tbuckley/cabot-search huggingface dataset:
Abstract 6803: TRIM16 regulates IL-6 secretion in head and neck cancer-associated fibroblasts
Authors: Thuc Ly, Bailey Pickard, Avisha Pandey, Noraida Martinez-Rivera, Eduardo Rosa-Molinar, Michael Washburn, Wen-Xing Ding, Sufi Mary Thomas
Journal: Cancer Research (2024)

Abstract Despite current therapy, head and neck squamous cell carcinoma (HNSCC), the 7th most common cancer worldwide, is associated with high morbidity and mortality. Response to current therapies could be improved with a better understanding of the tumor microenvironment of HNSCC. We previously reported that cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the HNSCC microenvironment, have elevated levels of basal autophagy than oral fibroblasts from cancer-free subjects (NF). Disrupting autophagy in CAFs with Beclin-1 siRNA reduced secretion of IL-6, IL-8, and other factors known to promote HNSCC progression. The recent emerging role of autophagy in secretion of tumor promoting factors has high impact because (i) the mechanism can provide a new target to block the secretion of protumor factors from CAFs that contribute to HNSCC progression, and (ii) these cytokines can serve as potential indicators for the efficacy of autophagy-targeted therapies. To this end, we carried out an unbiased assessment of the proteins associated with autophagosomes in primary CAFs from HNSCC samples using mass spectrometry. We performed immunoprecipitation of LC3B from the isolated small vesicles of the CAFs, identified and validated the association of several trafficking proteins in secretory autophagy including VAMP3 and SNAP23. Further, the tripartite motif (TRIM) proteins have been shown to mediate the fate of autophagosomes either for degradation or secretion. We hypothesized that TRIM proteins are involved in transport of secretory autophagosomes. Our data demonstrate CAFs express higher levels of TRIM16 mRNA than NF. We demonstrate immunogold labeling of TRIM16 or IL-6 localized to the autophagosomes using transmission electron microscopy. Further, using immunofluorescence, we demonstrated the colocalization of TRIM16 and IL-6, as well as IL-6 and LC3B in cytoplasmic puncta. In addition, we used proximity ligation assays to confirm the interaction of TRIM16 and IL-6, as well as IL-6 and LC3B. TRIM16 knockdown using siRNA in CAFs reduced the secretion of IL-6 as measured by ELISA. In conclusion, we demonstrate an important role of TRIM16 in secretory autophagy making it a potential therapeutic target to mitigate CAF-mediated HNSCC growth. Citation Format: Thuc Ly, Bailey Pickard, Avisha Pandey, Noraida Martinez-Rivera, Eduardo Rosa-Molinar, Michael Washburn, Wen-Xing Ding, Sufi Mary Thomas. TRIM16 regulates IL-6 secretion in head and neck cancer-associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6803.
Abstract 4367: PTEN/AKT signal promotes cholangiocyte fate in liver tumorigenesis by inducing SOX9 overexpression and crosstalk with Notch activation
Authors: Qi Tang, Jingyu Chen, Ni Zeng, Lina He, Shefali Chopra, Diala Alhousari, Phillip Nguyen, Guo Zhang, Bangyan L. Stiles
Journal: Cancer Research (2024)

Abstract Cholangiocarcinoma (CCA) is the second most dominant primary liver malignancy next to hepatocellular carcinoma (HCC), and among the most mortal among human cancers. The PI3K/AKT signaling pathway was considered a permissive signal for the development of CCA. To explore how the PI3K/AKT signal contributes to CCA development, we deleted Pten, the lipid phosphatase that negatively regulates the PI3K/AKT signal in the liver. The Lv-PTEN (PtenloxP/loxP; Alb-Cre+) mice developed a mixed HCC and CCA tumor phenotype with all mice developing CCA by 12-month age. Treatment of Lv-PTEN mice with DDC at 3 months to obstruct the bile duct leads to an earlier CCA oncogenesis. Deletion of Akt2 in the Lv-PTEN mice (Lv-DM, Akt2loxP/loxP; PtenloxP/loxP; Alb-Cre+) significantly attenuates tumor development. Compared with the Lv-PTEN mice, loss of AKT2 in Lv-DM mice robustly and significantly reduced the expression of SOX9, a cholangiocyte gene. This data suggests that the AKT signal may permit a cholangiocyte fate by inducing SOX9 expression. Supporting the role of PTEN/AKT in permitting a cholangiocyte fate, SOX9 expression is also induced in the livers of mice where Pten deletion is targeted to the hepatocytes via injection of AAV8-TGB-Cre (Hp-PTEN, PtenloxP/loxP; R26RYFP; AAV8-TBG-Cre). Similar to the Lv-PTEN mice, treatment with DDC induced early onset of CCA development in the Hp-PTEN mice. We next explore Notch signal for its crosstalk with PTEN loss that permits CCA development. Notch signal is robustly induced in the tumors of the Lv-PTEN mice and induced with DDC treatment in both Lv-PTEN and Hp-PTEN livers. We showed that exposure to Jag1 ligand-coated extracellular matrix or expression of NICD also induced the expression of SOX9 while DAPT time-dependently attenuated the expression of SOX9. In the Hp-Pten mice treated with DDC, inhibiting the Notch pathway with DAPT attenuated ductal reaction and led to downregulation of SOX9 in the Lv-PTEN livers, suggesting a positive regulatory role of Notch on SOX9. These data support that Notch activation regulates SOX9 and collaborates with PTEN loss to drive cholangiocyte fate and CCA development. Citation Format: Qi Tang, Jingyu Chen, Ni Zeng, Lina He, Shefali Chopra, Diala Alhousari, Phillip Nguyen, Guo Zhang, Bangyan L. Stiles. PTEN/AKT signal promotes cholangiocyte fate in liver tumorigenesis by inducing SOX9 overexpression and crosstalk with Notch activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4367.
Abstract 7287: High-grade serous ovarian carcinoma detected with <i>TP53</i> mutation panel and SiMSen-Seq
Authors: Amanda Olsson Widjaja, Peter Micallef, Benjamin Ulfenborg, Maria Lycke, Ulf Gyllensten, Therese Carlsson, Tobias Österlund, Anders Ståhlberg, Anna Linder, Karin Sundfeldt
Journal: Cancer Research (2024)

Abstract Background: Ovarian carcinoma (OC) has the highest mortality among gynecologic malignancies due to absent or unspecific symptoms. The high-grade serous ovarian carcinoma (HGSC) accounts for over 60% of the OC associated deaths. The most frequent genetic aberrations in HGSC are mutations in the TP53 gene, detected in approximately 96% of the tumors. Previous studies have proposed potential diagnostic utility of detecting mutations in circulating tumor DNA (ctDNA) from OC patients. However, the need for diagnostic methods capable of detecting asymptomatic HGSC is unmet. Objectives: The primary aims of this study were to design a screening tool for identification of HGSC and to evaluate the suitability of various clinical specimen types for diagnostic applications. Methods: In this study, we designed a highly sensitive and robust screening tool using the simple, multiplexed, PCR-based barcoding of DNA for sensitive mutation detection using sequencing (SiMSen-Seq) technique for identification of HGSC (n=11) by TP53 mutation profile in various clinical specimen for diagnostic applications. Specimens sampled included primary tumors, ascites, plasma, vaginal samples, and both liquid and solid samples from cyst-, endocervical-, and endometrial origin (n=94). Results: The in-house designed panel amplified 17 regions, encompassing 619 nucleotide positions within the TP53 gene. Pathogenic variants were identified in 10/11 of the primary tumors, with a VAF ≥ 9% (range: 9-91). Preliminary data indicated that all (100%) paired samples obtained corresponding somatic mutations between two or more of the different compartments from the same patient. In total 10/10 ascites-, 16/16 cyst-, 8/8 plasma-, 5/8 vaginal-, 17/22 endocervical-, and 14/19 endometrial samples showed somatic variants at a consensus read depth of 3 and a minimum VAF ≥ 0.1%. Conclusion: The present study suggests that the TP53 mutation panel can identify somatic variants in a variety of non-invasive liquid biopsies. Additionally, the assessment of the TP53 mutation panel exhibits potential for forthcoming clinical utilization as a diagnostic tool. Citation Format: Amanda Olsson Widjaja, Peter Micallef, Benjamin Ulfenborg, Maria Lycke, Ulf Gyllensten, Therese Carlsson, Tobias Österlund, Anders Ståhlberg, Anna Linder, Karin Sundfeldt. High-grade serous ovarian carcinoma detected with TP53 mutation panel and SiMSen-Seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7287.
Abstract 4338: A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution
Authors: Hanghui Ye, Thomas McDonald, Emi Sei, Darlan Conterno Minussi, Min Hu, Chenling Tang, Junke Wang, Kaile Wang, Anna Casasent, Hui Chen, Franziska Michor, Nicholas Navin
Journal: Cancer Research (2024)

Abstract Aneuploidy is a hallmark of human cancers and studies have shown that cancer patients harbor many differences in their copy number aberrations (CNAs) reflecting interpatient heterogeneity (IPH). While IPH has been studied extensively, the intratumoral heterogeneity (ITH) of CNAs within a tumor remains understudied. Here, we conducted a pan-cancer analysis of 94 human tumor samples at single cell genomic resolution, representing seven major cancer types: bladder, breast, colon, glioblastoma, kidney, lung, and ovary. In total, 62,646 aneuploid cells were analyzed by single cell copy number profiling and bulk exome sequencing was performed. In most cancer types, increased subclonal diversity was associated with higher CNA burden, whole genome doubling (WGD) events, and TP53 mutations. In all tumors, our data show that cancer cells share a clonal set of truncal CNAs or mutations, suggesting these tumors evolved from a single ancestral cell. In 18/94 cases we identified subclonal WGD events, which resulted in a higher number of copy number losses after tetraploidization. Macro-spatial sampling showed that increased clonal diversity also correlated with increased spatial geographical diversity. We found that many cancers evolved CNAs in short punctuated bursts of evolution, and that this was not restricted to a specific cancer type. Collectively, these data show that copy number ITH is universally associated with molecular features across these human cancer types. Citation Format: Hanghui Ye, Thomas McDonald, Emi Sei, Darlan Conterno Minussi, Min Hu, Chenling Tang, Junke Wang, Kaile Wang, Anna Casasent, Hui Chen, Franziska Michor, Nicholas Navin. A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4338.
Abstract 5113: Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma
Authors: Zi-Lu Huang, Zhi-Gang Liu, Qi Lin, Ya-Lan Tao, Xinzhuoyun Li, Patricia Baxter, Jack MF Su, Adekunle M. Adesina, Chris Man, Murali Chintagumpala, Wan Yee Teo, Yu-Chen Du, Yun-Fei Xia, Xiao-Nan Li
Journal: Cancer Research (2024)

Abstract Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of the biological activities beyond the classic DNA damage, we treated 6 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 4/6 PDOX models (P&amp;lt;0.05) and widespread γH2AX positivity in &amp;gt;95% tumor cells in tumor core and &amp;gt;85% in the invasive foci, accompanied by ~30% apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species buildup, were detected together with the accumulation of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies. Citation Format: Zi-Lu Huang, Zhi-Gang Liu, Qi Lin, Ya-Lan Tao, Xinzhuoyun Li, Patricia Baxter, Jack MF Su, Adekunle M. Adesina, Chris Man, Murali Chintagumpala, Wan Yee Teo, Yu-Chen Du, Yun-Fei Xia, Xiao-Nan Li. Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5113.
Abstract 3721: EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination in colorectal cancer
Authors: Jianling Yang, Jiaqi Huang, Qianqian Yin, Lixiang Xue
Journal: Cancer Research (2024)

Abstract The regulation of PD-L1 is the key question which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. The epigenetic mechanism is involved in transcriptional regulation towards PD-L1. However, besides the transcription level, the protein stability of PD-L1 is closely correlated to its function and has drawn more and more attention. In this study, EZH2 inhibition could enhance PD-L1 expression and protein stability, and the deubiquitinase ubiquitin-specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition upregulates the expression of USP22 via canonical mechanism, and upregulated USP22 further stabilize PD-L1. Importantly, a combination of EZH2 inhibitors with anti-PD-1 immune checkpoint blockade therapy could improve the tumor microenvironment, promotes immune cell infiltration, enhances sensitivity to immunotherapy and exerts synergistic anti-cancer effects. In addition, knocking down USP22 could potentially enhance the therapeutic efficacy of EZH2 inhibitor on colon cancer. These findings unveil the novel role of EZH2 inhibitors (EZH2i) in tumor immune evasion by upregulating PD-L1. Although it may be one reason of EZH2i inefficacy due to the fact that it elicits the immune suppressive effect, appropriately utilizing this drawback to arouse PD-L1 expression may convert the tumor into more responsive upon ICI cancer therapy. In addition, the EZH2-USP22-PD-L1 regulatory axis could further facilitating to identify populations sensitive to immunotherapy or provide novel strategy for combined treatment. Therefore, these findings provide valuable insights into the intricate interplay between EZH2 and PD-L1, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment. Citation Format: Jianling Yang, Jiaqi Huang, Qianqian Yin, Lixiang Xue. EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3721.
Abstract 3153: Regulation of ATF4-mediated stress responses by NUAK2 in ovarian cancer
Authors: Li Chen, Oscar GW Wong, Claire LY Cheung, Esther SY Wong, Karen KL Chan, Hextan YS Ngan, Yusanne YS Chan, Annie NY Cheung
Journal: Cancer Research (2024)

Abstract NUAK family kinase 2 (NUAK2) a member of the AMPK-related serine/threonine kinase family with crucial roles in various cancer cellular processes. The aim of this study was to elucidate the expression and functions of NUAK2 in ovarian cancer while investigating the underlying molecular mechanisms. Analysis of several publicly available databases suggested a significant increase in NUAK2 mRNA levels in ovarian cancer compared to normal tissue. The overexpression of NUAK2 in ovarian cancer was confirmed by immunohistochemistry of NUAK2 in our local collection of ovarian tumor tissues comprised of carcinomas of various histological types (N=88) as well as benign and borderline tumors (N=19). Intense nuclear NUAK2 immunoreactivity was observed in serous and clear-cell carcinomas. Furthermore, nuclear expression of NUAK2 was significantly correlated with higher tumor grade and poorer overall and disease-free survival. Knocking out NUAK2 in SKOV3 cells by CRISPR-Cas9 resulted in suppressed cell growth and migration. Transcriptome by RNA sequencing and pathway enrichment analysis of SKOV3 cells overexpressing NUAK2 revealed activation of activating transcription factor 4 (ATF4) -dependent unfolded protein response (UPR) in the cell. NUAK2 knockout exaggerated the reactive oxygen species level induced by the endoplasmic reticulum (ER) stress inducer tunicamycin treatment. NUAK2 upregulated ATF4 protein expression during ER stress, facilitating its translocation into the nucleus upon exposure to tunicamycin. SKOV3 with NUAK2 knockout grew significantly slower than its parental line in mice as demonstrated by in vivo imaging. Collectively, our study highlights NUAK2 as an oncogene in ovarian cancer and underscores its involvement in the UPR pathway. Citation Format: Li Chen, Oscar GW Wong, Claire LY Cheung, Esther SY Wong, Karen KL Chan, Hextan YS Ngan, Yusanne YS Chan, Annie NY Cheung. Regulation of ATF4-mediated stress responses by NUAK2 in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3153.
Abstract 5295: Tumor targeted-CD28 bispecific antibody with optimized potency, robust anti-tumoral activity and stringent CD3-dependence
Authors: Xiguang Zhang, Shiqi Cao, None Li, Shuaixiang Zhou, Yao Xiong, Dian Kang, Feifei Wang, Jie Ren, Keke Fei, Jianglu Wang, Jinchang Lu, Huizhong Xiong
Journal: Cancer Research (2024)

Abstract CD28 is an essential co-stimulatory signal (Signal 2) for optimal T cell function upon TCR/CD3 activation (signal 1). However, clinical development of CD28 agonist antibodies has been confounded by toxicities presumably from CD3-independent and/or tumor non-specific activation. Here we report a rationally screened CD28 agonist antibody with optimized potency, from which a PSMAxCD28 bispecific was made. The bispecific antibody had several unique features: (1) minimal activity in the absence of CD3, even under stringent conditions, (2) superior tumor killing in vivo alone and in combination with anti-PD1 antibody, (3) requirement of abundant level of PSMA for activation, sparing PSMAlow cells, and (4) extended half-life in human-CD28 KI mice. To summarize, our anti-CD28 bispecific antibody enhances dependence on TCR/CD3 (Signal 1), induces selective killing of PSMA high expressing cancer cells, and elicits robust tumor eradiation in-vivo with extended PK. These features may translate to further improvements in efficacy and safety for tumor-targeted CD28 bispecific antibodies. Citation Format: Xiguang Zhang, Shiqi Cao, Li, Shuaixiang Zhou, Yao Xiong, Dian Kang, Feifei Wang, Jie Ren, Keke Fei, Jianglu Wang, Jinchang Lu, Huizhong Xiong. Tumor targeted-CD28 bispecific antibody with optimized potency, robust anti-tumoral activity and stringent CD3-dependence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5295.
Abstract 4351: Differential dependency mapping of chimeric RNAs across cancer reveals a new landscape of functional fusion transcripts
Authors: Samir Lalani, Sehajroop Gadh, Justin Elfman, Sandeep Singh, Hui Li
Journal: Cancer Research (2024)

Abstract Chimeric RNAs are RNA transcripts containing sequences originating from multiple distinct genetic loci and can form through a variety of mechanisms such as DNA rearrangement, cis-splicing of adjacent genes, or RNA trans-splicing. Chimeras have long been known to be a hallmark of cancer and due to their unique properties are promising targets for precision medicine. Appropriately, fusion proteins transcribed from chimeras such as BCR-ABL1 and TPM3-NTRK1 have been shown to be effective targets. Due to these past successes, there exists an opportunity to identify new chimeras as therapeutic targets. While modern chimera prediction software allows for the fast and accurate identification of chimeric RNAs from RNA sequencing data, investigations separating therapeutically relevant transcripts from “transcriptional noise” remain lacking. In this study we performed an in-silico functional screen of chimeras across cell lines representing a wide variety of cancers. We used state-of-the-art chimeric RNA prediction software to create a database of chimeric RNAs across 1017 cell lines from The Cancer Cell Line Encyclopedia. For each chimera we assessed factors such as frequency, recurrence, breakpoint coordinates, frame, and coding potential. To identify specific functional transcripts, we integrated publicly available shRNA knockdown data with our predictions and developed an in-silico functional analysis pipeline comparing differential knockdown effects between chimera and corresponding parental transcripts. For each transcript we assessed the average fold change of chimera-mapping probes, a function score defined as the difference between the fold change of chimera-mapping and parent-specific probes, and a p-value assessing the confidence of our functional score. From our initial screen of 127,819 transcripts, we identified 1088 high-confidence functional chimeras. We successfully identified nearly all known functional chimeras screened including PAX3-FOXO1, EWSR1-FLI1, and TCF3-PBX1. We also identified previously unknown chimeras that that we predict have a function in cell growth and proliferation. Overall, the results of our study reveal a new landscape of functionally relevant chimeric transcripts in cancer. Follow-up studies can further investigate these transcripts to determine their potential as therapeutic targets. Citation Format: Samir Lalani, Sehajroop Gadh, Justin Elfman, Sandeep Singh, Hui Li. Differential dependency mapping of chimeric RNAs across cancer reveals a new landscape of functional fusion transcripts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4351.