bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 13: A non-surgical approach to develop an orthotopic colorectal cancer mouse model
Authors: Sharma Samantha , Van der Jeught Kevin , Zhou Zhuolong , Zhang Xinna , Lu Xiongbin 
Published: April 2023

Abstract
Recapitulating physiologically relevant tumor microenvironment is an important yet a significant challenge in modeling colorectal cancer (CRC) for basic and translational studies. Cecal-wall injection is most widely used for orthotopic animal models of CRC. However, this procedure involves complicated surgical procedures, and its ectotopic nature is a major issue for therapeutic development. Here, we report a non-surgical procedure for establishing orthotopic CRC mouse models, reflecting the appropriate tumor microenvironment to better model the disease development and facilitate translational studies, including drug identification and validation. For this procedure, the mice are fasted overnight. The following day, anesthesia is induced in the study mice (Balb/c or C57BL/6) while placed on a thermostat-controlled heating blanket. Next, a specialized catheter is inserted and distended into the mouse colon to gently block the colon and ensure the localization for tumor development. Hereafter, the colonic epithelium is treated with proteases and mechanical abrasion to cause mild disruption. Following the local gut inflammation, the targeted colon region is incubated with tumor cells, leading to the adhesion of tumor cells (CT26 or MC38) to the colonic epithelium. Based on the animal background and the cell line used, the tumor is developed within 4-6 weeks. Pathological assessment on hematoxylin and eosin stained tumor tissues confirmed the stages of tumor development. Additional adaptations of this procedure include i) tumor development in different mouse strains, ii) local delivery of adeno-Cre in transgenic mice for CRC, and iii) transplantation of tumor organoids in the mouse colon. Overall, our non-surgical procedure overcomes the technical difficulties of surgery and offers several advantages like ease of handling, cost-effectiveness, pain-free with nearly no procedure-associated mortality, and adaptability to several strains. To conclude, this non-surgical procedure is a novel and promising alternative to conventional orthotopic CRC mouse models for translational studies.
Citation Format: Samantha Sharma, Kevin Van der Jeught, Zhuolong Zhou, Xinna Zhang, Xiongbin Lu. A non-surgical approach to develop an orthotopic colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 13.
Abstract 1317: Exercise training prevents exosome mediated pre-metastatic niche formation in the liver
Authors: Yang Ruiqi , Haykal Tony , Tohme Celine , Wang Ronghua , Kaltenmeier Christof , Geller David , Yazdani Hamza , Tohme Samer 
Published: April 2023

Abstract
Introduction: Primary tumor cells release exosomes facilitating pre-metastatic niche formation in distant organs, initiating the process of metastasis. As metastasis is the main prognostic factor for patients, it is essential to understand the pre-metastatic niches and develop therapies to target them. It has been shown that Kupffer cells play an crucial role in the formation of pre-metastatic niche in the liver. We have recently shown that exercise training (ExT) alters the phenotype of Kupffer cells and attenuates tumor metastasis after surgery. Here, we hypothesize that ExT can interfere with exosome mediated pre-metastatic niches, hence decreasing metastasis.
Methods: Eight-week-old male mice were randomized into sedentary and ExT group. Mice were pre-educated with cancer exosomes for 4 weeks to induce pre-metastatic niche and intra-splenically injected with murine colorectal cancer (MC38) cells. Tumor metastasis and growth was followed by 3 weeks.
Results: Compared to the sedentary group, there was a significant decrease in metastatic nodules and hepatic tumor replacement in the ExT mice liver. To further study the effects of ExT, livers from both groups were harvested 4 weeks after exosome pre-education. We observed decrease in the uptake of tumor exosome, immune cells infiltration and fibronectin deposition in the ExT livers, which demonstrates less pre-metastatic niche formation. Bulk RNA sequencing was performed on Kupffer cells isolated from both groups. Ingenuity pathway analysis shows that Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling pathway was downregulated in EXT group, indicating less activation of Kupffer cells.
Conclusions: These results indicate that exercise reduces pre-metastatic niche formation and tumor metastasis by affecting the interaction between cancer exosomes and Kupffer cells. In light of these findings, potential may exist to reduce exosome-induced liver pre-metastatic niches through the use of ExT as a nonpharmacologic therapy in patients with cancer.
Citation Format: Ruiqi Yang, Tony Haykal, Celine Tohme, Ronghua Wang, Christof Kaltenmeier, David Geller, Hamza Yazdani, Samer Tohme. Exercise training prevents exosome mediated pre-metastatic niche formation in the liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1317.
Abstract 1344: myCAFs and iCAFs have similar lineage
Authors: Walter Thomas S. , Han Lu , Ostrowski Michael 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma primarily composed of cancer associated fibroblasts (CAFs). These fibroblasts are a diverse population of cells; some groups of fibroblasts have been shown to play tumor supporting roles while others have been shown to be tumor suppressing. Two prolific and well-characterized CAF subtypes—myofibroblasts (myCAFs) and inflammatory CAFs (iCAFs)—could potentially have different regulatory effects on tumor growth. Understanding the tissue origin of these two groups of CAFs could assist in understanding the complex and heterogeneous roles they might play in PDAC development. Previous studies in our group showed that the splanchnic mesenchyme, a layer of mesenchyme adjacent to the fetal pancreatic epithelium, gives rise to the majority of the total CAF population. Here, I aim to test the hypothesis that both iCAFs and myCAFs originate from the splanchnic mesenchyme. myCAFs have been previously observed to be proximal to tumor cells and express αSMA at a higher level, while iCAFs have been observed to be distal to tumor cells and express αSMA at a lower level. Here, we used a genetically engineered mouse PDAC model carrying KrasG12D/+;p53Frt/+;Pdx1FlpO/+;Isl1cre/+;R26Tomato/+ alleles. In this model, epithelial specific FlpO expression leads to Kras activation and p53 deletion, causing tumorigenesis. Simultaneously, splanchnic specific Cre expression leads to permanent tomato expression in the splanchnic descendants. The pancreata of these mice were harvested, fixed, and mounted onto slides. Co-immunostaining with αSMA and tomato was then done. The stained slides were scanned, and the Inform software was used to segment and phenotype the cells. More than 95% of αSMA high cells were tomato positive, and more than 95% of αSMA low cells were also tomato positive. We thus conclude that both myCAFs and iCAFs originate from the splanchnic mesenchyme. Consistent with previous in vitro studies, this lineage tracing study suggests that different CAF subtypes are likely due to patterning influenced by different factors within the tumor microenvironment.
Citation Format: Thomas S. Walter, Lu Han, Michael Ostrowski. myCAFs and iCAFs have similar lineage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1344.
Abstract 1346: Phagocytosis of solid tumors favors macrophage clusters and cooperativity in tumor elimination
Authors: Discher Dennis E. 
Published: April 2023

Abstract
Macrophages are abundant in many solid tumors and are potential effector cells for monoclonal antibody-based immunotherapies because they can in principle phagocytose IgG-opsonized cancer cells. However, it remains unknown whether phagocytic macrophages can overcome the cohesive forces between cancer cells in solid tumors. We show that maximum phagocytosis of B16 melanoma tumors and ‘tumoroids’ requires IgG-opsonization and very deep suppression of the macrophage checkpoint ligand CD47. Under these conditions, phagocytic macrophages cluster or ‘phase separate’, and the elimination exhibits clear cooperativity with respect to macrophage number and phagocytic activity. In vitro disruption of phagocytic clusters specifically implicates Mg2+ and macrophage integrins. Cytokine treatments and other inhibitors further implicate roles for integrins and phagocytic surface receptors. Although tumor-associated macrophages correlate with negative prognoses in many cancers, our findings are among the first to reveal advantages of high macrophage numbers, macrophage clusters, and resulting cooperative effects when combined with opsonizing antibodies and CD47 disruption. Lastly, the challenging B16 tumors are durably eliminated by the approach and induce de novo IgG's that also drive anti-cancer phagocytosis.
Citation Format: Dennis E. Discher. Phagocytosis of solid tumors favors macrophage clusters and cooperativity in tumor elimination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1346.
Abstract 135: Elucidating tumor evolution in pediatric cancers using stochastic models and mutation accumulation experiments
Authors: Massei Ana Beatriz , Platero Jasmin Jovel , Hong Kyungchan , Zeledon Sofia , Afzal Taha , Cha Hyunjeong , Kim Seung-Hwan 
Published: April 2023

Abstract
Ontology-based approaches have been utilized for identifying cancer genes. However, among the thousands of mutations in pediatric cancer genes, accurate prediction of driver genes is one of the biggest challenges. A binary logistic regression model was developed to distinguish pediatric and non-pediatric cancer genes. To build the predictive model, Gene Ontology (GO) enrichment analysis was performed, followed by the PANTHER overrepresentation test, using PANTHER GO-slim, PANTHER, Reactome pathways, and three sets of specific variables, the lists of pediatric cancer genes found in the germline, relapsed, and chemotherapy-resistant cells, respectively. This statistical model was pediatric cancer-specific, confirming known driver genes across cancers. In addition, mathematical models were developed using stochastic differential equation approaches and computational simulations to extend our understanding of the evolutionary dynamics during pediatric tumorigenesis. Moreover, our stochastic models in childhood cancers were validated by mutation accumulation experiments using E. coli strains carrying a mutation in replication restart genes. Finally, this study that elucidates tumor evolution in pediatric cancers could have profound implications for cancer therapy and drug design.
Citation Format: Ana Beatriz Massei, Jasmin Jovel Platero, Kyungchan Hong, Sofia Zeledon, Taha Afzal, Hyunjeong Cha, Seung-Hwan Kim. Elucidating tumor evolution in pediatric cancers using stochastic models and mutation accumulation experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 135.
Abstract 14: The impact of genetic background on cancer phenotypes of mouse models
Authors: Begley Dale A. , Krupke Debra M. , Neuhauser Steven B. , Jocoy Emily L. , Sundberg John P. , Bult Carol J. 
Published: April 2023

Abstract
The laboratory mouse is the premier animal model system for in vivo studies of the genetic and genomic basis of cancer in humans. Although thousands of mouse models have been generated, finding relevant data and knowledge about these models is complicated by a general lack of compliance in the published literature with nomenclature and annotation standards for genes, alleles, mouse strains, and cancer types. The Mouse Models of Human Cancer database (MMHCdb; tumor.informatics.jax.org) is an expertly curated knowledgebase of cancer phenotypes reported for diverse types of mouse models of human cancer such as inbred mouse strains, genetically engineered mouse models (GEMMs), Patient Derived Xenografts (PDXs), and mouse genetic diversity panels (e.g., the Collaborative Cross). MMHCdb includes data on more than 60,000 mouse models for over 1200 tumor classifications curated from more than 25,000 peer-reviewed publications.
One of the primary goals of the MMHCdb is to highlight the impact of genetic background on the incidence and presentation of different tumor types in mice. The same allele on different backgrounds can result in very different cancer characteristics and, therefore, impact the appropriateness of a model for a specific research application. In MMHCdb, users can review the impact of genetic background on the frequency of spontaneous tumors for inbred mouse strains using an interactive table generated from different published and unpublished data sources. In addition, color-coded tabular summaries of individual papers are available that allow researchers to quickly assess how genetic background affects cancer phenotypes in the mouse models reported in a specific publication. We will highlight examples of how genetic background can profoundly change the types and frequencies of tumor types that can be expected in mouse models of human cancer.
MMHCdb is supported by NCI R01 CA089713
Citation Format: Dale A. Begley, Debra M. Krupke, Steven B. Neuhauser, Emily L. Jocoy, John P. Sundberg, Carol J. Bult. The impact of genetic background on cancer phenotypes of mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 14.
Abstract 140: Clonal evaluation of ERG/SPINK1 status to determine disease progression using whole mount prostatectomy specimens
Authors: Cho Joonyoung , Suh In Hye , Chang HyeYoon , Kwak Tae-Yeong , Kim Sun Woo , Palanisamy Nallasivam 
Published: April 2023

Abstract
Most primary prostate cancers are multifocal, marked by distinct tumor foci. Multiclonality is not routinely incorporated at clinical evaluation, however, marker status as a pathological parameter holds great potential for improving prognostic accuracy. Here, we evaluated the frequency of multiclonality and whether ERG/SPINK1 status is correlated to aggressive disease in whole-mount specimens.
For each of the 89 radical prostatectomy cases, one H&E-stained whole-mount slide and a corresponding dual ERG/SPINK1 IHC stained slide were collected. Aperio AT2 scanner (Leica Biosystems) digitized these slides into whole-slide images (WSIs). All WSIs were reviewed by a pathologist with the aid of an automatic Gleason grading software to identify each tumor focus and determine its Gleason grade group (GG), and the expression levels (% uptake) of ERG and SPINK1, respectively. Grade groups 4 and 5 were treated as one high-grade group (GG4-5). The associations among GG, ERG, and SPINK1 expression levels were analyzed.
For each WSI, 1 to 7 (median 2, mean 2.53) tumor foci were identified, and the aforementioned values were determined, resulting in 225 data records. The number of tumor foci, ERG/SPINK1 expression statistics, and their association for each GG are shown in the table. ERG was expressed the most frequently in GG1, and its frequency decreased as the grade increased. Conversely, SPINK1 expression frequency increased with the grade group. The expression of ERG and SPINK1 was inversely correlated regardless of grade group. More detailed results on the exploratory data analysis and the association with BCR will be shared at the time of presentation.
ERG or SPINK1 expression do not appear to be associated with Gleason grade groups. More studies are needed to see if these markers may predict recurrence free survival or patient response to therapy. To our knowledge, this is the first study to map molecular subtypes in whole-mount samples utilizing a foci-based approach.
Table Grade group Total ERG SPINK1 ERG-SPINK1 positive ratio (%) positive ratio (%) co-positive co-negative mutually exclusive GG1 74 38 51.4 24 32.4 4 16 54 GG2 81 35 43.2 40 49.4 7 13 61 GG3 33 11 33.3 22 66.7 4 4 25 GG4-5 37 10 27.0 13 35.1 1 15 21 Overall 225 94 41.8 99 44.0 16 48 161
Citation Format: Joonyoung Cho, In Hye Suh, HyeYoon Chang, Tae-Yeong Kwak, Sun Woo Kim, Nallasivam Palanisamy. Clonal evaluation of ERG/SPINK1 status to determine disease progression using whole mount prostatectomy specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 140.
Abstract 145: Giant cells: A new paradigm to understand tumor origins and decode their complexity at the organismal level
Authors: Liu Jinsong 
Published: April 2023

Abstract
Traditionally, human cancers have been considered genetic-based diseases characterized by somatic mutations. However, despite its wide acceptance, this simple concept cannot explain cancers’ numerous oncogenic driver mutations, structural genomic changes in normal and embryonic tissues, nuclear atypia, and lack of tissue differentiation. Due to these pitfalls, the cancer research community is searching for a new paradigm to explain the complexity of tumors and guide future research. Here I proposed a new hypothesis based on the observation of different tumors and their correlation with stages of early embryonic development in humans to explain human tumors' complexity and origin. I consider cancer a developmental disease of sexual or asexual origin. In tumors of sexual origin, the giant egg cell undergoes cleavage after fertilization to form blastomeres that generate genomic chaos via the rapidly increasing genomic contents of the zygote. The compacted embryo then forms a blastocyst, resulting in embryonic transformation and the formation of the trophectoderm. After implantation, the trophectoderm develops into a placenta, and the inner cell mass develops into a baby or a differentiated tumor resembling a specific embryonic tissue stage or fetal organ if one or more germ layers fail to complete differentiation. In tumors of asexual origin, the tumor starts with senescent somatic cells. Following environmental and genetic stresses, the senescent cells undergo escape via genomic duplication or multiplication, giving rise to polyploid giant cancer cells (PGCCs), the somatic equivalent of blastomeres. This leads to genome duplication or multiplication to create genomic chaos and the development of high-grade cancer with a high level of nuclear atypia, a process analogous to sexual-mediated pre-embryogenesis but without subsequent differentiation. This new hypothesis not only explains the different tumor entities and their benign and malignant natures but also provides a unified explanation of the chaotic genomics and somatic mutations of cancer during embryonic development. The evidence to support this hypothesis will be presented from the pathology, developmental, and genetic perspectives. The switch from conceiving cancer as a disease of mitosis-based cell proliferation to conceiving it as a disease arising from giant cell-mediated development provides a new paradigm to decode tumors' complexity, understand their origins at the organismal level, and guide future cancer research.
Citation Format: Jinsong Liu. Giant cells: A new paradigm to understand tumor origins and decode their complexity at the organismal level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 145.
Abstract 1495: Developing a model to investigate the roles of biomolecular condensates in papillary renal cell carcinoma
Authors: So Choon Leng , Lee Jane , Huang Binglin , Cai Danfeng 
Published: April 2023

Abstract
Cells are compartmentalized into “classical” membrane-bound organelles such as the endoplasmic reticulum and mitochondria. Cells also have membrane-less organelles (MLOs), which are formed through phase separation. Examples of MLOs include stress granules and nucleoli, where macromolecules (proteins, DNAs, RNAs) coherently and dynamically concentrate into biomolecular condensates resembling droplets in lava lamps. MLOs play central role in cellular processes - choreographed events such as transcription and RNA splicing take place in MLOs. MLOs are highly organized, and their dysregulation always led to diseases. Papillary renal cell carcinoma (PRCC) is the second most common RCC in America. PRCC is an aggressive cancer, yet the uncharacterized molecular etiology results in the lack of effective treatment for patients. Our lab and others have observed dysregulated oncoproteins MLOs in PRCC. However, the molecular properties and functions of these aberrant MLOs have not been characterized. The photolyase homology region of Arabidopsis thaliana Cry2 (Cry2WT) is a light-sensitive protein that self-associate with blue light exposure. We hypothesize that fusing dysregulated MLOs oncoproteins with Cry2WT will allow us to tune and study the oncoproteins condensates. We aim to develop an optogenetic model to study how oncoproteins condensates function in PRCC cells. Dysregulated oncoproteins were fused to mCherry-Cry2WT, introduced into cell line models, light-activated and imaged using a ZEISS LSM 900 microscope. We found that blue-light indeed induced proteins clustering when oncoproteins were fused to mCherry-Cry2WT but not with mCherry-Cry2WT alone. This model will allow us to tune the formation of oncoproteins condensates. Future work will involve studying how optogenetically tuned oncoproteins condensates function in PRCC patient-derived cell lines.
Citation Format: Choon Leng So, Jane Lee, Binglin Huang, Danfeng Cai. Developing a model to investigate the roles of biomolecular condensates in papillary renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1495.