasion suppressor depending on the correlation between transcription factor expression and organoid invasion. Studies are ongoing investigating the impact of invasion-promoting and invasion-suppressing transcription factors on cellular transcriptional states and metastatic dissemination in-vivo. We propose that targeting invasion-suppressing pathways could be combined with therapies that specifically target and eliminate K14+ invasive cells. To this end, we have identified multiple candidate druggable targets and specific surface markers expressed in K14+ invasive cells.

Citation Format: Andrea E. Doak, Rose Qu, Kevin J. Cheung. Transcriptional regulation of basal leader cell identity during collective breast cancer invasion [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 A014.
Abstract B038: Remodeling the extracellular matrix environment and establishing distinct immune cell profiles enables the formation of brain metastasis in non-small cell lung cancer adenocarcinoma
Authors: Wang Albert R. , Brown Jared , Baschnagel Andrew , Buehler Darya , Kendziorski Christina , Iyer Gopal
Published: January 2023

Dissemination of tumor cells from the primary site of the lung to distant sites in non-small cell lung cancer (NSCLC) is poorly understood. With distinct mutation signatures in patients, altering pathways is critical to preventing tumor cell dissemination to distant sites. Towards this, we characterized 21 "trios" patient-matched brain metastases (BrM), primary tumors (LT), and normal samples (LN), revealing a pattern of extracellular matrix remodeling which suppressed immune cell infiltration. Our objectives were to (i) determine if clinically sampled primary lung tumors encode gene expression patterns distinct from normal tissue, suggestive of increased tumor invasiveness including brain metastasis, and (ii) determine the biologic underpinning of immune-suppressive information carryover from primary lung tumor to brain metastasis. Transformation of the normal lung cells to primary tumor cells suggested a breakdown in ECM axes primarily governed by upregulation of collagen (COL1A1, COL1A2, COL3A1, COL10A1), fibronectin (FN1), and matrix metalloproteinases (MMP7, MMP9, MMP11, MMP12, MMP13, MMP14) genes. Collectively, the primary tumor cells used MMPs to break down the main components of lung ECM and reorganized collagen and fibronectin in the tumor microenvironment to facilitate migration and invasion. Migration and subsequent cell adhesion in the brain microenvironment revealed upregulation of neural cell adhesion molecule (NCAM1) and phosphoprotein 1 (SPP1). These changes in ECM profiles between LT and BrM signify primary tumor cells' adaptation in the brain microenvironment. Further computational deconvolution revealed reduced HLA class II gene expression (HLA-DMA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2, HLA-DRA) correlated with lower CIBERSORTx enrichment scores of immune cell populations in BrM. Overall, using the matched sequencing information, we will present the underlying signaling gradients that dictate dissemination of primary lung tumor cells to the brain environment in the background of altered ECM environment using cellular models harboring EGFR, KRAS, and ALK driver mutations.

Citation Format: Albert R. Wang, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer. Remodeling the extracellular matrix environment and establishing distinct immune cell profiles enables the formation of brain metastasis in non-small cell lung cancer adenocarcinoma [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 B038.
Abstract B040: Leader cells mediate tumor engraftment and promote immunosuppression to drive ovarian cancer progression in vivo
Authors: Wilson Amy L. , Doran Brittany R. , Basri Bashirah , Moffitt Laura R. , Plebanski Magdalena , Stephens Andrew N. , Bilandzic Maree
Published: January 2023

Epithelial ovarian cancer (EOC) is most frequently diagnosed at an advanced stage, and is characterized by its high recurrence rate and almost-universal acquisition of chemoresistance. Metastasis of EOC is driven by heterogenous spheroids that passively disseminate throughout the peritoneal cavity, promoting tumor spread and recurrence. We previously identified a sub-population of highly motile and invasive “Leader cells” (LCs) that express the basal epithelial protein KRT14 as an absolute determinant of invasive potential. We demonstrated KRT14 knockout in EOC cells does not impact viability or proliferation, however completely ablates their ability to invade through Matrigel in 2D and 3D format in vitro. Although a role for LCs in mesothelial clearance and invasion has been established, these mechanisms remain poorly understood. Here we show a critical role for KRT14+ LCs in immunosuppression and tumor-immune privilege in vivo. In the ID8 syngeneic EOC mouse model, tumor-specific LC (KRT14) loss (LCKO) impaired ovarian intrabursal primary tumor engraftment and subsequent metastatic spread. Immune phenotyping by flow cytometry revealed that mice bearing LCKO tumors displayed decreased proportions of immunosuppressive tumor-adjacent Tregs and M2 macrophages, and improved CD8+ T-cell/Treg ratios. Conversely, forced LC-overexpression (LCOE) in EOC tumors accelerated metastasis, and promoted tumor-immune evasion via upregulated secretion of suppressive chemokines including CCL22 and CCL5. In addition to their critical role in migration and invasion, the current study provides in vivo evidence that leader cells are mediators of immune suppression in ovarian cancer. This work supports the basis that defining novel strategies to target LCs to promote anti-tumor immunity and limit metastatic progression may be a useful strategy for improved epithelial ovarian cancer therapy.

Citation Format: Amy L. Wilson, Brittany R. Doran, Bashirah Basri, Laura R. Moffitt, Magdalena Plebanski, Andrew N. Stephens, Maree Bilandzic. Leader cells mediate tumor engraftment and promote immunosuppression to drive ovarian cancer progression 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 B040.
Abstract B050: Reproducible and effective preclinical models of prostate cancer metastasis established with PDXs
Authors: Yin JuanJuan I. , Daryanani Asha , Alilin Aian , Lake Ross , Kelly Kathy
Published: January 2023

Metastatic castration resistant prostate cancer (mCRPC) is a lethal disease. Understanding the intricacy of this disease and developing targeted treatment is hampered by the lacking of clinically relevant animal models. LuCaP patient-derived xenografts (PDXs), established from advanced metastatic prostate cancer, are a large cohort that encompass the molecular and cellular heterogeneity of mCRPC. We have established four prostate cancer metastasis models from three androgen receptor (AR) positive lines (LuCaP136, LuCaP167 and LuCaP23.1) and one AR negative line LuCap145.2. The three AR positive LuCap lines metastasized to vertebrae and long bones with differing bone-associated histology while the AR negative LuCap145.2 metastasize to brain and spinal cord. The bone metastasis phenotypes of the models encompass: osteolytic (LuCaP136), mixed bone destruction and new bone formation (LuCaP167), and a highly osteoblastic histology (LuCaP23.1). LuCap136 and LuCap167 also metasize to soft tissues including adrenal, kidney and liver. Castration responses were studied on LuCap136 and LuCap167 models. Although both models are castration resistant, LuCap136 model initially are sensitive to castration with decreased tumor progression, and AR down-regulated in the metastatic sites. In contrast, tumor progression was not affected after castration in LuCap167 model. AR and ARV7 were up-regulated in metastatic cells. In summary, the LuCap PDX lines have the capacity for systemic growth in clinically accurate metastatic sites. In addition, the two AR positive models show different castration response which may be driven by different pathways. Understanding the complexity of these pathways would guide optimal selection of drug combinations to achieve the best outcome for patients with mCRPC.

Citation Format: JuanJuan I. Yin, Asha Daryanani, Aian Alilin, Ross Lake, Kathy Kelly. Reproducible and effective preclinical models of prostate cancer metastasis established with PDXs [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 B050.
Abstract IA025: About motifs, non-codingRNAs and metastases
Authors: Calin George A.
Published: January 2023

MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies.

Citation Format: George A. Calin. About motifs, non-codingRNAs and metastases [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 IA025.
High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis
Authors: Cortese Nina , Carriero Roberta , Barbagallo Marialuisa , Putignano Anna Rita , Costa Guido , Giavazzi Fabio , Grizzi Fabio , Pasqualini Fabio , Peano Clelia , Basso Gianluca , Marchini Sergio , Colombo Federico Simone , Soldani Cristiana , Franceschini Barbara , Di Tommaso Luca , Terracciano Luigi , Donadon Matteo , Torzilli Guido , Kunderfranco Paolo , Mantovani Alberto , Marchesi Federica
Published: January 2023

Patients with colorectal liver metastasis (CLM) present with heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (Mϕ) hold promise as prognostic classifiers and therapeutic targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two Mϕ markers associated with distinct populations with opposite clinical relevance. The invasive margin of CLM was enriched in pro-inflammatory monocyte-derived Mϕ (MoMϕ) expressing the monocytic marker SERPINB2, and a more differentiated population, tumor-associated Mϕ (TAM), expressing glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2+ MoMϕ had an early inflammatory profile, whereas GPNMB+ TAMs were enriched in pathways of matrix degradation, angiogenesis, and lipid metabolism and were found closer to the tumor margin, as confirmed by spatial transcriptomics on CLM specimens. In a cohort of patients, a high infiltration of SERPINB2+ cells independently associated with longer disease-free survival (DFS; P = 0.033), whereas a high density of GPNMB+ cells correlated with shorter DFS (P = 0.012) and overall survival (P = 0.002). Cell–cell interaction analysis defined opposing roles for MoMϕ and TAMs, suggesting that SERPINB2+ and GPNMB+ cells are discrete populations of Mϕ and may be exploited for further translation to an immune-based stratification tool. This study provides evidence of how multi-omics approaches can identify nonredundant, clinically relevant markers for further translation to immune-based patient stratification tools and therapeutic targets. GPNMB has been shown to set Mϕ in an immunosuppressive mode. Our high dimensional analyses provide further evidence that GPNMB is a negative prognostic indicator and a potential player in the protumor function of Mϕ populations.
Thirty-Year-Old Male Patient with Non-Seminoma and Coincidental Rectal Cancer
Authors: Nolting Julia , Dräger Desiree Louise , Hakenberg Oliver W. , Schneidewind Laila
Published: January 2023

We present the case of a 31-year-old male patient with non-seminoma (90% embryonal carcinoma, 10% teratoma) pT1b L1 V0 Pn0 R0 cN2 cM0, Clinical Stage IIb and “good prognosis group” according to IGCCCG of the left testis. According to EAU guidelines, he received three cycles of BEP. After the second cycle, he developed recurrent, clinically not significant rectal bleeding, which we associated with deep thrombocytopenia. Following chemotherapy, there was one lymph node in the CT scan left, with a diameter of 0.9 cm at the inferior mesenteric arteria and the rectal bleeding did not stop; so coloscopy and staging revealed rectal cancer (adenocarcinoma) with peritoneal carcinosis. The patient was scheduled for radio-chemotherapy. Next-generation sequencing of the adenocarcinoma showed two mutations in KRAS and TP53 genes. To our knowledge, this is the first case of non-seminoma and coincidental rectal cancer. Furthermore, this case underlines the significance of molecular biological studies for the development of individualized targeted therapies, especially in younger patients and in chemo- and/or platin-resistance.
Efficacy of Local Treatment in Lymph Node Metastasis from Hepatocellular Carcinoma
Authors: Lee Byung min , Choi Jin-Young , Seong Jinsil
Published: January 2023

Introduction: We aimed to investigate the significance of lymph node metastasis from hepatocellular carcinoma and the efficacy of local treatment. Methods: We included patients diagnosed hepatocellular carcinoma with lymph node metastasis. The pattern of lymph node metastasis was evaluated based on imaging examinations and stratified by three locations: regional (group A), beyond regional intra-abdomen (group B), and extra-abdomen (group C) lymph node metastasis. Results: Among 14,474 patients, 852 (5.8%) were identified as having lymph node metastasis. Regarding the location of presentation, group A showed the highest incidence, followed by groups B and C. The 1-year overall survival of patients was 31.7%. The survival significantly differed according to the location of lymph node metastasis. The 1-year overall survival rates were 39.8%, 25.5%, and 22.2% in groups A, B, and C, respectively. All patients underwent systemic treatment, with others receiving additional local treatment. Local treatment yielded superior overall survival compared with no local treatment. After propensity score matching, local treatment was associated with improved survival. Additionally, patients were stratified based on disease status at the time of diagnosis of lymph node metastasis: lymph node alone and combined extra-nodal metastasis. The survival benefits of local treatment were observed in both groups. Conclusions: Our findings demonstrated the clinical significance of lymph node metastasis from hepatocellular carcinoma, which was well discriminated according to location, favoring regional metastasis. In patients with hepatocellular carcinoma presenting lymph node metastasis, active application of local treatment for lymph node metastasis can improve oncologic outcomes.
Avaliação da ocorrência do fenômeno de ilha de calor na área urbana do município de Taubaté, SP
Authors: Barduco Guilherme Luis , Galvani Emerson
Published: January 2023

A população mundial está próxima de atingir 8 bilhões de habitantes, porém, somente no século XXI a população urbana superou a população rural. Com o aumento das áreas urbanas mundiais, muitas facilidades foram alcançadas, contudo muitas adversidades fazem parte do dia a dia dos citadinos, trânsito, violência, poluição. O presente trabalho investigou a ocorrência de ilhas de calor no município de Taubaté, que está localizado na região sudeste do estado de São Paulo, na região metropolitana do Vale do Paraíba. O estudo foi realizado com a adoção da metodologia de transectos móveis. Realizaram-se 18 transectos móveis, simultâneos, com orientação de sul para norte e de oeste para leste durante o mês de julho de 2019, nos dias 18, 19 e 20, em três horários distintos do dia, as 5 horas e 10 minutos, as 14 horas as 20 horas. Foram coletados dados de temperatura e umidade relativa do ar ao longo de 37 pontos de sul para norte e 42 pontos de oeste para leste na área de estudo. A análise dos dados considerou a variação da urbanização e uso do solo para determinar as diferenças de temperatura entre os pontos dos transectos. Os resultados demonstraram que as áreas mais urbanizadas são mais aquecidas que as áreas menos urbanizadas durante o período da tarde, noturno e da madrugada. As intensidades das ilhas de calor foram, durante as 20 horas, de intensidade moderada a forte, indicando aquecimento nas superfícies urbanas.
A Copa do Mundo FIFA 2022 e o flagelo da homofobia
Authors: Silva Alessandro Soares da , Menon Gustavo , Barboza Renato
Published: January 2023

A homofobia é um instrumental de dominação psicopolítica que priva sujeitos de sua condição humana por meio da injúria e da violação da dignidade. Causa dor e sofrimento, aliena a pessoa da capacidade de agir e de se perceber como capaz de existir em todas as esferas da vida. Em tempos de Copa do Mundo FIFA 2022 no Qatar, emergem muitas questões que atingem sujeitos e instituições no tocante a garantias de direitos e da dignidade humana, sobretudo, em um país que criminaliza com prisão ou mesmo apedrejamento o amor entre iguais. A homofobia mata. Ela tem vitimado pessoas no mundo e a cultura do futebol tem contribuído para essa triste realidade. Esse ensaio tece reflexões sobre como uma instituição da envergadura da FIFA tem pautado essa questão e como as nações que celebram esse megaevento têm encarado o flagelo da homofobia no mundo do futebol.
Futebol e cartografia: uma análise do Campeonato Brasileiro Série A
Authors: Sousa Igor Breno Barbosa de , Sampaio Mateus de Almeida Prado , Mendes Jéssica Neves , Leite Igor Mendes , Mattos Junior José Sampaio de
Published: January 2023

O futebol no mundo, cada vez mais, movimenta um misto de sentimentos que variam desde a alegria à tristeza, nos torcedores, nos apreciadores e nos investidores desse esporte. Os campeonatos, particularmente o brasileiro masculino, apresentou ao longo de sua história metamorfoses e adotou novas configurações nas regras e em seu formato. Este artigo interrelaciona Cartografia e Geografia dos Esportes promovendo discussões acerca da conjuntura recente do “Brasileirão - Série A”. Tem por objetivo analisar a distribuição geográfica dos clubes participantes da divisão de elite do Campeonato Brasileiro, promovendo um debate de cunho regional. Para o seu desenvolvimento foram levadas em consideração aspectos da conjuntura socioeconômica e política no Brasil. Os procedimentos metodológicos se pautam em levantamento bibliográfico, leitura crítica, coleta de dados, produção cartográfica e análises dos resultados. Os resultados apresentam uma tendência à crescente concentração espacial dos clubes participantes e, principalmente, dos campeões. Estes com frequência integram o eixo Rio-São Paulo e apenas perifericamente também Minas Gerais e parte da região Sul do Brasil. As demais regiões, Nordeste, Norte e Centro-Oeste, perderam espaço na divisão principal do campeonato e agora buscam se consolidarem no cenário futebolístico nacional a partir de suas divisões secundárias.
denúncia do racismo e a contestação da democracia racial pela imprensa negra nos primórdios do futebol paulistano
Authors: Abrahão Bruno Otávio de Lacerda , Oliveira George Roque Braga , Soares Antonio Jorge Gonçalves
Published: January 2023

A Imprensa Negra surgiu em São Paulo nos primeiros anos do Século XX como um coletivo que abordava a questão racial em seu contexto econômico, político e cultural. Tais veículos provocaram o debate através das discussões sobre a estrutura de poder, os modelos de organização social e cultural e as formas de reconhecimento e status ao descortinarem as tentativas de negação destas iniquidades sociais. Diante desta constatação, o objetivo deste artigo é analisar a denúncia de episódios de discriminação racial e a contestação do mito identitário de democracia racial no futebol paulistano do início do Século XX através das publicações da Imprensa Negra. Como fonte utilizamos seus jornais disponibilizados nos microfilmes da Biblioteca Nacional. Após lermos as matérias que tematizavam o esporte, selecionamos duas que se ocuparam de repercutir o preconceito e a discriminação racial no futebol paulistano naquele contexto. No período analisado, podemos observar que no futebol de São Paulo ocorria a inclusão em determinados espaços e exclusão em outros, o que impedia a efetivação de relações democratizadas e proporcionava a reprodução das contradições do racismo na sociedade.  Concluiu-se que havia tensão entre a coexistência da denúncia do racismo e o louvor da democracia racial nos primórdios do futebol de São Paulo.
Urubu-Rei: A palávora experimental de Gramiro de Matos
Authors: Bugelli Arthur Lungov
Published: January 2023

O objetivo do presente artigo é explorar, por meio da leitura de Urubu-Rei (Gernasa, 1972), livro de estreia de Gramiro Matos (1944), e de bibliografia que analisa a poesia moderna brasileira, do modernismo às neovaguardas concretas, os elementos da poesia gramiriana que permitem inseri-la em determinada tradição experimental da poesia brasileira.
Association of Eating and Sleeping Intervals With Weight Change Over Time: The Daily24 Cohort
Authors: Zhao Di , Guallar Eliseo , Woolf Thomas B. , Martin Lindsay , Lehmann Harold , Coughlin Janelle , Holzhauer Katherine , Goheer Attia A. , McTigue Kathleen M. , Lent Michelle R. , Hawkins Marquis , Clark Jeanne M. , Bennett Wendy L.
Published: January 2023

Background

We aim to evaluate the association between meal intervals and weight trajectory among adults from a clinical cohort.

Methods and Results

This is a multisite prospective cohort study of adults recruited from 3 health systems. Over the 6‐month study period, 547 participants downloaded and used a mobile application to record the timing of meals and sleep for at least 1 day. We obtained information on weight and comorbidities at each outpatient visit from electronic health records for up to 10  years before until 10 months after baseline. We used mixed linear regression to model weight trajectories. Mean age was 51.1 (SD 15.0) years, and body mass index was 30.8 (SD 7.8) kg/m
2
; 77.9% were women, and 77.5% reported White race. Mean interval from first to last meal was 11.5 (2.3) hours and was not associated with weight change. The number of meals per day was positively associated with weight change. The average difference in annual weight change (95% CI) associated with an increase of 1 daily meal was 0.28 kg (0.02–0.53).

Conclusions

Number of daily meals was positively associated with weight change over 6 years. Our findings did not support the use of time‐restricted eating as a strategy for long‐term weight loss in a general medical population.