bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B065: Eosinophils alter metastatic spread in pancreatic cancer
Authors: Hoffman Megan T , Lenehan Patrick J , Bertocchi Alice , Wang Jen , Ali Lestat , Qiang Li , Uchida Amiko , Vayrynen Sara , Costa Andressa Dias , Dougan Michael , Heckler Max , Nowak Jonathan , Wolpin Brian W , Dougan Stephanie K 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the US with a 11% 5-year survival rate. A key contributor of this dismal prognosis is early and frequent metastatic spread with limited treatment options for patients. Metastasis in PDA is facilitated by a robust fibroinflammatory response in the primary tumor site, a large portion of which is composed of infiltrating immune cells, and survival during transit to establish in the secondary site. In the primary tumor reactive stroma, we found increased eosinophils in both human and mouse PDA compared to the normal pancreas. Eosinophils are an innate immune cell best known for their ability to control parasite responses and have been implicated in either pro- or anti-cancer roles in various solid tumors. We used the ΔdblGata mice, which lack eosinophils, to study the role of eosinophils during metastatic spread using a resectable model of PDA metastasis. This model of metastasis was developed to facilitate consistent seeding of lung metastasis in approximately 50 percent of mice from a transient subcutaneous tumor which undergoes subsequent surgical removal and harvest to evaluate metastasis at 4 weeks. We found that mice lacking eosinophils have increased metastasis to the lung in our resectable model of PDA metastasis but no difference in establishment of IV injected PDA tumor cells, suggesting eosinophil control at the primary tumor site. Single cell sequencing of the subcutaneous tumors finds no difference in the immune cell compartment but alterations in the EMT states of the tumor cells. Staining confirms a decreased level of E-cadherin with unchanged vimentin and zeb1 suggesting a partial EMT state in eosinophil knockout mice. We conclude that eosinophils in PDA inhibit the metastatic process, in part, through control of tumor cell state.
Citation Format: Megan T Hoffman, Patrick J Lenehan, Alice Bertocchi, Jen Wang, Lestat Ali, Li Qiang, Amiko Uchida, Sara Vayrynen, Andressa Dias Costa, Michael Dougan, Max Heckler, Jonathan Nowak, Brian W Wolpin, Stephanie K Dougan. Eosinophils alter metastatic spread in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B065.
Abstract B076: Morphological diversity predicts functional traits in pancreatic cancer
Authors: Gong Dennis , Hwang William L 
Published: September 2024

Abstract
Cell morphologies represent a phenotypic integration of intrinsic cellular processes, changes in cell state, and interactions with neighboring cells. While analyses of large cell line collections such as the Cancer Dependency Map (DepMap) have greatly enhanced discovery of novel molecular biomarkers and therapeutic targets, morphological analysis of these models has not yet been performed. Hence, there is a rich opportunity to discover novel regulators and functional properties of cell morphologies by linking image-based profiling to -omics based assays. Here, we studied the transcriptional and functional properties of 16 human pancreatic cancer cell lines, associations with distinct cell morphologies, and treatment-induced remodeling. At baseline, we observed extensive morphological heterogeneity across and within cell lines, as well as differences in multicellular organization. We categorized cell line morphologies into epithelial, mesenchymal, and spheroid, and organizational patterns into tightly aggregated, multilayered, and dispersed. We performed differential expression analysis across morphological subtypes utilizing DepMap transcriptomics data and queried functional correlates including CRISPR dependency, drug sensitivity, and proclivity for metastasis. For example, we discovered that the mesenchymal morphology and multilayered organizational pattern [WH3] were associated with metastatic potential, while expressing reduced levels of tight junction and cell adhesion genes. We then explored treatment associated morphological changes and their potential as cost-effective biomarkers for cell-intrinsic resistance to chemotherapy (e.g., 5-FU and gemcitabine) and KRAS inhibitors (e.g., MRTX1133 and RMC- 6236). Cells were treated continuously and monitored with live cell imaging (Incucyte SX5) followed by Cell Painting at the three-day endpoint. We observed conserved morphological responses to therapy across cell lines including a shift towards spindle-like cell shapes with neurite-like projections in chemotherapy-treated conditions, and a cell bloating phenomena characterized by an increase in cell area in KRAS inhibitor treated conditions. To directly link transcriptional state to morphology, we performed 1000-plex spatial molecular imaging (Nanostring CosMx) at subcellular resolution to pools of cell lines, demonstrating that morphological diversity within cell lines corresponded to distinct transcriptional states. In conclusion, this study highlights the potential of harnessing cell morphological information in a rapid, cost-effective phenotyping assay to aid precision oncology efforts leveraging patient- derived in vitro models.
Citation Format: Dennis Gong, William L Hwang. Morphological diversity predicts functional traits in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B076.
Abstract B079: Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases
Authors: Yugawa Deanne E , Kawalerski Ryan , Gonçalves Mariana Torrente , Pan Chun-Hao , Tseng Robert , Roa-Pena Lucia , Leiton Cindy V , Torre-Healy Luke A , Boyle Taryn , Chowdhury Sumedha , Snider Natasha T , Shroyer Kenneth R , Escobar-Hoyos Luisa F 
Published: September 2024

Abstract
Keratin 17 (K17), an intermediate filament protein typically expressed during embryonic development, is a hallmark of one of the most aggressive pancreatic ductal adenocarcinoma (PDAC) subtypes. Its expression is also associated with poor patient survival and resistance to first-line therapies. However, the mechanistic roles of K17 in malignancy remain largely unexplored. Here, we demonstrate that K17 expression and disassembly enhance tumor growth, increase metastatic potential, and shorten overall survival. Using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) stratified by K17 phosphorylation status, we found that increased K17 phosphorylation correlated with worse survival. Mass spectrometry of untreated PDAC patient samples identified a phosphorylation hotspot at serines 10-13, which is conserved across species and type I keratin proteins. We found that K17 phosphorylation, mediated by the PKC/MEK/RSK pathway, led to increased disassembly and nuclear translocation in pancreatic cancer cells. Mice with phosphomimetic mutations at the serine hotspot showed increased metastases and decreased survival compared to wild-type and phosphorylation-resistant K17. Lastly, detergent-soluble nuclear K17 promoted metastasis- related genes in both patient and murine tumors. These findings suggest that disassembly of K17 mediated by phosphorylation at serines 10-13 is sufficient to promote metastases and decrease overall survival in PDAC. This opens the door for further investigation into K17 phosphorylation as a novel therapeutic target to enhance PDAC patient survival, especially in those with more aggressive, chemoresistant subtypes.
Citation Format: Deanne E Yugawa, Ryan Kawalerski, Mariana Torrente Gonçalves, Chun-Hao Pan, Robert Tseng, Lucia Roa-Pena, Cindy V Leiton, Luke A Torre-Healy, Taryn Boyle, Sumedha Chowdhury, Natasha T Snider, Kenneth R Shroyer, Luisa F Escobar-Hoyos. Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B079.
Abstract B089: Identification of novel drivers of gemcitabine resistance in pancreatic cancer
Authors: Bilalbegovic Amina D , Fu Bowen , Nwosu Zeribe 
Published: September 2024

Abstract
Pancreatic cancer is an aggressive disease with limited therapeutic options. Gemcitabine is a clinically used chemotherapy for pancreatic cancer treatment but has limited efficacy. The molecular mechanisms responsible for gemcitabine resistance in pancreatic cancer are still unclear. Here, we analyzed the genomics of drug sensitivity in cancer dataset and identified various pancreatic cancer cells with distinct sensitivity to gemcitabine. Validation with proliferation and clonogenic assays confirmed that while CFPAC1 and PANC0327 are highly gemcitabine-sensitive, ASPC1 and PANC1 display intrinsic gemcitabine resistance. Analysis of the gene expression profile of these cells identified several genes that are differentially upregulated in resistant versus sensitive cells. Pathway enrichment analysis using the differential genes revealed the upregulation of Hippo, Wnt, MAPK signaling pathways as well as autophagy and glutathione metabolism in the resistant cells. Using quantitative PCR, immunoblotting and biochemical assays, and extracellular flux analysis methods, we have characterized the molecular distinctions between gemcitabine sensitive and resistant cells. Our results provide insight on the molecular mechanisms driving gemcitabine resistance in pancreatic cancer and could lead to novel therapeutic strategies to overcome resistance and improve patients’ treatment.
Citation Format: Amina D Bilalbegovic, Bowen Fu, Zeribe Nwosu. Identification of novel drivers of gemcitabine resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B089.
Abstract B092: PP2A activation alters macropinosome processing in pancreatic cancer cells leading to metabolic stress and cancer cell death
Authors: Baral Garima , Pfeffer Claire M , Doraivel Indiraa , Filippelli Sara N , Heil Brittany N , Allen-Petersen Brittany L 
Published: September 2024

Abstract
The majority of pancreatic ductal adenocarcinoma (PDAC) patients present with late-stage, metastatic disease that is often resistant to therapeutics, resulting in the lowest survival rate of all major cancers. Metabolic rewiring in response to oncogenic signals plays a critical role in PDAC cell survival, tumor growth, and metastasis. In contrast to normal epithelial cells, these metabolic alterations make PDAC tumors dependent on glutamine and glucose for survival, highlighting a unique metabolic vulnerability that can be therapeutically exploited. However, during times of nutrient stress, PDAC cells can circumvent this vulnerability by engulfing extracellular fluids to replenish amino acids, including glutamine, in a process called, macropinocytosis. Macropinocytosis occurs downstream of oncogenic KRAS, a small GTPase that is almost universally mutated in PDAC patients. The inhibition of macropinocytosis in vivo reduces PDAC tumor growth, underscoring the importance of this pathway to cancer cell survival. However, the signaling mechanisms that regulate this process and the contribution of macropinocytic signaling to aggressive cancer phenotypes remains poorly understood. Protein phosphatase 2A (PP2A) is a heterotrimeric complex that reguates a wide variety of cell signaling pathways, inlcuding KRAS, and is commonly deregulated in human PDAC tumors. Recently, PP2A has been implicated as an important regulator of macropinocytosis, but the mechanism by which this occurs is unknown. We demosntrate that suppression of PP2A accelerates the formation of KRAS-driven precursor lesions in an in vivo mouse model of PDAC, implicating PP2A as a critical regulator of mutant KRAS phenotypes. Here, we show that acute PP2A activation prevents the fusion of macropinosomes with the lysosome, robbing PDAC cells of critical metabolic nutrients and driving cell death. Furthermore, we find PP2A associates with the lipid kinase, PIKfyve, a key regulator of macropinosome-lysosome fusion. Finally, we determined that PP2A activating compounds can function synergistically with metabolic inhibitors, support a new therapeutic strategy in this aggressive and deadly cancer. Together, our results implicate PP2A as a critical suppressor of PDAC metabolic plasticity and highlight the use of PP2A activating compounds to prevent PDAC nutrient scavenging.
Citation Format: Garima Baral, Claire M Pfeffer, Indiraa Doraivel, Sara N Filippelli, Brittany N Heil, Brittany L Allen-Petersen. PP2A activation alters macropinosome processing in pancreatic cancer cells leading to metabolic stress and cancer cell death [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B092.
Abstract B093: The evaluation of the gene expression profile of pancreatic ductal adenocarcinomas (PDACs) in 3D cell culture vs in vivo and development of new 3D PDACs' models for an evaluation of anti-cancer drug testing
Authors: Krzykawski Marcin , Earnshaw David , Kus Krzysztof , Pirog Artur , Kote Sachin , Treherne Mark , Kocik-Krol Justyna 
Published: September 2024

Abstract
In the ever-evolving landscape of biomedical research, 3D Cell Culture (3DCC) systems have emerged as pivotal tools for mimicking in vivo environments and fostering more physiologically relevant cellular responses. Despite promises, 3DCC based drug discovery efforts didn’t fulfil the hopes. The classic way 3DCC is done, always starts with 2D cell culture (2DCC) followed by brief 3 day 3DCC and finally drug testing. Following those observations we decided to mimic much more than just brief 3DCC state but enhance the culture by constant 3DCC to 3DCC passages. We characterized the gene expression profiles and proteomic characteristics of pancreatic tumors concluding that prolonged 3DCC is the closest to an in vivo model. The protracted cultivation periods mimic the intricacies of the in vivo environment, enabling a more accurate representation of the molecular dynamics within pancreatic tumors. In our study, we identified a panel of genes characterized by similar expression levels between prolonged 3D cell culture and in vivo conditions, while displaying significant divergence between 2D cultures and short-term 3D cultures when compared to in vivo. These genes play a pivotal role in the progression and treatment of cancer, underscoring the potential of prolonged 3DCC of LifeGel® significance in understanding tumor biology and devising therapeutic strategies. Furthermore, we also investigated the implications of prolonged 3D in vitro cultures on evaluating anti-cancer drug activities. The findings highlight the significance of 3DCC in enhancing our understanding of pancreatic tumor biology and in refining drug screening methodologies for more effective therapeutic interventions. By providing a biomimetic microenvironment, our hydrogels facilitate the formation of complex cellular structures, enabling more accurate representation of tissue architecture and cellular interactions. We delivered LifeGel® platform which presents a myriad of opportunities for researchers seeking to enhance the fidelity and translatability of their in vitro studies into pre-clinial models.
Citation Format: Marcin Krzykawski, David Earnshaw, Krzysztof Kus, Artur Pirog, Sachin Kote, Mark Treherne, Justyna Kocik-Krol. The evaluation of the gene expression profile of pancreatic ductal adenocarcinomas (PDACs) in 3D cell culture vs in vivo and development of new 3D PDACs' models for an evaluation of anti-cancer drug testing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B093.
Abstract C010: Single-cell profiling unleashes KRAS-driven redrafting of the tumor microenvironment before cancer onset
Authors: Allgoewer Chantal , Breunig Markus , Hohwieler Meike , Mulaw Medhanie , Kleger Alexander 
Published: September 2024

Abstract
Pancreatic cancer is a highly lethal and aggressive disease, commonly characterized by a unique tumor microenvironment, where mutant KRAS signaling plays a pivotal role in its pathophysiology. To deepen our understanding of KRAS-dependent signaling in earliest tumor development, oncogenic KRAS (KRASG12D) expression was induced in human stem cell-derived pancreatic ductal-like organoids (PDLOs), followed by time-resolved single-cell RNA and bulk ATAC sequencing. This unique precancerous state model facilitated a comprehensive characterization of early oncogenic events at cellular resolution. Furthermore, a machine learning approach was applied to accurately predict KRAS-dependent cell identities. Within seven days, mutated KRAS triggers distinct gene signature programs related to extracellular matrix remodeling and inflammation. Although derived from dysplastic yet non-cancerous states, these gene signatures negatively correlated with overall survival in PDAC (pancreatic ductal adenocarcinoma) patients. The KRAS-dependent signatures retrieved with the machine learning approach allowed the grouping of 24 published PDAC cases, showing differences in niche composition and communication patterns. Various co-culture systems demonstrated that KRASG12D-expressing PDLOs could activate pancreatic stellate cells, inducing a cancer- associated fibroblast (CAF)-like state. Simultaneously, these KRAS-activated organoids were protected from T cell infiltration in vitro. Furthermore, in silico approaches were employed to reconstruct a virtual pancreatic cancer space, demonstrating that our PDLOs transcriptionally bridge healthy and malignant ductal states. This also revealed potential KRAS-driven pathways mediating CAF activation and T cell shielding preceding cancer onset. In summary, our human PDLO model enables us to explore the transition from normal to cancerous states, addressing gaps in our understanding of tumor development and tumor niche preparation.
Citation Format: Chantal Allgoewer, Markus Breunig, Meike Hohwieler, Medhanie Mulaw, Alexander Kleger. Single-cell profiling unleashes KRAS-driven redrafting of the tumor microenvironment before cancer onset [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C010.
Abstract C011: Targeting STAT3 overcomes PDAC resistance to EGFR/RAF1 inhibition leading to complete and durable tumor regression
Authors: Liaki Vasiliki , Barbacid Mariano , Guerra Carmen 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) belongs to the tumors with worst prognosis due to the lack of effective treatment. It was previously demonstrated that combined elimination of EGFR and RAF1, two main mediators of the KRAS signaling, induces complete regression of a limited subset of small tumors in a genetically engineered mouse model (Blasco et al., 2019). In the current study, we show that resistance of PDACs with big sizes to the elimination of RAF1 and EGFR is mediated by STAT3. Indeed, combined genetic ablation of EGFR, RAF1 and STAT3 both in vitro and in vivo, results in complete and irreversible regression of more than 40 independent mouse PDAC tumors driven by Kras/Trp53 mutations. Importantly, all PDACs were characterized by increased initial tumor size and highly heterogeneous molecular profile similar to that of Basal human tumors. Moreover, we have validated the efficacy of this novel therapeutic strategy using pharmacological agents, such as EGFR inhibitors approved for clinical use and the STAT3 PROTAC degrader SD-36. Finally, inhibition of RAF1, EGFR and STAT3 expression effectively blocked in vitro and in vivo tumor progression in ten independent patient-derived organoid (PDO) and patient-derived xenograft (PDX) cultures carrying KRAS and TP53 mutations. These results open the door to the development of novel targeted therapies for PDAC patients.
Citation Format: Vasiliki Liaki, Mariano Barbacid, Carmen Guerra. Targeting STAT3 overcomes PDAC resistance to EGFR/RAF1 inhibition leading to complete and durable tumor regression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C011.
Abstract C012: Overcoming Cell Subtype-Specific Adaptive Resistance to KRAS G12D Inhibition in KRAS G12D-Mutant Pancreatic Cancer
Authors: Lin Qingxiang (Nick) , Morales Alvin , Barnes Haley , Corcoran Ryan Bruce 
Published: September 2024

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 12%, with limited treatment options. Oncogenic KRAS mutations drive PDAC tumor progression, which occur in the majority of PDAC tumors. KRAS G12D is the most common KRAS mutation, found in 36% of PDAC cases, which is associated with the worst clinical outcomes. Mutant-selective KRAS G12D inhibitors (KRASi G12D), such as MRTX1133, have recently demonstrated initial responses in KRAS G12D-mutant preclinical models. However, mechanisms of adaptive resistance to KRAS G12D inhibition are largely under-investigated and novel therapeutic strategies to overcome drug resistance are urgently needed. Results: Adaptive RAS signaling reactivation was found to dampen KRAS G12D inhibition in a library of KRAS G12D PDAC cell lines, thereby minimizing drug efficacy. Quantitative downstream analyses of drug combination screening using a KRAS G12D cell line library further identified this adaption to KRAS inhibition was cell subtype specific. Fibroblast growth factor receptor (FGFRs) drove adaptive RAS reactivation specifically in mesenchymal PDAC cells, which are aggressive, and intrinsically resistant to KRASi. In contrast, epithelial growth factor receptor (EGFR) reactivated RAS G12D signaling in epithelial cells, which are sensitive to KRASi G12D. Genetic and pharmacological inhibition of FGFR1 or FGFR2 improved drug efficacy by decreasing FGFR-mediated RAS reactivation specifically in mesenchymal PDAC lines. Pharmacological blockade of EGFR enhanced drug efficacy by inhibiting EGFR-mediated RAS reactivation specifically in epithelial PDAC lines. Furthermore, low-concentration of a novel pan- RAS inhibitor, which inhibits both wild-type and mutant RAS, completely abrogated MAPK signaling and significantly improved efficacy, when combined with KRASi G12D, suggesting a pro-survival dependency on wild-type RAS as a compensatory mechanism in response to KRAS G12D inhibition. Conclusion: Upstream RTK-mediated adaptive RAS signaling re-activation in response to KRAS inhibition in PDAC is cell subtype specific. Complete inhibition of RAS signaling by overcoming adaptive RAS rebound improves efficacy of KRASi G12D.
Citation Format: Qingxiang (Nick) Lin, Alvin Morales, Haley Barnes, Ryan Bruce Corcoran. Overcoming Cell Subtype-Specific Adaptive Resistance to KRAS G12D Inhibition in KRAS G12D-Mutant Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C012.