bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR003: Lineage plasticity dictates responsiveness to anti-GD2 therapy in neuroblastoma
Authors: Mabe Nathaniel W. , Huang Min , Schaefer Daniel A. , Dalton Guillermo N. , Digiovanni Giulia , Alexe Gabriela , Geraghty Anna C. , Khalid Delan , Mader Marius M. , Sheffer Michal , Linde Miles H. , Ly Nghi , Rotiroti Maria Caterina , Smith Benjamin A. H. , Wernig Marius , Bertozzi Carolyn R. , Monje Michelle , Mitsiades Constantine , Majeti Ravindra , Satpathy Ansuman T. , Stegmaier Kimberly , Majzner Robbie G. 
Published: December 2022

Abstract
Epigenetic dysregulation is frequently observed in the disease pathology of pediatric cancers, including neuroblastoma, the most common extracranial solid tumor in pediatric patients. Neuroblastoma tumors co-opt developmentally linked adrenergic or mesenchymal super-enhancer landscapes that rewire their transcriptional programs. Here, we describe that the lineage commitment to a mesenchymal epigenetic state is an important mechanism of resistance to anti-GD2 therapy through loss of GD2 antigen, a ganglioside glycolipid expressed on the cell surface. Low GD2 expression was significantly correlated with the mesenchymal state in a large panel of neuroblastoma cell lines and a forced adrenergic-to-mesenchymal transition conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2 expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Genome-wide CRISPR/Cas9 screening to identify regulators of GD2 in neuroblastoma revealed that the ablation of the polycomb repressive complex 2 (PRC2) significantly upregulates GD2 expression in GD2-low cells. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells into an adrenergic-like state, re-expressed ST8SIA1, and restored surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential PRC2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
Citation Format: Nathaniel W. Mabe, Min Huang, Daniel A. Schaefer, Guillermo N. Dalton, Giulia Digiovanni, Gabriela Alexe, Anna C. Geraghty, Delan Khalid, Marius M. Mader, Michal Sheffer, Miles H. Linde, Nghi Ly, Maria Caterina Rotiroti, Benjamin A. H. Smith, Marius Wernig, Carolyn R. Bertozzi, Michelle Monje, Constantine Mitsiades, Ravindra Majeti, Ansuman T. Satpathy, Kimberly Stegmaier, Robbie G. Majzner. Lineage plasticity dictates responsiveness to anti-GD2 therapy in neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR003.
Abstract PR008: An epigenetic memory of inflammation controls context-dependent lineage plasticity and KRAS-driven tumorigenesis in the pancreas
Authors: Falvo David J. , Grimont Adrien , Zumbo Paul , Yang Julie L. , Osterhoudt Alexa , Pan Grace , Rendeiro Andre F. , Wilkinson John Erby , Dundar Friederike , Elemento Olivier , Yantiss Rhonda K. , Betel Doron , Koche Richard , Chandwani Rohit 
Published: December 2022

Abstract
Tissue homeostasis depends on responses to environmental insults to restore cellular phenotype, microenvironment composition, and tissue architecture. Inflammation is essential to the disruption of homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. Herein we employ lineage-traced mouse models to delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and unveil the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. In vivo, this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that both persistent chromatin and transcriptional changes constituting memory are recalled with oncogenic stress. Together, our findings define a capacity for an environmental insult to control future cell-fate decisions in a context-dependent manner. The ability of epigenetic memory to potentiate tumor initiation both broadens the relationship between inflammation and cancer and raises the possibility that inducing epigenetic ‘amnesia’ of an inflammatory insult could be leveraged as a novel cancer prevention strategy.
Citation Format: David J. Falvo, Adrien Grimont, Paul Zumbo, Julie L. Yang, Alexa Osterhoudt, Grace Pan, Andre F. Rendeiro, John Erby Wilkinson, Friederike Dundar, Olivier Elemento, Rhonda K. Yantiss, Doron Betel, Richard Koche, Rohit Chandwani. An epigenetic memory of inflammation controls context-dependent lineage plasticity and KRAS-driven tumorigenesis in the pancreas. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR008.
Abstract A001: The development of a multilevel risk prediction model to identify risk of failure to complete CRC screening
Authors: Petrik Amanda F. 
Published: December 2022

Abstract
Context: The use of predictive analytics can help health systems target the right services to the right patients at the right time while improving population health. Multilevel data, or data at the interpersonal, organizational, community, and policy levels, is rarely sought after but may be used to improve risk prediction by providing information about a patient and the many groups to which they belong. Colorectal cancer screening promotion can be expensive and not all patients need it. Objective: This study sought to develop a risk prediction model using individual data available in the EHR, and then compared a multilevel risk prediction model using publicly available multilevel data. Study design and analysis: Retrospective data was used to develop a risk model, using logistic regression, first in data available in the EHR, and then adding multilevel data. Setting or dataset: This retrospective data only study was conducted at Kaiser Permanente Northwest. Population studied: Patients were eligible who were 50-75 years old, had been members at KPNW for at least a year before their birthday in 2018, and if they were due for screening. Results: The individual level model was sufficient and included 14 characteristics, and had a bootstrap corrected C-statistic of 0.722. The multilevel model added 9 variables, and the bootstrap corrected C-statistic was 0.724. Conclusions: Models can be used to identify patients unlikely to screen, although the performance of the model after adding multilevel data did not improve. Screening models could help in population health management of CRC screening.
Citation Format: Amanda F. Petrik. The development of a multilevel risk prediction model to identify risk of failure to complete CRC screening [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A001.
Abstract A015: Targeting necroptosis and RIP3 in colorectal cancer to overcome chemotherapeutic resistance
Authors: Ermine Kaylee A. , Chen Dongshi , Wang Peng , Yu Jian , Zhang Lin 
Published: December 2022

Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. When metastatic, chemotherapeutic drug 5-fluorouracil (5-FU) is typically used for treatment, but resistance often occurs. Many studies have shown that 5-FU induces apoptosis in cancer cells, but when apoptosis is inhibited, cell death can still occur, suggesting that other forms of cell death are occurring. Necroptosis, or regulated necrosis, is an alternative form of cell death, controlled by RIP1, RIP3, and MLKL, and its role in anticancer therapy remains unclear. TCGA RNAseq data show that RIP3 is significantly downregulated in primary CRC tumors, with RIP3 downregulation correlating with worse clinical outcomes. Analysis of numerous established CRC cell lines revealed that RIP3 expression was downregulated in ~50% of the cell lines, with low RIP3 expression being associated with decreased 5-FU sensitivity. These data led us to hypothesize that RIP3 expression and necroptosis may play a critical role in response to anticancer therapies, such as 5-FU, and that restoring defective necroptosis may enhance therapeutic sensitivity. Our preliminary studies have shown that RIP3-expressing (RIP3+) CRC cell lines are able to undergo both apoptosis and necroptosis in response to 5-FU, which could explain the enhanced sensitivity. As expected, knock-out of RIP3 in RIP3+ cells resulted in decreased 5-FU sensitivity, as well as abrogated necroptosis induction. Additionally, transient restoration of RIP3 in RIP3-silenced (RIP3-) CRC cells appeared to enhance 5-FU sensitivity, and so, we generated a stable RIP3-expressing cell line through retroviral infection. Although the stable RIP3-expressing cell line did not appear to be more sensitive to 5-FU alone, it did show enhanced sensitivity under conditions where apoptosis is inhibited. Together, our results suggest that RIP3 plays an important role in 5-FU-induced cell death in CRC, and that restoring RIP3 when the apoptosis pathway is implicated could provide a way to enhance 5-FU sensitivity and overcome resistance. The results from this project provide novel insight into the role of RIP3 in mediating response to anticancer therapy in CRC, which could be used for development of improved therapies and personalized medicine based on RIP3 status in the clinic.
Citation Format: Kaylee A. Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang. Targeting necroptosis and RIP3 in colorectal cancer to overcome chemotherapeutic resistance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A015.
Abstract B001: Inverse relationship between tissue fusobacterium nucleatum amount and CD274 (PD-L1) expression of colorectal carcinoma
Authors: Ugai Tomotaka , Shimizu Takashi , Kawamura Hidetaka , Takashima Yasutoshi , Väyrynen Juha P. , Kahaki Seyed Mostafa Mousavi , Okadome Kazuo , Masugi Yohei , da Silva Annacarolina , Zhang Xuehong , Chan Andrew T. , Wang Molin , Meyerhardt Jeffrey A. , Nowak Jonathan A. , Song Mingyang , Giannakis Marios , Ogino Shuji 
Published: December 2022

Abstract
Background: The CD274 (programmed cell death ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence suggests that Fusobacterium nucleatum (F. nucleatum) promotes colorectal carcinogenesis through its suppressive effect on antitumor immunity. We hypothesized that tumor CD274 overexpression and intratumor abundance of F. nucleatum might tend to be mutually exclusive immune evasion mechanisms in colorectal cancer. Methods: We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative polymerase chain reaction in 812 cases among 4,465 incident colorectal cancer cases that had occurred in the Nurses’ Health Study and the Health Professionals Follow-up Study. To adjust for potential confounders and selection bias due to tissue data availability, inverse probability weighting was integrated into multivariable ordinal logistic regression analyses to examine the association of tumor CD274 expression with the amount of intratumor F. nucleatum. Results: Tumor CD274 expression was negative in 93 (11%), low in 231 (28%), intermediate in 210 (26%), and high in 278 (34%) of 812 cases. F. nucleatum DNA was detected in tumor tissue in 109 (13%) cases of 812 cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue. For one category increase in three ordinal F. nucleatum categories (negative, low, and high), multivariable-adjusted odds ratios (with 95% confidence intervals) of the low, middle, and high CD274 expression categories (vs. negative) were 0.78 (0.41-1.51), 0.64 (0.32-1.28), and 0.50 (0.25–0.99), respectively (Ptrend=0.032). Conclusions: We found that CD274 expression was inversely associated with the amount of F. nucleatum in colorectal cancer tissue. Our findings suggest that a colorectal tumor tends to have either of the immune evasion mechanisms, i.e., PDCD1 (PD-1) immune checkpoint activation and intratumor abundance of F. nucleatum.
Citation Format: Tomotaka Ugai, Takashi Shimizu, Hidetaka Kawamura, Yasutoshi Takashima, Juha P. Väyrynen, Seyed Mostafa Mousavi Kahaki, Kazuo Okadome, Yohei Masugi, Annacarolina da Silva, Xuehong Zhang, Andrew T. Chan, Molin Wang, Jeffrey A. Meyerhardt, Jonathan A. Nowak, Mingyang Song, Marios Giannakis, Shuji Ogino. Inverse relationship between tissue fusobacterium nucleatum amount and CD274 (PD-L1) expression of colorectal carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B001.
Abstract B007: LIN28B promotes collective cell invasion and colorectal cancer metastasis via a novel CLDN1 and NOTCH3 axis
Authors: Shin Alice E. , Sugiura Kensuke , Masuike Yasunori , Suzuki Kensuke , Lengner Christopher J. , Rustgi Anil K. 
Published: December 2022

Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death worldwide. The 5-year survival rate is 90% in patients with localized tumors, but the survival rate drastically decreases to 14% in patients with distant metastasis. Therefore, it is imperative to elucidate the molecular mechanisms underlying CRC metastasis. The RNA-binding protein LIN28B is overexpressed in over 30% of patients with CRC and is associated with poor prognosis. Indeed, our previous work revealed that LIN28B promotes liver metastasis in a subcutaneous xenograft model of CRC as well as a portal vein injection model. In the present study, we investigated the mechanism by which LIN28B promotes colorectal tumor progression and metastasis. To assess biological changes induced by LIN28B, we established CRC cells (DLD-1 and LoVo) with high expression of LIN28B (LIN28Bhigh). LIN28B overexpression upregulated Claudin-1 (CLDN1), a protein that functions as a major constituent of the tight junction complexes. RNA immunoprecipitation revealed that LIN28B directly binds to and stabilizes CLDN1 at a post-transcriptional level. Knockdown of CLDN1 expression in LIN28Bhigh cells suppresses cell aggregation, wound healing rate, and collective invasion. Using a mouse model of metastatic CRC, we reveal that knockdown of CLDN1 inhibits liver metastasis of LIN28Bhigh CRC cells. RNA-sequencing of metastatic liver tumors from LIN28Bhigh cells showed that NOTCH3 works downstream of the LIN28B-CLDN1 axis to induce cell aggregation, collective invasion, and metastatic liver tumor formation. Inhibition of Notch signaling by DAPT, an inhibitor of the γ-secretase complex, significantly reduced metastatic liver tumors in vivo. Taken together, our results indicate that LIN28B promotes cell aggregation, invasion, and liver metastasis in CRC through post-transcriptional induction of CLDN1 and upregulation of NOTCH3. Development of new therapies that target LIN28B-CLDN1-NOTCH3 axis may provide an effective strategy for stage 4 CRC. This work was supported by 9R01CA277795-22.
Citation Format: Alice E. Shin, Kensuke Sugiura, Yasunori Masuike, Kensuke Suzuki, Christopher J. Lengner, Anil K. Rustgi. LIN28B promotes collective cell invasion and colorectal cancer metastasis via a novel CLDN1 and NOTCH3 axis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B007.
Abstract B014: Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death
Authors: Jenkins Laura J. , Luk Ian Y. , Fairlie Walter D. , Lee Erinna F. , Palmieri Michelle , Schoffer Kael L. , Tan Tao , Ng Irvin , Vukelic Natalia , Tran Sharon , Tse Janson , Nightingale Rebecca , Alam Zakia , Chionh Fiona , Iatropoulos George , Ernst Matthias , Afshar-Sterle Shoukat , Desai Jayesh , Gibbs Peter , Sieber Oliver M. , Dhillon Amardeep S. , Tebbutt Niall C. , Mariadason John M. 
Published: December 2022

Abstract
The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumor organoids in vitro,and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only pro-apoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in CRCs, by combining a HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT ; KRASG12C , BRAFV600E CRC cell lines respectively. These findings identify a series of ERK/MAPK genotype tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.
Citation Format: Laura J. Jenkins, Ian Y. Luk, Walter D. Fairlie, Erinna F. Lee, Michelle Palmieri, Kael L. Schoffer, Tao Tan, Irvin Ng, Natalia Vukelic, Sharon Tran, Janson Tse, Rebecca Nightingale, Zakia Alam, Fiona Chionh, George Iatropoulos, Matthias Ernst, Shoukat Afshar-Sterle, Jayesh Desai, Peter Gibbs, Oliver M. Sieber, Amardeep S. Dhillon, Niall C. Tebbutt, John M. Mariadason. Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B014.
Abstract B016: Inhibition of KRASG12C in colon cancer illustrates a link between beta-catenin, WNK, and the GID complex
Authors: Nayak Kasturi , Hwang Yeonjoo , Wang LeeAnn , Swaney Danielle L. , Krogan Nevan J. , Gordan John D. 
Published: December 2022

Abstract
KRAS is mutated in 35%-45% of colorectal cancers (CRC), and KRAS mutational status determines the prognosis and therapeutic options available to patients with advanced CRC. Direct KRASG12C inhibitors have proven to be highly effective for patients with non-small cell lung cancers, but unfortunately are relatively ineffective in the treatment of CRC. Thus, we have investigated tissue-specific mechanisms of resistance to direct KRAS inhibition. We used multiplex inhibitor bead kinome profiling (MIBs) and global phosphoproteomic analysis to determine the signaling response to the KRASG12C inhibitor ARS-1620 in four human colon cancer cell lines. Analyzing the kinome revealed a profound reprogramming beyond the Ras/MAPK pathway. We used network propagation to integrate analysis across these lines and define essential signaling nodes modified by direct KRAS inhibition, including two distinct signaling nodes containing RAS/MAPK and WNT-regulating kinases. Two additional smaller nodes contained WNK kinases and their effectors, followed by Hippo and a number of cell cycle-related kinases. The WNK kinases have been identified to modulate beta-catenin, a major driver of CRC biology, via the GID E3 ubiquitin ligase complex. Thus, to understand the signaling that links KRAS and beta-catenin, we used small molecule inhibitors of these kinases along with ARS-1620, we tested how they affected the transcription of beta-catenin targets. Additionally, we assessed the correlation between WNK/GID complex, and beta-catenin transcriptional output using western blot and quantitative real time PCR and observe that inhibition of KRASG12C also modulates beta-catenin transcriptional output. Our results identify new families of possible kinase targets in CRCs expressing KRAS mutations and shed light on the relationship of KRAS, beta-catenin, and WNK/GID in CRC maintenance. By dissecting these signaling relationships, we hope to identify potential drug combinations to overcome primary resistance KRASG12C inhibition in CRC.
Citation Format: Kasturi Nayak, Yeonjoo Hwang, LeeAnn Wang, Danielle L. Swaney, Nevan J. Krogan, John D. Gordan. Inhibition of KRASG12C in colon cancer illustrates a link between beta-catenin, WNK, and the GID complex [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B016.