tbuckley/cabot-search huggingface dataset:
Abstract C050: The unique metabolic signatures of keratin-17 expressing pancreatic ductal adenocarcinomas
Authors: Mahmoud M. Salem, Michael Horowitz, Lyanne Oblein, Chun-Hao Pan, Natalia Marchenko, Luisa Escobar-Hoyos, Bo Chen, Kenneth Shroyer
Journal: Cancer Research (2024)

Abstract Background: Overexpression of Keratin 17 (K17) is associated with upregulation of de novo pyrimidine synthesis, which is linked to resistance to gemcitabine (dC analog) and 5-fluorouracil (dT analog) in pancreatic ductal adenocarcinomas (PDAC). The metabolic rewiring associated with K17 in upstream pathways has not been defined, and the spatial relationships between K17 overexpression and the metabolome are unknown. Understanding these relationships may elucidate the roles of K17 in drug resistance and metabolic phenotypes of PDACs. We test the hypothesis that K17 is spatially linked to alterations of various metabolites, and that there exists an association with the upregulation of upstream pathways to de novo pyrimidine synthesis. Methods: KPC cells transduced to express wtK17 versus an empty vector were orthotopically implanted into the head of the pancreas of mice. Mice were administered 5-FU at 50 mg/kg twice a week. To evaluate the metabolic profile in situ, MALDI-MSI (Matrix-assisted laser desorption/ionization mass spectrometry imaging) was performed on snap-frozen tumor specimens. Following removal of the MALDI matrix, immunohistochemistry (IHC) was performed on the same sections for K17 to define elevated or low expressing regions. ROIs were selected within the MALDI-MSI for High K17, Low K17, and empty vector viable tissue. Principal component analysis was then performed on the mass spectra of these regions to provide unbiased pattern recognition. Results: The principal component analysis segregated K17-positive ROIs from empty vector (EV) ROIs, revealing that K17-positive tissue has a unique metabolic signature compared to EV tissue. Metabolites with loadings outside the 95th percentiles in the 5-component PCA included UMP, UDP, orotate, sedoheptulose 7-phosphate, glucose 6-phosphate, glutamate, malate, phosphoglycerate, and lactate. Conclusion: These metabolites, therefore, distinguish between the EV and K17-positive clusters. Further hierarchical clustering will be performed to provide a more comprehensive evaluation of the rewired pathways in pancreatic cancer. Citation Format: Mahmoud M. Salem, Michael Horowitz, Lyanne Oblein, Chun-Hao Pan, Natalia Marchenko, Luisa Escobar-Hoyos, Bo Chen, Kenneth Shroyer. The unique metabolic signatures of keratin-17 expressing pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C050.
Abstract A103: Developing small molecules to disrupt IL-17RB and MLK4 interaction for pancreatic cancer treatment
Authors: I-Chih Chen, Yi-Ling Ko, Ching-Hsuan Huang, Jiin-Horng Lee, Yung-Cheng Lo, Chun-Mei Hu
Journal: Cancer Research (2024)

Abstract Nearly 40% of pancreatic cancer overexpressed pro-inflammatory Interleukin-17 receptor B (IL-17RB), and this signal pathway plays an essential role in promoting tumorigenesis and metastasis. Targeting the initial event of IL-17B/IL-17RB oncogenic signaling by disrupting IL-17RB-MLK4 interaction represents an excellent strategy for treating pancreatic cancer. To develop specific and effective small molecule disruptors, we have established a high-throughput screening (HTS) method using pY447 IL-17RB signal-based assay to identify blockers inhibiting IL-17B/IL-17RB oncogenic signaling. Three FDA-approved drugs were found to inhibit IL-17B-induced pY447 of IL-17RB signaling after screening 2560 FDA-approved drugs and 11000 TKI-related compounds. These drugs are more effective than the original loop peptide in inhibiting soft agar colony formation and spheroid formation of pancreatic tumor cells. Furthermore, we identified Drug H, which was not an anticancer drug before, could efficiently and specifically disrupt the interaction between IL-17RB and MLK4. Oral administration of Drug H can significantly suppress pancreatic tumor growth and metastasis and extend the life of mice with pancreatic tumors. Combining Drug H with gemcitabine treatment also showed synergistic effects in suppressing pancreatic tumor growth and metastasis. These data suggest Drug H may be a promising lead compound for disrupting IL-17RB/MLK4 and treating pancreatic cancer. Citation Format: I-Chih Chen, Yi-Ling Ko, Ching-Hsuan Huang, Jiin-Horng Lee, Yung-Cheng Lo, Chun-Mei Hu. Developing small molecules to disrupt IL-17RB and MLK4 interaction for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A103.
Abstract A026: Senescence driven by pharmacological RAS inhibition potentiates anti-tumor activity of combination therapies in pancreatic cancer
Authors: Caroline Broderick, Riccardo Mezzadra, Alejando Jiminez-Sanchez, Almudena Chaves-Perez, Janelle Simon, Yu-Jui Ho, Exequiel Sisso, Sha Tian, Amanda Kulick, Elisa DeStanchina, Scott W. Lowe
Journal: Cancer Research (2024)

Abstract Senescence is a form of stable proliferative arrest that occurs in response to various forms of cellular stress. In established cancer, these include unresolved DNA damage triggered by chemotherapeutic agents or irradiation, re-establishment of tumor suppressive programs, and by drugs that target cell cycle progression. Senescent cells take on a “Senescence Associated Secretory Phenotype” or SASP, characterized by increased expression of proinflammatory cytokines and other factors that modulate the tissue environment. The SASP triggers immune cell infiltration and, in the context of cancer, potent antitumor immunity. This implicates the use of senescence-inducing agents clinically and suggests that senescence biology may be harnessed to increase the fraction of patients that respond to immunotherapy. RAS is mutated in over 90% of pancreatic cancers, but until recently, has been considered to be “undruggable” due to its small size and lack of drug binding pockets. Recent advances in chemical biology have led to the development of several mutant isoform-specific and broad-spectrum RAS-GTP inhibitors, which hold great clinical promise. We have found that, in mouse models of pancreatic cancer, the non-covalent broad-spectrum inhibitor RM-042 and the covalent KRASG12D specific inhibitor RM-044 trigger a senescence-like phenotype characterized by cell cycle arrest and increased SASP expression. RAS inhibitor-mediated senescence enhances the immune surveillance of tumor cells, and this effect is potentiated by certain combination agents. Our results suggest that senescence contributes to RAS inhibitor efficacy in PDAC and reveal strategies to harness the immune system to improve therapy outcomes and circumvent resistance. Citation Format: Caroline Broderick, Riccardo Mezzadra, Alejando Jiminez-Sanchez, Almudena Chaves-Perez, Janelle Simon, Yu-Jui Ho, Exequiel Sisso, Sha Tian, Amanda Kulick, Elisa DeStanchina, Scott W. Lowe. Senescence driven by pharmacological RAS inhibition potentiates anti-tumor activity of combination therapies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A026.
Abstract C022: T cell movement through complex obstacles presented by the microenvironment of pancreatic tumor spheroids
Authors: Shambojit Roy, Zhongming Chen, Guhan Qian, Paolo P. Provenzano
Journal: Cancer Research (2024)

Abstract Immunotherapy has emerged as a promising approach for treating pancreatic cancer, however its efficacy against solid tumors has been largely limited. In order to be effective, cell-based immunotherapies are required to be in close proximity with the target cancerous cells. However, owing to its dense desmoplastic stroma, many regions of a pancreatic tumor, have areas within the tumor volumes that exclude anti-tumor immune cells. Therefore, we need to define mechanisms used by therapeutic T cells to navigate effectively in some tumor regions and the barriers that limit their infiltration and distribution in other regions of the tumor microenvironment (TME). In this work, we have advanced our knowledge of T cell migration and infiltration through complex TMEs by analyzing T cell dynamics in 3D engineered in vitro environments that can replicate key TME features of pancreatic ductal adenocarcinoma (PDA). Using our state-of the-art imaging techniques with multiphoton excitation (MPE) and second harmonic generation (SHG), we have monitored the migration of engineered human mesothelin reactive CAR-T cells through fibrous microenvironments and their interactions with pancreatic tumor spheroids. Quantitative analysis of interactions between CAR-T cells and carcinoma cells, in terms of velocity, directionality and mean square displacement (MSD) were performed, with the aim of utilizing these phenotypes as “design criteria” for the development of more effective engineered T cell therapies. The therapeutic efficacy of engineered T cells was also evaluated in standard 2D killing assays and then new 3D assays of increased complexity, both of which revealed mesothelin specific cancer cell death. Overall, we are starting to define the physical and molecular mechanisms that result in resistance to immunotherapy against pancreatic cancer, and we anticipate that our work will be applicable to other solid tumors with similar challenges and address key unanswered question in cancer biology. Citation Format: Shambojit Roy, Zhongming Chen, Guhan Qian, Paolo P. Provenzano. T cell movement through complex obstacles presented by the microenvironment of pancreatic tumor spheroids [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C022.
Abstract C058: Identifying cell-intrinsic drivers of transcriptional plasticity in pancreatic cancer
Authors: Yuzhou Evelyn Tong, Walaa E. Katan, Alex Bott, Julia Joung, Alex K. Shalek, Peter S. Winter, Srivatsan Raghavan
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with few effective therapies. Contributing to the complexity of this deadly cancer, PDAC tumors with similar genomic backgrounds can express divergent transcriptional programs with clinical importance. These transcriptional subtypes, termed “cell states”, have prognostic significance: PDAC tumors in the “classical state” generally have better outcomes and are thought to be more responsive to chemotherapy while those in the “basal state” are more aggressive. Currently, cell state is not used to direct therapy. Cell state is an integrative property shaped by both cell-intrinsic (e.g., mutations, epigenetics) and cell-extrinsic (e.g., growth factors, cytokines) factors. In our prior work, single-cell analysis of clinical PDAC samples demonstrated notable intra-tumoral cell state heterogeneity with evidence for cells that co-expressed both basal and classical markers, suggestive of cell state plasticity. In addition, longitudinal monitoring of patient-derived organoids has shown that cells can shift from classical to coexpressor/basal states as the environment changes, and this shift in cell states can drastically influence drug response. However, it remains unknown which signaling and transcriptional pathways induce basal or classical states, and whether these gene regulatory networks can be targeted therapeutically. Thus, there is a pressing need to devise scalable methods to determine essential drivers for prognostically-relevant cancer cell states. Here, we aim to define transcriptional drivers of basal and classical cell states in pancreatic cancer. We are currently optimizing a flow cytometry-fluorescence in situ hybridization (Flow-FISH) workflow to enable a multi-gene cell state readout. We plan to perform a transcription factor over-expression screen within a cohort of PDAC models using this Flow-FISH readout to identify those factors that can drive cells toward basal (n=3), classical (n=2), or coexpressor (n=3) states. As a proof of concept, we have confirmed that TP63A overexpression induces basal state expression, even in models that initially express a classical phenotype. Through these efforts, we aim to construct high-fidelity isogenic but state-variant PDAC models for use both in therapeutic screening and as a substrate for investigating mechanisms governing cancer cell state plasticity. Citation Format: Yuzhou Evelyn Tong, Walaa E. Katan, Alex Bott, Julia Joung, Alex K. Shalek, Peter S. Winter, Srivatsan Raghavan. Identifying cell-intrinsic drivers of transcriptional plasticity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C058.
Abstract B053: Physical activity regulates targetable transcriptomic changes in the adipose tissue of obese PDAC mice
Authors: Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Ericka Vélez-Bonet, Lei Cao, Wei Huang, Zobeida Cruz-Monserrate
Journal: Cancer Research (2024)

Abstract Background: Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a highly aggressive cancer with a low 5-year survival rate. The association between obesity and PDAC could be attributed to the inflammatory effects of obesity and its impact on the adipose microenvironment. Physical activity (PA) is a potential approach to counteract obesity and its associated inflammation. Moreover, a recent study revealed that exercise-induced interleukin (IL)-15 in tumors has an anti-tumor response. However, there is still limited understanding of the mechanisms underlying how PA impacts the adipose-tumor microenvironments in PDAC. In this study, we hypothesized that PA could upregulate anti-inflammatory signaling in the adipose tissue and that targeting some of these signaling pathways could be a novel therapy for obesity-associated PDAC. Methods: Transcriptomic analysis was performed on adipose tissue obtained from a genetically engineering mouse model of obesity-associated PDAC. The mice were fed an obesogenic high-fat diet and divided into groups with and without PA intervention for one month. An adipose-specific recombinant adeno-associated vector (rAAV) was generated and mouse IL-15 cDNA was subcloned into the vector. C57BL/6J mice were administered intraperitoneal injections of either the rAAV/empty or rAAV/IL-15 vectors. Three weeks after rAAV intraperitoneal injection, mice were orthotopically injected with mouse KRasG12D/Trp53−/−/PDX-1-CRE cells expressing firefly luciferase to monitor growth in vivo and expression of IL-15 in the adipose tissue was confirmed via qPCR. Results: PA intervention increased the expression of genes related to metabolic and inflammation-related pathways. The administration of a novel adipose-targeted rAAV resulted in the upregulation of IL-15 within the adipose tissue and not the tumor. Increasing IL-15 expression in the adipose tissue led to a notable delay in tumor growth in an orthotopic mouse model. Conclusions: Here, we show that PA modulates gene expression in the adipose tissue and the beneficial impact of adipose tissue molecular remodeling on anti-tumor effects. However, more studies are needed to characterize the full extent of the adipose-tumor interactions and how they can be effectively targeted for therapeutic interventions. Citation Format: Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Ericka Vélez-Bonet, Lei Cao, Wei Huang, Zobeida Cruz-Monserrate. Physical activity regulates targetable transcriptomic changes in the adipose tissue of obese PDAC mice [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B053.
Abstract C105: Functional dissection of the basal cell state in pancreatic cancer
Authors: Anupriya Singhal, Hannah Styers, Yan Yan, Simon Joost, Kenneth Pitter, Olivera Grbovic-Huezo, Hulya Sahin, Olca Basturk, Tuomas Tammela
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy with a dismal prognosis. Cancer cell plasticity – the capacity to differentiate and adapt to cell-extrinsic pressure via non-genetic mechanisms – promotes PDAC progression and drives resistance to treatment. Thus, targeting plasticity is a promising therapeutic strategy yet plasticity drivers in PDAC remain poorly understood. Using genetically engineered mouse models driven by oncogenic KrasG12D and loss of p53 (“KPC” model), we profiled primary PDAC tumors using single-cell RNA sequencing and single cell ATAC sequencing. We identified a cancer cell differentiation state that co-expresses both epithelial and mesenchymal programs and has a distinct epigenetic landscape with accessible chromatin across gene sets that mark cancer cell states with divergent phenotypes, suggesting that this cell state is primed for cell state switching. Notably, this high-plasticity cell state (HPCS) signature aligns with a "basal" signature in human PDAC, which associates with poor prognosis and resistance to chemotherapy. To functionally interrogate the HPCS in PDAC progression, we developed a novel lineage-tracing and ablation system allowing (1) visualization of cells in a specific state; (2) timed introduction of a heritable mark allowing us to track cell state progeny; and (3) timed cell state killing via a suicide gene. Lineage-tracing experiments revealed that the HPCS has a robust capacity for differentiation into epithelial/”classical” and mesenchymal states, indicating that the HPCS is functionally plastic and acts as a source of fixed malignant states. Strikingly, targeted elimination of the HPCS over short time periods resulted in tumor collapse, underscoring a critical role in tumor maintenance. Taken together, our data indicates that PDAC harbors a striking dependency on the HPCS, which drives malignant cell state transitions, promotes intra-tumoral diversity, and is critical for tumor maintenance. Our results strongly encourage therapeutic approaches aimed at eradicating this critical subset of cancer cells to improve outcomes in PDAC. Citation Format: Anupriya Singhal, Hannah Styers, Yan Yan, Simon Joost, Kenneth Pitter, Olivera Grbovic-Huezo, Hulya Sahin, Olca Basturk, Tuomas Tammela. Functional dissection of the basal cell state in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C105.
Abstract B060: Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy
Authors: Alexander C. Smith, John Muschler, Mike Munks, Rosalie C. Sears, Jonathan Brody
Journal: Cancer Research (2024)

Abstract Cancer modeling systems can be advantageous in enabling personalized medicine through rapid testing of therapeutic responsiveness. However, modeling systems often fail in these efforts due to 1) inadequately replicating unique patient genetics, 2) inadequately modeling the patient tumor microenvironment (TME), and 3) lack of internal validation references when isolated from clinical drug response data. We have developed a patient-derived models of cancer (PDMC) program for pancreatic cancer that addresses these challenges. By integrating patient cancer modeling and tissue engineering efforts with clinical trial protocols that perform serial tissue biopsies and analyses during treatment, we can make direct assessments of how different modeling systems replicate actual patient outcomes. Clinical trial protocols include tissue biopsies pre- and post- treatment using targeted therapeutics including MEK and PARP inhibitors. The modeling program, meanwhile, includes collecting metadata from pre- and post- treatment biopsies, the banking of patient tissues, cell line and xenograft generation from each biopsy, multiomic comparisons of models to patient tissue, comparisons of therapeutic responsiveness in models, and ultimately tissue re-engineering through bioprinting of tumor cells along with TME components. Whole exome sequencing is used to confirm that genetic alterations are preserved in each model, and we have established models representing a range of human PDAC genomic profiles. This includes common KRAS and TP53 mutations, as well as rare BRCA mutations and KRAS-wild-type tumors with BRAF mutations. Many cancer-associated fibroblast (CAF) lines have also been established through this program. Including patient derived cell lines, CAD lines, endothelial cells, and PBMCs into 3D bioprinted tumors allows us to better model the TME. Assays performed upon bioprinted tissues can then be directly compared to the same assays performed on the patient tumor to assess similarities as well as further obstacles. Ongoing efforts include building a resource of precise and validated PDMCs for diverse pancreatic cancers, and establishing a path forward for improved cancer modeling for the actualization of personalized medicine in PDAC treatment. Citation Format: Alexander C. Smith, John Muschler, Mike Munks, Rosalie C. Sears, Jonathan Brody. Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B060.