tbuckley/cabot-search huggingface dataset:
Abstract 6216: Single cell DNA sequencing of BRAF treatment resistant anaplastic thyroid cancer
Authors: Aatish Thennavan, Maxime Tarabichi, Per Wu, Meghan Martin, Ramona Dadu, Maria Cabanillas, Nafia Busaidy, Ying C. Henderson, Mark Zafereo, Michelle D. Williams, Stephen Lai, Nicholas Navin, Jennifer R. Wang
Journal: Cancer Research (2024)

Abstract Anaplastic thyroid cancer (ATC) is one of the most lethal cancers. Although dramatic responses to BRAFV600E-mutated ATC are seen with BRAF/MEK inhibition, treatment resistance inevitably develops, limiting survival. In this study we sequentially profiled BRAFV600E-mutated ATC at diagnosis, after BRAF/MEK targeted therapy and at the time of disease recurrence using both bulk and single-cell DNA/RNA sequencing. We profiled (~400-800 single cells) for each patient - Patient 1 (n = 704 cells); Patient 2 (n = 817 cells) and Patient 3 (n = 407 cells). At diagnosis, we show that tumor cell populations were characterized by a predominance of arm-level aneuploidies. Across all patients, there is a sharp decline in tumor cells post BRAF-targeted treatment. Interestingly, we observe at least 2 distinct tumor subclones present in the pre-treatment tumor and subsequently there was an expansion event that occurred in each patient after BRAF treatment. This was associated with acquiring unique copy number aberrations (CNA)events and the dominance of these subclones in the recurrent disease. For Patient 2, we also performed single-cell RNA sequencing and show that the recurrent tumor cells have high proliferation and stem-cell like cell states even though they had higher differentiation scores. Importantly, correlating the scDNAseq identified CNA with the inferred CNA from scRNAseq, we show proof of concept that copy number aberrations can be directly correlated with gene expression changes and gene dosage effects. Collectively our data reveal an early polyclonal dissemination model of clones in BRAF-mutated ATCs and suggests that treatment resistance to BRAF inhibition develops as a results of incomplete elimination of viable tumor cell reservoirs in ATC. Citation Format: Aatish Thennavan, Maxime Tarabichi, Per Wu, Meghan Martin, Ramona Dadu, Maria Cabanillas, Nafia Busaidy, Ying C. Henderson, Mark Zafereo, Michelle D. Williams, Stephen Lai, Nicholas Navin, Jennifer R. Wang. Single cell DNA sequencing of BRAF treatment resistant anaplastic thyroid 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 6216.
Abstract 5862: Retrotransposable elements mediate the drug-tolerant persistence in claudin-low breast cancer chemo-treatment
Authors: Zijian Zhang, Yiyang Wang, Xinlong Luo, Xiaomei Zhan, Jun Ding, Tao P. Wu
Journal: Cancer Research (2024)

Abstract The emergence of acquired drug resistance through treatment remains a critical threat to efficient cancer therapies, which most often lead to relapse and metastasis. The development of resistance is an evolutionary adaptation process that heavily depends on tumor heterogeneity (underpinned by cellular plasticity). Therefore, a longitudinal deconvolution of treatment adaptation is critical to uncover the driving-force mechanisms underpinning resistance adaptation. In the clinic, chemotherapy remains the mainstream treatment for TNBC, and one of the primary chemo-agents is doxorubicin. Although the initial responsive rate of doxorubicin-based chemotherapies is up to 70%, it is well recognized that TNBC cells usually generate an adaptive response and result in acquired drug-resistance and multi-drug resistant phenotypes. Although numerous mechanisms of chemo-resistance evolution have been proposed, most of these studies focused on the initial and terminal states, from which we could not deconvolute the adaptation routes and might miss the transient fate-switching events. We hypothesize that the claudin-low TNBC chemo-resistant cells may derive from the early-stage reversible chemo-tolerant persistent state, and early-stage state-switching mediated by epigenetic landscape reprogramming might determine the adaptation through treatment. We developed an in vitro “pulsing-treatment” model to test the hypothesis, which could mimic the clinical treatment and provide therapeutically relevant insights into the acute drug-induced stress response and regrowth. Unexpectedly, we found that the human endogenous retrovirus-like elements (HERVs) show an aberrant bursting in the adaptation. To further interrogate the adaptation, we did the longitudinal single-cell multi-omics sequencing. With a novel bioinformatic workflow, we integrated the HERV’s expression information with protein-coding genes profiling and chromatin accessibility. The preliminary result indicated that a subpopulation of HERV-high cells might transiently mediate the persistence of cancer cells at the early stage of the treatment, which coupled with whole transcriptomic and chromatin landscape reprogramming, and molecular subtype switching. In this study, we employed a new strategy to investigate the longitudinal adaptation route through treatment and uncover a non-canonical element, which shed new light on drug resistance research and novel target screening. Citation Format: Zijian Zhang, Yiyang Wang, Xinlong Luo, Xiaomei Zhan, Jun Ding, Tao P. Wu. Retrotransposable elements mediate the drug-tolerant persistence in claudin-low breast cancer chemo-treatment [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 5862.
Abstract 5868: Upregulation of HER3 and MET in non-small cell lung cancer cells resistant to EGFR tyrosine kinase inhibitor
Authors: Margaret Larsen, Hui Lyu, CongCong Tan, Yakun Wu, Bolin Liu
Journal: Cancer Research (2024)

Abstract Introduction: Prior research demonstrates the importance of studying epidermal growth factor receptor (EGFR) activating mutations for better understanding the biology of non-small cell lung cancer (NSCLC), which comprises the majority (~80%) of lung cancers. EGFR-targeted tyrosine kinase inhibitors (TKIs) have been used in the clinic to treat NSCLC with EGFR activating mutations. First and second-generation EGFR-TKIs are effective in NSCLC patients with the most common EGFR mutations (exon 19 deletion (Del19) and exon 21-point mutation (L858R)). A third generation EGFR-TKI, osimertinib (AZD9291), has been developed to target the T790M resistance mutation, but patients are starting to show resistance to this line of therapy as well. Our study aims to elucidate the underlying mechanism(s) of EGFR-TKI resistance in NSCLC cells. Methods: NSCLC cell lines, including PC-9 and HCC827, which have the Del19 EGFR activating mutation, were utilized for experiments. From the parental cell lines, several cell lines resistant to the EGFR-TKIs were previously established. Cell proliferation (MTS) assays were used to confirm the resistance phenotype of the established cell lines. Western blot assays and RT-qPCR were utilized to determine changes in the expression level of several membrane receptors and their downstream effectors. Results: Our preliminary analysis showed that both human epidermal growth factor 3 (HER3) and mesenchymal-epithelial transition factor (MET) were upregulated in the EGFR-TKI-resistant cell lines as compared to their parental counterparts. Further studies revealed an increased level of phosphorylated STAT3 (p-STAT3) and ERK1/2 (p-ERK1/2) in the resistant cell lines when compared to the parental cell lines, suggesting the possible involvement of HER3 and/or MET in the activation of downstream signaling pathways. Upregulation of HER3 and MET was found at both the protein and mRNA level. Conclusion: Based on our initial findings, membrane receptors, including HER3 and MET, could be working together to continue activating downstream signaling pathways to evade the effects of osimertinib, resulting in resistance. Additional work is underway to define the role of HER3 and MET in the NSCLC cells resistant to EGFR-TKIs. Citation Format: Margaret Larsen, Hui Lyu, CongCong Tan, Yakun Wu, Bolin Liu. Upregulation of HER3 and MET in non-small cell lung cancer cells resistant to EGFR tyrosine kinase inhibitor [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 5868.
Abstract 1840: MYBBP1A AMPylated by SELO to influence its function
Authors: Wu Li
Journal: Cancer Research (2024)

Abstract Introduction: MYBBP1A, named Myb-binding protein 1A, is a protein that mainly locates in nucleolar and shuttles between the nucleus and cytoplasm, nuclear import may be mediated by KPNA2, however export depend partially on XPO1/CRM1. It activates or represses transcription via interactions with sequence specific DNA-binding proteins. Repression may be mediated at least in part by histone deacetylase activity (HDAC activity). Acts as a corepressor and in concert with CRY1, represses the transcription of the core circadian clock component PER2. Preferentially binds to di-methylated histone H3 'Lys-9' (H3K9me2) on the PER2 promoter. MYBBP1A overexpressed in tumor than normal and have a significantly negative correlation with patient overall survival. We aim to explore the role of MYBBP1A in PDAC progression and underlying mechanism. In our research, we find and prove the novel AMPylating enzyme SELO-AMPylate MYBBP1A inhibits PDAC progression and modified site in S1353 and further influence downstream relative RNA, such as 18s rRNA, 28S rRNA. Methods and Materials: 1. The function of MYBBP1A in tumorigenesis at the organismal and cellular levels. MYBBP1A is widely expressed in different tissues. Firstly, we explored the correlation between MYBBP1A expression level and PDAC through TCGA database and Kaplan-Meier plotter. We then established MYBBP1A gene knockout mice mating with PDX/P53K172H/KRASG12C to induced a primary PDAC model to analyze the progression of pancreatic cancer. The effect of MYBBP1A on tumor cell growth and proliferation was explored through cell proliferation analysis and a nude mouse tumor xenograft model. 2. The MYBBP1A AMPylated by SELO influence MYBBP1A function in cell proliferation was investigated at the molecular and cellular levels. AMPylation-specific antibodies were used to confirmed MYBBP1A AMPylated by SELO in both cell lysates and purified proteins through experiments such as CO-IP and WB. Stably expressed MYBBP1A WT/S1353A were constructed to verify the function in cell proliferation or migration by SELO. The signaling molecules were further explored through CO-IP and WB to identify the changed molecular by SELO-AMPylate-MYBBP1A, revealing the entire signaling pathways of AMPylation-mediated regulation of PDAC proliferation. Conclusion: We have demonstrated the function of MYBBP1A in the formation of pancreatic cancer, and further revealed SELO-AMPylate-MYBBP1A importance in the process of reversing MYBBP1A’s role, which has played a certain significance for the treatment of pancreatic cancer and the exploration of related therapeutic targets. Citation Format: Wu Li. MYBBP1A AMPylated by SELO to influence its function [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 1840.
Abstract 2765: Novel WNT-RIP1-GDF15 pathway promotes migration and invasion of colorectal cancer cells
Authors: A-Ram Kang, Do Hoon Kim, Jong Kuk Park
Journal: Cancer Research (2024)

Abstract Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor β (TGF-β) family protein, also known as NSAID-activated gene 1 (NAG-1) or macrophage inhibitory cytokine 1 (MIC-1), and is a major cause of cancer cachexia, cardiovascular disease, and various inflammatory diseases. Roles of GDF15 as major inflammatory response factor also have been demonstrated in animal models, and it has also showed various malignant functions such as regulating metabolism, promoting metastasis by inducing EMT in cancer. Here, we revealed a novel potential role for RIP1 in colorectal cancer (CRC) in enhancing metastasis by controlling WNT-RIP1-GDF15 signaling. We showed that WNT3A treatment increased the expression of GDF15 and GFRAL. Immunohistochemical analysis of human CRC tissue arrays consisting of primary cancer and metastatic cancer also confirmed that the expression of GDF15 and GFRAL was increased in metastatic cancer. Human XL cytokine assay, western blot, and ELISA results confirmed that GDF15 expression was reduced in cell lines in which RIP1 was knocked down. Reduction of GDF15 expression and secretion by RIP1 knockdown showed suppression of EMT induction resulting to decrease of migration and invasion of CRC cells. Taken together, these results suggest a novel EMT-enhancing role for RIP1 in the WNT pathway and suggest a novel WNT-RIP1-GDF15 pathway contributing to CRC malignancy by promoting EMT. Citation Format: A-Ram Kang, Do Hoon Kim, Jong Kuk Park. Novel WNT-RIP1-GDF15 pathway promotes migration and invasion of colorectal cancer cells [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 2765.
Abstract 281: The function of FGFR2+ cancer-associated fibroblasts on cancer stem cell expansion of esophageal squamous cell carcinoma
Authors: Ying Wang, Ping Feng, Tong-chao Jiang, Xin-yuan Guan, Yun-fei Xia
Journal: Cancer Research (2024)

Abstract Aims: FGFR2+ fibroblasts were reported to promote tumor progression, but the mechanisms remained unexplored in esophageal squamous cell carcinoma (ESCC).Methods: Multiplex immunohistochemistry (mIHC) displayed the distributions of FGFR2+ fibroblasts and cancer stem cells (CSCs). After FGFR2+ fibroblast isolation, tumor cells were stimulated with fibroblasts supernatant to assess radioresistance and CSC properties. RNA-seq analysis identified the downstream BMP5 expression.Results: In our preliminary study, the immunohistochemistry results showed that FGFR2+ fibroblasts were always represented in the area near cancer stem cells (CSCs), and FGFR2+ fibroblasts infiltration was associated with poor outcomes. When we cocultured FGFR2+ fibroblasts with tumor cells, we found the proportion of CSCs were upregulated. The results of RNA sequencing and ELISA showed that FGFR2+ fibroblasts overexpressed BMP5. Using FGFR2+ fibroblasts or BMP5 to stimulate cancer cells, the proportion of cancer stem cells was increased, the capabilities of sphere formation and survival after radiation were enhanced. Both RNA sequencing and immunoblotting results indicated that BMP5 affected H2AX phosphorylation in DNA repair pathway and activated its potential upstream pathway MAPK signaling pathway. In vivo experiments also showed that FGFR2+ fibroblasts could upregulate CSCs proportions.Conclusions: Our findings suggested that BMP5 derived from FGFR2+ fibroblasts might induce CSCs expansion and led to poor prognosis in the ESCC. Citation Format: Ying Wang, Ping Feng, Tong-chao Jiang, Xin-yuan Guan, Yun-fei Xia. The function of FGFR2+ cancer-associated fibroblasts on cancer stem cell expansion of esophageal squamous cell carcinoma [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 281.
Abstract 5806: Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus
Authors: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Chiung-Tong Chen, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chen-Lung Huang, Ya-Ping Chen, Hong Zhuang
Journal: Cancer Research (2024)

Abstract Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A (AURKA) inhibitor that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer (BC) cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC- overexpressing xenografts including SCLC, triple-negative breast cancer (TNBC), hepatocellular carcinoma and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Chiung-Tong Chen, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chen-Lung Huang, Ya-Ping Chen, Hong Zhuang. Discovery of a long half-life AURKA inhibitor to treat MYC-amplified solid tumors as a monotherapy and in combination with everolimus [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 5806.
Abstract 2814: Rectal implantation paves the path to evaluate the metabolic machinery responsible for CRC metastasis
Authors: Said M. Afify, Chen Shen, Siva B. Merugu, Daniel T. Wynn, Anmada Nayak, Wenhui Lu, Ricardo M. Calderin, Evan Pannkuk, Sung H. Hong, Nagi G. Ayad, David J. Robbins
Journal: Cancer Research (2024)

Abstract Introduction: Colorectal carcinoma patients die most often from distant metastases in liver and lung. It is crucial to develop metastatic models for the CRC in order to better understand the process, which will help in treatment. Method: Using orthotropic transplantation techniques, we tried to test whether rectal implantation could produce spontaneous metastases in-vivo mimicking colorectal cancer. The rectum was injected orthotopically with 0.2 × 106 HCT116 cells. In order to confirm metastasis, histopathological examinations were performed. Further, we generated cancer organoids to evaluate population susceptibility to CRC metastasis and metabolic mechanisms responsible for metastasis process. Results: We found that rectal implantation was an effective method for simulating CRC cancer metastasis using H&amp;E staining and immunohistochemistry. In less than four weeks after the implant, HCT116 spontaneously metastasized to the liver, lungs, and D lymph node. When compared with cancer organoids derived from primary tumors, liver and lung metastases organoids proliferated more often, were more aggressive, and displayed distinct characteristics. Using non-targeting metabolomic analysis, it was found that metastases derived organoids and primary tumors derived organoids were distinguished by novel metabolites. Conclusion: By implantation in the rectal cavity, we can evaluate the metabolic machinery that leads to CRC metastasis. In the future, implantation of patient-derived samples will become increasingly important. Citation Format: Said M. Afify, Chen Shen, Siva B. Merugu, Daniel T. Wynn, Anmada Nayak, Wenhui Lu, Ricardo M. Calderin, Evan Pannkuk, Sung H. Hong, Nagi G. Ayad, David J. Robbins. Rectal implantation paves the path to evaluate the metabolic machinery responsible for CRC metastasis [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 2814.
Abstract 4654: Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs
Authors: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Melina Khorrami, Melika khorrami, Raul caballero Montes, Paria Mosaffa, Ashley Hoffman, Amber Su
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian cancer (HGSOC) is remarkably responsive to chemotherapy and yet recurs at high rates as resistant disease. Using novel technology that selects for rare clonogenic cells which recapitulate HGSOC in immunodeficient mice, we have identified, in therapy-naive HGSOC, a minor population of clones that are intrinsically resistant to paclitaxel/carboplatin as well as to a broad spectrum of oncology drugs. These intrinsic "polyresistant" cells are a common, albeit minor, component of clonogenic cells in all therapy-naive tumors analyzed. Importantly, the polyresistant clonogenic cells share a gene expression signature distinct from the majority of clonogenic cells that are exquisitely sensitive to paclitaxel/carboplatin, and this gene signature of polyresistant cells extends to all polyresistant clones within a patient and across HGSOC cases. We have exploited these polyresistant clones to perform high-throughput screening of small molecule "bioactive" libraries to identify compounds that circumvent this resistance. While single agent "hits" were obtained, these showed minimal therapeutic windows relative to normal stem cells of the liver and gastrointestinal tract. Adaptations of synthetic lethal strategies have yielded lead drug combinations that eliminate polyresistant clones from all four cases tested at low nanomolar concentrations in vitro. We have improved these combinations via the synthesis of new chemical entities that show potent effects against both subcutaneous and peritoneal tumor models in immunodeficient mice derived from polyresistant HGSOC clones. Clonogenic analyses of these treated and untreated xenografts support the notion that these drug combinations are targeting the stem cell populations within these tumors. We anticipate that these drug combinations will assist in preventing or treating recurrent HGSOC. Citation Format: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Melina Khorrami, Melika khorrami, Raul caballero Montes, Paria Mosaffa, Ashley Hoffman, Amber Su. Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs [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 4654.