tbuckley/cabot-search huggingface dataset:
Abstract 295: Induction of senescent cancer associated fibroblasts promotes cancer cell growth
Authors: Shengliang Zhang, Lanlan Zhou, Leiqing Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2025)

Abstract Cancer associated fibroblasts (CAF) are heterogenous and plastic population in the tumor microenvironment (TME), and each of the CAF subtypes plays a different role in cancer progression and suppression. Chemotherapy can induce CAF senescence, and cell senescence has been known to promote tumor growth and drug resistance. To investigate the role and molecular mechanism of the senescent CAF to promote tumor growth, we set up methods to induce CAF senescence by Chemotherapy or Radiation therapy using two gastrointestinal CAF cell lines CK4520 and CK8612. The flow cytometry showed around 40% of the cells with beta-gal staining in both CK8612 and CK4520 by the Etoposide (40 uM) treatment, and around 80-90% of the cells with beta-gal staining by the X-ray (20 Gy) treatment in both CK8612 and CK4520. Western blot assay showed an increase in p21 and p53 at protein level, and a decrease in Lamin B1 at the protein level in both CK8612 and CK4520 by the X-ray treatment. The cytokine profiling showed an increase in IL6, IL8, and CXCL2 and other factors related to senescence in CK4520 cells treated with X-ray and Etoposide. These results indicate the CAF senescence. In addition, the cytokine profiling also showed the different senescence-associated secretory phenotype (SASP) in CK4520 cells between X-ray and Etoposide treatment, and the different SASP also observed between CK4520 and CK8612 upon the X-ray treatment. To determine if the senescent CAF promotes tumor growth, we generated the conditioned medium using the senescent CK4520. Cancer cells cultured with the conditioned medium showed an increase in cell viability in different cancer cell lines. These results suggest that SASP of the senescent CAF promotes cancer cell growth. Citation Format: Shengliang Zhang, Lanlan Zhou, Leiqing Zhang, Wafik S. El-Deiry. Induction of senescent cancer associated fibroblasts promotes cancer cell growth [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 295.
Abstract 112: ROR1 drives tumor-initiating cells in pancreatic cancer
Authors: Masaya Yamazaki, Takatsugu Ishimoto
Journal: Cancer Research (2025)

Abstract Tumor-initiating cells are key players in driving chemoresistance and metastasis, making them promising targets for cancer therapy. However, the identity of tumor-imitating cells and molecular mechanisms underlying their capacity in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. To address this, we conducted single-cell RNA sequencing and functional studies in human PDAC xenografts to identify targetable tumor-initiating cells. We found that a subpopulation characterized by a partial epithelial-mesenchymal transition (EMT)-like signature and high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) serves as the origin of intratumor heterogeneity in PDAC. Functional analyses demonstrated that ROR1high cells have high tumorigenicity and ROR1 promotes tumor growth, relapse following chemotherapy, and metastasis. We also showed that ROR1 prevents PDAC progression. Mechanistically, ROR1 activates the E2F transcriptional network via c-Myc, accelerating tumor cell hyperproliferation by inducing Aurora kinase B (AURKB). Moreover, epigenomic analyses revealed that ROR1 expression is flexibly controlled by the enhancer through the YAP/BRD4 axis. Targeting this pathway with a BET inhibitor effectively downregulated ROR1 expression and suppressed PDAC organoid growth. Collectively, our findings implicate ROR1high cells as tumor-initiating cells in PDAC and illuminate the therapeutic potential of ROR1 as a promising strategy for PDAC. Citation Format: Masaya Yamazaki, Takatsugu Ishimoto. ROR1 drives tumor-initiating cells in pancreatic 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 112.
Abstract 517: YAP-TEAD-mediated tumor suppression and immune modulation of gastric adenocarcinoma by HSP90 inhibition
Authors: Katsuhiro Yoshimura, Gengyi Zou, Yibo Fan, Kohei Yamashita, Jingjing Wu, Ruiping Wang, Shan Shao, Ailing Scott, Jiankang Jin, Melissa Pizzi, Xiaodan Yao, Calena Brown, Lingzhi Wang, Linghua Wang, Qiong Gan, Rebecca Waters, Yin Feng, Shumei Song, Shilpa Dhar, Jaffer Ajani
Journal: Cancer Research (2025)

Abstract Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the in-vitro and in-vivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, evoking in down-regulation of target functional genes. AUY922 additionally altered the TME into an inflamed state with increased cytokine production in T-cells and inhibition of M2-polarization of tumor-associated macrophages, rendering it a favorable partner for immune checkpoint inhibition. Our findings highlighted the suggestion of targeting HSP90 in GAC therapy via down-regulating YAP1/TEAD signaling. Further, results suggest that AUY922's ability to reshape the GAC TME favoring the host sets the stage for a clinical trial that combines HSP90 and checkpoint inhibition, where HSP90 could serve as a biomarker for patient selection. Citation Format: Katsuhiro Yoshimura, Gengyi Zou, Yibo Fan, Kohei Yamashita, Jingjing Wu, Ruiping Wang, Shan Shao, Ailing Scott, Jiankang Jin, Melissa Pizzi, Xiaodan Yao, Calena Brown, Lingzhi Wang, Linghua Wang, Qiong Gan, Rebecca Waters, Yin Feng, Shumei Song, Shilpa Dhar, Jaffer Ajani. YAP-TEAD-mediated tumor suppression and immune modulation of gastric adenocarcinoma by HSP90 inhibition [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 517.
Abstract 3394: Impact of gBRCAs mutation on the surgery decisions of Chinese breast cancer (BC) patients: a single-center real world study in Xijing Hospital, Northwest China
Authors: Ting Wang, Jing Fan, Jiajun Ding, Jing Kong, Mengxuan Li, Yidi Wang, Huimin Meng, Haoyi Zi, Qingxia Li, Shuai Wang, Fei Yao, Changbing Zhu
Journal: Cancer Research (2025)

Abstract Background and Objective: Germline BRCA (gBRCA) mutations complicate clinical surgery management due to a higher risk of initial breast cancer, as well as increased chances of new primary cancers or local recurrence. In this study, we examined the surgical decisions for individuals carrying gBRCA mutations. Methods: In this real world study, 1050 female patients with unilateral operable invasive breast cancer getting gBRCA mutation test were enrolled. Pearson chi-square test, continuous correction chi-square test and Fisher's exact test were used to explored the association between gBRCA mutation and surgery choice appropriately. Results: Germline BRCA1 mutations (gBRCA1mut), Germline BRCA2 mutations (gBRCA2mut) and gBRCA1/2mut were found in 5.1% (54/1050), 4.9% (51/1050), 10.0% (105/1050) BC patients separately. Among all patients, those with gBRCAsmut preferred contralateral prophylactic mastectomy than those without mutation (9.3% gBRCA1mut patients compared with 2.0% gBRCA1wt patients, 7.8% gBRCA2mut patients compared with 2.1% gBRCA2wt patients, 8.6% gBRCA1/2mut patients compared with 1.7% gBRCA1/2wt patients, all p&amp;lt;0.05). This tendency could also be found in early-stage BC patients (n=699). While in young (≤40) BC patients (n=346), there were no significant differences in choice between gBRCAsmut cohort and gBRCAswt cohort. Though in all patients, the selection of specific surgery [breast-conserving surgery (BCS), mastectomy or reconstruction surgery] was not affected by gBRCAs mutations. In young BC patients, patients with gBRCA2mut were more likely to choose mastectomy or reconstruction surgery rather than BCS (10.3% gBRCA2mut patients selected BCS compared with 34.4% gBRCA2wt patients, p=0.011). The same tendency could also be found in early-stage BC patients though the difference was not statistically significant (p=0.074). The gBRCA1 mutation had no influence on the specific option. Conclusion: Northwest Chinese BC patients made their surgery choice under the influence of gBRCA1/2 mutation. gBRCA2mut played an more crucial role on it. Citation Format: Ting Wang, Jing Fan, Jiajun Ding, Jing Kong, Mengxuan Li, Yidi Wang, Huimin Meng, Haoyi Zi, Qingxia Li, Shuai Wang, Fei Yao, Changbing Zhu. Impact of gBRCAs mutation on the surgery decisions of Chinese breast cancer (BC) patients: a single-center real world study in Xijing Hospital, Northwest China [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 3394.
Abstract 1035: Western lifestyle leads to obesity and cancer via a common factor FTO
Authors: Dong Wu, Ying Qing, Keith Leung, Meiling Chen, Zhicong Zhao, Yangchan Li, Li Han, Wei Li, Zhenhua Chen, Chao Shen, Yuan Che, Tingting Tang, Kitty Wang, Lillian Sau, Zhaoxu Xu, Xiaolan Deng, Jianjun Chen
Journal: Cancer Research (2025)

Abstract FTO, the first identified RNA N6-methyladenosine (m6A) demethylase, has been reported by our group to play an oncogenic role in acute myeloid leukemia (AML) and by others in various solid tumors, including colorectal and liver cancers. Additionally, FTO was the first gene identified through genome-wide association studies (GWAS) to be associated with obesity risk, with evidence linking elevated FTO expression to increased food intake and obesity development. While obesity is a recognized risk factor for cancer, whether FTO serves as a shared factor driving both obesity and cancer remains unclear. To address this knowledge gap, we employed in vivo mouse models with Fto expression manipulated through genetic knockout or pharmacological inhibition to investigate its respective roles in tumorigenesis and obesity. In an ENU-treated spontaneous tumor model, we confirmed that Fto-WT mice showed greater susceptibility to tumorigenesis than Fto-KO mice. When fed a Western diet high in sugar and fat, Fto-KO mice exhibited resistance to diet-induced obesity compared to Fto-WT mice. Similar protective effects against diet-induced obesity were observed in models treated with CS1, a potent small-molecule FTO inhibitor developed by our group. To explore the interplay between obesity and cancer, we established combined obesity-tumor models. Western diet-fed obese mice were either treated with ENU to induce spontaneous tumors or transplanted with MC-38 cells. In both scenarios, CS1 treatment simultaneously reduced obesity and tumorigenesis significantly. Mechanistically, FTO inhibition partially reversed Western diet-induced alterations in immune cell populations, indicating an immune-modulatory role for FTO in the pathogenesis of obesity and cancer. Together, our findings identify FTO as a common factor in the development of obesity and tumor and highlight the potential of targeting FTO for the simultaneous prevention and intervention of these conditions. Citation Format: Dong Wu, Ying Qing, Keith Leung, Meiling Chen, Zhicong Zhao, Yangchan Li, Li Han, Wei Li, Zhenhua Chen, Chao Shen, Yuan Che, Tingting Tang, Kitty Wang, Lillian Sau, Zhaoxu Xu, Xiaolan Deng, Jianjun Chen. Western lifestyle leads to obesity and cancer via a common factor FTO [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 1035.
Abstract 2979: Deletion of p53-related protein kinase (TP53RK) suppresses solar UV-induced photocarcinogenesis by inhibiting PDL1 expression and enhancing CD8+ T cell infiltration
Authors: Qiushi Wang, Eunmiri Roh, Asad Khan, Sally Dickinson, Georg T. Wondrak, Ann Bode, Clara Curiel-Lewandrowski, Tianshun Zhang
Journal: Cancer Research (2025)

Abstract Nonmelanoma skin cancers (NMSCs), including cutaneous squamous cell carcinoma (cSCC), are primarily caused by solar ultraviolet (UV) exposure and represent the most common cancers in the United States. TP53RK (p53-related protein kinase, also known as PRPK) is a protein kinase involved in multiple cancer progression such as colon cancer, myeloma and skin cancer. In this study, we generated epidermal-specific TP53RK knockout mice using CRISPR/Cas9 technology in SKH1 hairless mice with loxP-flanked TP53RK alleles, crossed with keratin 14-Cre (K14.Cre) mice. Our findings reveal that epidermal-specific deletion of TP53RK significantly suppresses tumor growth in solar-simulated light (SSL)-induced NMSC. Mechanistically, TP53RK deletion inhibits proliferating cell nuclear antigen (PCNA) and programmed death-ligand 1 (PDL1) expression, as well as the transcription factors c-Myc, c-Jun, and NF-κB, which mediate PDL1 expression. Using a 3D culture system, we further demonstrate that TP53RK deletion suppresses cSCC cell growth. Flow cytometry analysis indicates that TP53RK deletion enhances CD8+ T cell infiltration into the tumor microenvironment. This is accompanied by significant reductions in IL-6, MIP-2, and VEGF levels, reprogramming the tumor microenvironment to support CD8+ T cell infiltration. In summary, our study demonstrates that TP53RK deletion suppresses solar UV induced photocarcinogenesis by inhibiting PDL1 expression and enhancing CD8+ T cell infiltration, highlighting its potential as a therapeutic target for NMSC. Citation Format: Qiushi Wang, Eunmiri Roh, Asad Khan, Sally Dickinson, Georg T. Wondrak, Ann Bode, Clara Curiel-Lewandrowski, Tianshun Zhang. Deletion of p53-related protein kinase (TP53RK) suppresses solar UV-induced photocarcinogenesis by inhibiting PDL1 expression and enhancing CD8+ T cell infiltration [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 2979.
Abstract 1184: Studying circadian disruption in pancreatic ductal adenocarcinoma
Authors: Ksenija Korac, Sean Ronnekleiv-Kelly
Journal: Cancer Research (2025)

Our long-term goal is to understand the role of the circadian clock in pancreatic ductal adenocarcinoma (PDAC) to shift the therapeutic landscape for patients with this lethal cancer. The circadian clock is a highly conserved molecular feedback loop where cell-autonomous cycling of the core clock genes (e.g. BMAL1, PER1, PER2) controls the expression of numerous other genes to regulate functions such as apoptosis, proliferation, metabolism and immune function. Research has shown that malignant tumors, including pancreatic ductal adenocarcinoma, can dampen the circadian clock to accelerate cancer progression making it an attractive target in cancer therapy. Existing evidence shows that BMAL1 suppression in PDAC leads to a more aggressive phenotype and worse prognosis. To investigate the role of the clock disruption in PDAC, we created and validated a Kras- and p53-mutant PDAC cell line with a disrupted clock, by knocking out the core circadian clock gene BMAL1 which is essential for clock function. We performed syngeneic heterotopic tumor implant studies and found that clock-disrupted PDAC demonstrated substantially increased tumor growth in vivo compared to PDAC with an intact clock. Secondly, we developed a novel patient-derived xenograft approach to discern circadian parameters and identify which patient cancers harbor an intact versus suppressed clock. RNA sequencing of the tumors over 24 hours revealed a striking suppression of BMAL1 expression in patients who presented with a more aggressive disease. Thirdly, to assess the possibility that dysregulation of BMAL1 in PDAC drives a more aggressive phenotype through rewiring of the tumor metabolism, we assessed oxygen consumption and glycolytic flux in our KPC-WT and KPC-BKO cells and found marked differences in mitochondrial respiration and glycolytic function. Overall, targeting the circadian clock in cancer offers a promising avenue for improving patient prognosis by enabling the development of novel therapies. Citation Format: Ksenija Korac, Sean Ronnekleiv-Kelly. Studying circadian disruption in pancreatic ductal adenocarcinoma [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 1184.
Abstract 3411: Transcriptional modulations of tumor microenvironment by BH3120, a PD-L1x4-1BB bispecific antibody, in patient-derived organotypic tumor spheroids (PDOTS) model
Authors: Jun Wang, Jiangcheng Xu, Jing Wang, Jiawang Liu, Kyoungwoo Lee
Journal: Cancer Research (2025)

Abstract BH3120 is an heterodimeric IgG like bispecific antibody in clinical stage targeting PD-L1 (CD274) and 4-1BB (CD137) simultaneously. It binds 4-1BB with moderate affinity while binds PD-L1 with relatively higher affinity, with the aim to focuss PD-L1 binding dependent 4-1BB agonism in tumor microenvironment. De-coupling of immune modulation between tumor and normal tissues were confirmed in multiple non-clinical studies, and the results were consistent with favorable safety profiles. In the meantime, BH3120 shows synergistic anti-tumor efficacy with PD-1 inhibitors without systemic safety concerns in vivo. To understand how BH3120 and the combination with a PD-1 inhibitor modulate the tumor microenvironment, ex vivo studies with patient-derived organotypic tumor spheroids (PDOTS) were generated from freshly obtained tumor tissues of non-small cell lung cancer (NSCLC) patients, and cultured in microfluidic devices containing extracellular matrix. After incubation of the test articles in the ex vivo model, anti-tumor activities and immune modulations were observed by RNA analysis as the response to BH3120, a PD-1 inhibitor, and the combination. In responding tumor spheroids, multiple genes were significantly upregulated or down-regulated. In particular, RNAs representing CD4+ T cell, CD8+ T cell, NK cell, and B cell signals, and certain co-stimulators, proinflammatory cytokines, and chemokines were notably increased. Combination of BH3120 and PD-1 inhibitor resulted in the relevant genetic modulations with high magnitudes implicating potential synergism in RNA level. Citation Format: Jun Wang, Jiangcheng Xu, Jing Wang, Jiawang Liu, Kyoungwoo Lee. Transcriptional modulations of tumor microenvironment by BH3120, a PD-L1x4-1BB bispecific antibody, in patient-derived organotypic tumor spheroids (PDOTS) model [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 3411.
Abstract 1121: Pan-cancer prevalence of unusual MTAP alterations: data from the AACR GENIE database
Authors: Mohamed A. Gouda, Camila B. Xavier, Carlos Torrado, Pooja A. Shah, Kunal Rai, Natalie Vokes, Omar Alhalabi, Mark T. Bedford, Jianjun Gao, Nazanin K. Majd, Jenny Li, Milind Javle, Funda Meric-Bernstam, Jordi Rodon
Journal: Cancer Research (2025)

Abstract Background: PRMT5 inhibitors has shown promising clinical activity in MTAP deficient tumors. Ongoing studies focus on tumors with homozygous MTAP deletions; but that doesn’t span the whole spectrum of MTAP dysfunctional tumors. Herein, we tried to characterize the pan-cancer prevalence of MTAP oncogenic alterations. Methods: We used the AACR GENIE database v.16.1 to extract data on the prevalence of MTAP alterations across different tumor types. OncoKB was used to obtain data on functional significance. Results: We reviewed data from 214, 475 samples obtained from 184, 980 patients. Structural variants, mutations, and copy number alterations in MTAP were profiled in 55, 021, 58, 144, and 57, 382 samples across different cancers; respetively. A total of 46 MTAP fusions were identified; all were likely oncogenic per OncoKB including 12 with level 4 alterations. The most common fusions were MTAP intragenic, MTAP::CDKN2A, and MTAP::CDKN2B fusions. The highest rates of MTAP structural variants were observed in CNS cancers (0.4%; n=1), gastrointestinal neuroendocrine tumor (0.3%; n=1), hepatobiliary cancer (0.2%; n=3), melanoma (0.2%; n=3), and glioma (0.1%; n=5). A total of 356 MTAP mutations were identified; including 82 that were likely oncogenic per OncoKB. The most common mutations that were annotated as likely oncogenic were MTAP A191Rfs*6, MTAP X231_splice, and MTAP X116_splice. The highest rates of MTAP mutations were observed in endometrial cancer (1.6%; n=36), small bowel cancer (1.6%; n=3), non-melanoma skin cancer, (1.5%; n=6), colorectal cancer (1.2%; n=72), and bladder cancer (1%; n=20). The highest rates of MTAP homozygous deletions were observed in glioma (24.6%; n=899), blastic plasmacytoid dendritic cell neoplasm (23.1%; n=3), nerve sheath tumor (18.3%; n=28), mesothelioma (17.7%; n=79), and bladder cancer (16.9%; n=350) (Table 1). Conclusions: The spectrum of MTAP alterations expands beyond MTAP deletions; and could be explored in clinical trials targeting MTAP loss. Citation Format: Mohamed A. Gouda, Camila B. Xavier, Carlos Torrado, Pooja A. Shah, Kunal Rai, Natalie Vokes, Omar Alhalabi, Mark T. Bedford, Jianjun Gao, Nazanin K. Majd, Jenny Li, Milind Javle, Funda Meric-Bernstam, Jordi Rodon. Pan-cancer prevalence of unusual MTAP alterations: data from the AACR GENIE database [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 1121.