tbuckley/cabot-search huggingface dataset:
Abstract 6674: Leucine sensing and mTOR activation drive SNAIL-mediated EMT in pancreatic cancer cells
Authors: Hironori Koga, Yasuko Imamura, Atsutaka Masuda, Hiroyuki Suzuki, Toshimitsu Tanaka, Takahiko Sakaue, Hideki Iwamoto, Toru Nakamura, Takumi Kawaguchi
Journal: Cancer Research (2025)

Abstract Background: Pancreatic cancer, characterized by a highly fibrotic and hypovascular tumor microenvironment, possesses unique metabolic adaptations that enable survival and proliferation in malnourished conditions. Aim: This study aimed to compare the metabolic adaptations of pancreatic cancer cells to glucose deprivation with those of liver cancer cells, which are representative of hypervascular tumors. Methods: Three pancreatic cancer cell lines (BxPC-3, Panc-1, MIA PaCa-2) and two liver cancer cell lines (HuH-7, Hep3B) were analyzed. We examined transcriptional expression levels of genes involved in amino acid transport, including LAT1, CD98, CD147, EPCAM, and ASCT2; epithelial-mesenchymal transition (EMT), including SNAIL, SLUG, and ZEB1; and cancer stemness, including CD24, CD44, and DCLK1, under glucose-deprived conditions. Results: Pancreatic cancer cells displayed significantly lower proliferative activity under glucose deprivation compared to liver cancer cells. While glucose-starved cells did not undergo significant apoptosis, they exhibited cell cycle arrest. Pancreatic cancer cells showed mild arrests in both the G0/G1 and G2/M phases, whereas liver cancer cells exhibited a clear G0/G1 arrest. Among amino acid transporters, LAT1 was uniquely upregulated in pancreatic cancer cells, correlating with increased SNAIL (EMT regulator) and DCLK1 (cancer stemness marker) expression. LAT1 knockdown abolished SNAIL upregulation in glucose-starved pancreatic cancer cells, indicating a mechanistic link. Stimulation of LAT1 by branched-chain amino acids (BCAAs; valine, leucine, isoleucine) under glucose-free conditions induced dose-dependent SNAIL upregulation by leucine, accompanied by increased expression of leucine sensors SAR1B and Sestrin2. This activation triggered mTOR pathway signaling, as evidenced by phosphorylation of S6K1 and 4E-BP1. Conversely, rapamycin inhibited mTORC1 activation, suppressing leucine-induced SNAIL upregulation. Conclusion: Pancreatic cancer cells reprogram their metabolism to adapt to energy crises via leucine-mediated upregulation of SNAIL, potentially enhancing metastatic capabilities through EMT. Targeting LAT1 or the mTOR pathway may represent promising therapeutic strategies for pancreatic cancer. Citation Format: Hironori Koga, Yasuko Imamura, Atsutaka Masuda, Hiroyuki Suzuki, Toshimitsu Tanaka, Takahiko Sakaue, Hideki Iwamoto, Toru Nakamura, Takumi Kawaguchi. Leucine sensing and mTOR activation drive SNAIL-mediated EMT in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6674.
Abstract 4575: mRNA expression in paired saliva and blood samples from different cancer indices
Authors: Srinivas V. Koduru, Mark Kidd, Abdel Halim
Journal: Cancer Research (2025)

Abstract Introduction: Liquid biopsies have become gradually accepted, as a non-invasive alternative to traditional tumor biopsies in the field of oncology. The FDA and other regulatory bodies have already approved blood-based tests and researchers are working on validating urine, saliva and buccal swabs as alternative sample sources. This study’s main goal was to compare mRNA expression levels, in matched blood and saliva samples from cancer patients, as well as apparently healthy individuals. Methods: We collected matched saliva and blood samples from 35 individuals, including 27 patients diagnosed with cancers including Breast (4), Lung (4), Colon (5), Melanoma (3), Pancreatic (4), Prostate (7) cancer along with 9 healthy participants. The samples were collected in Wren’s proprietary buffer kit and RNA was extracted via TRIzol-based method. RNA sequencing was carried out on an Illumina Novaseq 6000. The data was analyzed using high performance computing (HPC) through PartekFlow software with the BWA aligner (hg38). Results: Nearly 94% of the genes found in saliva and 60% of the genes in blood were matched across all cancer types, with the exception of pancreatic cancer in blood, which showed only about 30% matching. We further evaluated both groups based on housekeeping genes (1003 genes) and the known cancer-associated genes as listed in the OncoKB database (1154 genes) for each cancer type. In addition, we investigated the expressions of 412 and 241 cancer genes priorly validated and used in IVD assays, respectively, in our lab. We found that 78-80% of the genes in blood were common across all cancer types, while saliva samples showed 64-73% commonality. Only 43% of genes detected in saliva from pancreatic cancer matched other cancer types. Out of the 241 internally validated cancer genes 68-71% genes were detected in blood and 57-65% in saliva in this cohort except pancreatic cancer where only 30% was detected. Out of the 412 genes, we found 67-69% in blood and 51-58% in saliva, again with the exception of pancreatic cancer, exhibits only 26% of genes. Additionally, 98% of housekeeping genes from blood and 71-87% of housekeeping genes from saliva were consistent, except for pancreatic cancer, which showed only 35%. Conclusion: Our study indicates that the majority of mRNA (94%) detected in saliva from various cancer types was also detected in blood, compared to healthy controls. This suggests that exploring mRNA-based biomarkers development in saliva could be even a more convenient alternative to blood. Citation Format: Srinivas V. Koduru, Mark Kidd, Abdel Halim. mRNA expression in paired saliva and blood samples from different cancer indices [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4575.
Abstract 6659: Defective lipid homeostasis induced by QKI loss is a mutator on gliomagenesis
Authors: Yinglu Guan, Takashi Shingu, Kaylene J. Lu, Ece Kilinc, Traver G. Hart, Jianhua Zhang, Yiwen Chen, Betty Y. Kim, Jian Hu
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is also one of the deadliest and most treatment-resistant cancers with more than 14, 490 cases diagnosed in the United States in 2023. Tumorigenesis is a multistep process that starts with the occurrence of an oncogenic mutation in a single somatic cell. Despite extensive information about mutators for many cancers, the specific mutator driving GBM development remains unclear. Interrogating human glioma genomic and transcriptomic data revealed that defective lipid metabolism is associated with increased structural variants, particularly extrachromosomal DNA (ecDNA) formation. Quaking (QKI) is frequently mutated or deleted in human GBMs. Mechanistically, QKI acts as an RNA binding protein to regulate pre-mRNA stability of genes that regulates lipid components of endolysosomes, particularly the unsaturated fatty acids. We identified that QKI modulates neural stem cells and glioma stem cells lipid metabolism and further maintains membrane integrity in mitochondria and nuclear envelope. Deleting Qki on the Nestin-CreERT2; PtenL/L; Trp53L/L background (QPP) strongly enhances gliomagenesis in mice. Using this model, we found Qki loss promoted somatic driver alterations including focal DNA alterations and oncogene amplification on ecDNA, especially Pdgfra/Kit, which as common oncogenes in ecDNA across both human and QPP mouse GBMs. Collectively, this work elucidates novel mechanisms underlying defective lipid homeostasis induced by QKI loss acts as a mutator in promoting gliomagenesis through inducing genomic instability. Our study provides a deeper insight into lipid metabolic dysregulation of GBM and a candidate for diagnosis and therapy. It will also contribute to the development of therapeutic strategies that specifically target QKI-depleted GBM. Citation Format: Yinglu Guan, Takashi Shingu, Kaylene J. Lu, Ece Kilinc, Traver G. Hart, Jianhua Zhang, Yiwen Chen, Betty Y. Kim, Jian Hu. Defective lipid homeostasis induced by QKI loss is a mutator on gliomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6659.
Abstract 6443: Glia committed progenitor cells orchestrate medulloblastoma relapse
Authors: Kendell Peterson, April Salvador, Pritika Shahani, Maria Turos-Cabal, Valentin Kliebe, Jezabel Rodriguez-Blanco
Journal: Cancer Research (2025)

Abstract Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. Genomic-based classification has stratified MB into four molecular subgroups: Wingless/Int-1 (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. This classification has significantly improved our understanding of MB and facilitated the development of better treatments. However, despite these advancements, approximately 30% of children with MB experience relapse. Recurrent MB is often metastatic, and nearly all children with relapse succumb to the disease within one year, underscoring the urgent need for therapies to prevent recurrence. Tumor relapse in MB is thought to be driven by progenitor cells resembling stages of the neuronal stem cell lineage. These quiescent cells are less susceptible to therapies targeting dividing cells and are therefore unlikely to be driven by mechanisms distinct from the bulk tumor. In our recent work, we described a population of Smoothened (SMO) inhibitor-resistant SRY-box 2 (SOX2)-labeled progenitor cells that facilitate MB recurrence. Single-cell transcriptomic analyses identified these SOX2+ cells as astrocyte progenitor cells (APCs) and revealed their dependence on GLI activity for propagation. In line with this dependency, inhibiting GLI-driven transcription not only reduced tumor size but also depleted APCs, leading to tumors less likely to relapse. However, some treated tumors retained the ability to engraft in vivo, suggesting that additional cells or mechanisms contribute to recurrence. Further studies identified therapy-resistant oligodendrocyte progenitor cells (OPCs) as another population driving MB relapse. OPCs, marked by OLIG2 expression, were enriched following treatment with GLI/SMO inhibitors and standard chemotherapy. Transcriptomic analyses revealed that Nuclear factor-κB (NF-kB) signaling, activated by tumor necrosis factor-alpha (TNF-α) release from microglia, promotes OPC enrichment. Therefore, inhibiting NF-kB signaling in ex vivo and in vivo models prevented therapy-induced OPC enrichment and significantly reduced tumor self-renewal capacity. In conclusion, therapeutic debulking of MB leads to the enrichment of glia-committed progenitor cells (APCs and OPCs), which drive recurrence. Combining therapies that target MB growth with agents that deplete or prevent progenitor cell enrichment may be necessary to prevent relapse. Citation Format: Kendell Peterson, April Salvador, Pritika Shahani, Maria Turos-Cabal, Valentin Kliebe, Jezabel Rodriguez-Blanco. Glia committed progenitor cells orchestrate medulloblastoma relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6443.
Abstract 6666: Translocation-dependent regulation of nucleotide metabolism in response to drug-induced nucleotide stress
Authors: Zaffar Iqbal Bhat, Iqra Ishrat, XiaoMi Lu, Justin L. Tan
Journal: Cancer Research (2025)

Abstract Nucleotide metabolism plays a significant role in cancer development and progression. Cancer cells have an increased demand for nucleotides, which are the building blocks of DNA and RNA, due to their uncontrolled proliferation. Targeting nucleotide metabolism is an important strategy for cancer therapy. However, existing therapies have a small therapeutic window as they induce toxicity in cancer and normal cells alike. Little is known about the mechanisms of nucleotide stress-induced toxicity in cells. In prokaryotes, the PyrR protein senses nucleotide levels by binding UMP. This regulates the ability of PyrR to bind the attenuator region of the pyr operon transcript, thus altering transcription of downstream nucleotide metabolism genes. PyrR therefore acts as a nucleotide sensor in prokaryotes. The paralog of this protein in mammals is yet to be discovered. It is unknown if similar nucleotide sensing mechanisms occur in mammalian cells. Our study aims focused to identify new nucleotide binding proteins that regulate nucleotide metabolism in humans. Here, we identified human proteins that had conserved homology to regions of the prokaryotic PyrR protein. We found similar amino acid sequences to the UMP binding site of PyrR in some candidate eukaryotic proteins. We analyzed the effect of nucleotide stress induction, via treatment with two clinical nucleotide biosynthesis inhibitors, on candidate protein P. P is normally localized in the cytoplasm but upon inhibitor treatment, P translocates into the nucleus. Knockdown of P resulted in decreased, cell viability, which could be rescued by nucleotide addition. Computational simulations identified potential nucleotide binding sites on P. We mutated the potential binding site aminos acids of P and expressed P mutant protein in cells. Unlike wildtype P, P mutant did not translocate into the nucleus upon nucleotide stress. Chromatin immunoprecipitation with high-throughput sequencing (ChIP)-seq revealed that P binds to the promoter regions of nucleotide metabolic genes. Through these studies, we have identified a novel mammalian protein sensor that transcriptionally regulates nucleotide metabolism through nuclear localization. These findings suggest an additional pathway by which nucleotide metabolism is directly regulated in response to the availability of end-product nucleotides. Knowledge of this pathway could propose ways to improve the therapeutic window of nucleotide biosynthesis-based chemotherapy. Citation Format: Zaffar Iqbal Bhat, Iqra Ishrat, XiaoMi Lu, Justin L. Tan. Translocation-dependent regulation of nucleotide metabolism in response to drug-induced nucleotide stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6666.
Abstract 6439: ROME, a novel membrane protein in vertebrates, is a key modulator of embryonal development and cancer metastasis
Authors: Anna Molotkova, Emre Deniz, Matthew Swift, Eric Glasgow, Jeffrey Toretsky, Aykut Üren
Journal: Cancer Research (2025)

Despite many advances in cancer treatment, metastasis remains the major cause of mortality: over 90% of cancer-related deaths are due to metastasis. We chose Ewing sarcoma (ES) as a model to study cancer metastasis since less than 25% of ES patients with metastatic disease live beyond five years and there are no effective therapies available to specifically target metastatic disease. Through an in vivo genome-wide CRISPR/Cas9 transcriptional activation screen using human ES cells as xenografts, we identified the human INAFM2 gene as a strong driver of metastasis and therefore named the vertebrate gene and its protein product, ROME (Regulator of Metastasis). Up until now, INAFM2 has not been studied in-depth and INAFM2 protein expression profile or function is not known. We characterized aspects of ROME expression and function in vertebrate development, physiology, and pathology. Blocking ROME expression in zebrafish embryos resulted in severe developmental defects and early mortality. Single cell RNA sequencing of zebrafish embryos with rome knockdown and RNA sequencing of cancer cell lines with ROME modulation revealed that ROME negatively regulates calcium and canonical Wnt pathways. We also discovered that ROME directly interacts with CAV1, FLOT1, and Vimentin proteins. ROME overexpression increased metastasis of ES xenografts in zebrafish and immunodeficient mice while ROME knockout in ES xenografts reduced metastasis. Human tumor RNA sequencing data revealed a negative correlation between ROME expression and patient survival. In summary, we discovered a previously unstudied human glycoprotein located on the plasma membrane that can regulate cell motility and invasion, is essential for normal development in vertebrates, and increases the metastatic phenotype of human tumor cells. Citation Format: Anna Molotkova, Emre Deniz, Matthew Swift, Eric Glasgow, Jeffrey Toretsky, Aykut Üren. ROME, a novel membrane protein in vertebrates, is a key modulator of embryonal development and cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6439.
Abstract 4059: CDK1-dependent hyperphosphorylation of NFIB governs its pro-metastatic function in SCLC
Authors: Pawel Nowialis, Lina Song, Thi Na Nguyen, Thi Kim Ngan Bui, Wenjing Na, Ryan Clay, Kunyang Li, Lingtao Jin
Journal: Cancer Research (2025)

Abstract Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer. Its ability to form a metastatic spread in the early stages of disease accounts for high morbidity rates. Despite initial high rates of response to the most common line of treatment - conventional chemotherapy, majority of SCLC patients suffer from chemoresistant recurrence. Lack of full understanding of molecular basis driving metastasis and resistance are main obstacles in developing more efficient treatments. Several recent studies reported that nuclear factor I/B (NFIB) plays a role in promoting metastasis of SCLC through modulating chromatin accessibility. Moreover, NFIB is frequently found to be overexpressed or amplified in human SCLC and its high levels correlate with poor overall survival. Although oncogenic properties of NFIB have also been reported in studies on melanoma and triple negative breast cancer, other research, involving non-small cell lung cancer, glioblastoma, osteosarcoma and cutaneous squamous cell carcinoma suggest, that NFIB may also function as a tumor suppressor. The nature of this contradictions remains elusive and implies that the function of NFIB might depend on tissue specific regulation, e.g. post-translation modification (PTM). In this study we demonstrate that NFIB undergoes hyperphosphorylation during M-phase. Utilizing kinase specific inhibitors, siRNA and in vitro assays with recombinant proteins, we identified cyclin-dependent kinase 1 (CDK1) as a specific enzyme responsible for phosphorylation of NFIB during M-phase. Using Mass Spectrometry analysis of PTM of NFIB protein, we discovered specific amino acid targets of CDK1 and generated a quadruple NFIB mutant (Ser-&amp;gt;Ala) construct, unable to undergo hyperphosphorylation during M-phase. qPCR analysis revealed that expression of phospho-incompetent form of NFIB in human SCLC cell lines resulted in altered expression of EMT-related genes in the fashion similar to NFIB knock-down. Altogether, these results suggest that phosphorylation of NFIB by CDK1 regulates its pro-metastatic function in SCLC. It also underlines the value of further research on targeting phosphorylation state of NFIB in aiding standard chemotherapeutic regimes. Citation Format: Pawel Nowialis, Lina Song, Thi Na Nguyen, Thi Kim Ngan Bui, Wenjing Na, Ryan Clay, Kunyang Li, Lingtao Jin. CDK1-dependent hyperphosphorylation of NFIB governs its pro-metastatic function in SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4059.
Abstract 7227: An inducible, spatially restricted mouse model of lung cancer
Authors: Israel Ifeoluwa Odekunle, Sydney Remington, Allison Racela, David J. Seward
Journal: Cancer Research (2025)

Abstract Accurately modeling human lung tumor initiation and progression in genetically engineered mouse models (GEMMs) remains a challenge. In contrast to human lung cancer development, where patients typically present with a solitary tumor nodule, the majority of GEMMs produce numerous independent primary lung lesions. Each of these lesions then evolves as an independent tumor, a situation not relevant to human lung cancer biology. The Cre-loxP recombination system is widely used to generate GEMMs, including the inducible, tamoxifen-dependent systems that allow cell-specific conditional activation via promoter regulation. We have used this system extensively to generate KRAS-driven Lung adenocarcinomas arising from club cells via the club cell secretory protein (CCSP) Cre-ERT2 system. While powerful, this model has limitations. Specifically, limiting tumor induction to a single location within the lung is impossible. To address this limitation, we have combined the highly efficient photoactivable Cre (PA-Cre) recombinase mouse (JAX: 033544) with a novel CCSP-FlpO mouse to spatially limit tumor formation based on targeted blue-light exposure. Exploiting the CCSP promoter enables us to limit FlpO recombinase expression to club cells, thereby confining the two light-activatable Cre halves to club cells. Following focal trans-cutaneous blue light exposure, the PA -Cre halves dimerize and induce the oncogenic alleles, KRAS p.G12D, and Serine Threonine Kinase 11 loss, respectively. We assert that utilizing this approach will overcome major limitations inherent in current GEMMs used to study lung cancer and provide a paradigm-shifting platform to study lung cancer initiation and progression. Citation Format: Israel Ifeoluwa Odekunle, Sydney Remington, Allison Racela, David J. Seward. An inducible, spatially restricted mouse model of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7227.