About

Dannielle Engle, PhD, is an Assistant Professor of Regulatory Biology at the Salk Institute for Biological Studies. Her research focuses on pancreatic cancer, one of the deadliest cancers, which is often diagnosed late and has limited effective therapies. Engle's work aims to improve early detection and treatment by creating more accurate models of pancreatic disease using stem-cell techniques and biochemistry methodologies. She has developed powerful new mouse models that incorporate human-specific aspects of pancreatic biology, such as the carbohydrate CA19-9, which has advanced understanding of how CA19-9 influences pancreatic inflammation and tumor development. Additionally, Engle has pioneered the development of miniature pancreas organ cultures, or organoids, which accurately recreate tumor development and retain key cancer features over time. These organoids serve as a renewable resource for studying pancreatic transformation, identifying therapeutic targets, and distinguishing between pancreatitis and pancreatic cancer through improved evaluation of biomarkers like CA19-9. Her personal connection to pancreatic cancer, having lost close family members to the disease, fuels her scientific passion to facilitate progress in this challenging field.

Research topics

• Cancer research
• Medicine
• Biology
• Internal medicine
• Oncology

Selected publications

• Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis within the PDAC Tumor Microenvironment

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-17

  articleOpen access

  Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy where metabolic homeostasis is maintained by tumor and stromal cells within the tumor microenvironment (TME). To better assess pathways supporting macromolecule biosynthesis in PDAC tumors, we apply 13 C metabolic flux analysis (MFA) to slice cultures of treatment-naïve human tumors and mouse models that retain the native TME. Glycans, lipid headgroups, and very long-chain fatty acids are the most dynamic metabolic pools, while long chain fatty acids, purines, and pyrimidines are predominantly salvaged locally in situ . We use targeted pharmacological modulators to highlight the importance of recycling pathways and metabolic redundancies which mitigate changes in lipid abundances. Finally, we leverage targeted lipid fluxomics and the distinct ganglioside and globoside profiles of tumor and stromal cells, respectively, to demonstrate the role of the lipid kinase PIKfyve in supporting ganglioside homeostasis via sialic acid and ceramide salvage. These data establish application of MFA to slice cultures of PDAC tumors as an effective approach for assessing metabolic mechanisms and therapeutic responses within an intact TME.

  PublisherDOI

• CA19-9 promotes liver metastasis of pancreatic cancer through E-selectin mediated extravasation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-10

  articleOpen accessSenior authorCorresponding

  Abstract Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, which drives patient mortality. CA19-9 is elevated in most PDAC tumors and is widely used as a clinical biomarker. Elevated serum levels are associated with poor outcomes. However, whether CA19-9 functionally contributes to metastatic progression has not been fully defined, in part because mice lack endogenous CA19-9 expression. Here, using syngeneic murine PDAC cells engineered to express CA19-9, we investigated its functional role in liver metastasis. In splenic injection models, CA19-9 expression markedly increased liver metastatic burden by promoting both metastatic seeding and subsequent metastatic outgrowth. In vitro , CA19-9 enhanced tumor cell adhesion to endothelial cells through interaction with E-selectin. Metastatic seeding of CA19-9-expressing cells was reduced by genetic deletion of E-selectin or antibody neutralization of either CA19-9 or E-selectin in vivo . Therapeutic targeting of CA19-9 with a neutralizing antibody markedly reduced liver metastatic burden after metastatic seeding. CA19-9 expression increased AKT signaling in PDAC cells and liver metastases, and CA19-9 levels correlated with AKT activation in human PDAC tissues. These findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.

  PublisherDOI

• Altered PI3K and ERK/MAPK Signaling in KRASG12R-Driven Pancreatic Cancer Presents Opportunities for Precision Therapy

  Cancer Research · 2026-04-15

  articleSenior author

  Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies with near-universal KRAS mutation. Although KRASG12D and KRASG12V are predominant, KRASG12R is also prevalent in PDAC yet rare in other KRAS-driven cancers such as lung and colorectal adenocarcinoma, suggesting pancreas-specific selective pressures. Unlike other KRAS mutants, KRASG12R fails to productively engage key nodes that amplify oncogenic output including wild-type (WT) RAS and PI3K signaling. Furthermore, KRASG12R-mutant PDAC has been shown to be more sensitive to MAPK/ERK inhibition compared with other KRAS-mutant tumors. Three complementary studies now clarify how KRASG12R promotes PDAC growth and why this genotype may carry distinct therapeutic vulnerabilities. First, Burge and colleagues identify KRASG12R-independent PI3K maintenance driven by PTEN oxidation and broad PI3K isoform utilization, with nutrient limitation further enhancing PTEN oxidation. Second, in a separate study, Burge and colleagues develop KRASG12R mouse models and show that KRASG12R tumors exhibit reduced ERK/MAPK transcription, collagen deposition, and metastasis. Third, Kamgar and colleagues demonstrate an impaired cross-talk of KRASG12R with WT RAS and stoichiometric dependencies that help explain heightened MEK inhibitor sensitivity, supported by clinical trials combining MEK and autophagy inhibition. Together, these articles reposition KRASG12R PDAC as a biologically constrained yet therapeutically exploitable subtype. See related article by Burge et al., p. 1854 See related article by Burge et al., p. 1868 See related article by Kamgar et al., p. 2042.

  PublisherDOI

• Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis

  Journal of Clinical Investigation · 2025-09-09 · 3 citations

  articleOpen access

  3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here, we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells, and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor and factor VIIa. Furthermore, plasma from patients with PDAC showed accumulation of HSAT, suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor-suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.

  PublisherDOI

• Abstract A104: The CA19-9 glycan is a viable target for CAR T cell therapy in PDAC

  Cancer Research · 2025-09-28

  article

  Abstract Chimeric antigen receptor (CAR) T cell therapy for pancreatic ductal adenocarcinoma (PDAC) has been challenging, in part due to the paucity of tumor-specific cell-surface targets. Here, we explored the feasibility and efficacy of CAR T cells directed against carbohydrate antigen 19-9 (CA19-9), a clinically useful tumor marker that is significantly elevated in most PDAC cases with limited expression in normal tissues. We designed and screened 14 CA19-9 CAR constructs harboring different single-chain variable fragments (scFvs) and intracellular signaling domains. Using both in vitro tumor coculture assays and in vivo cell- and organoid-derived xenograft models of human PDAC, we identified one design – AbLIFT15.28z – that enabled efficient and specific anti-tumor activity, including a high frequency of durable complete responses. Next, we engineered a murine version of AbLIFT15.28z and tested its efficacy in a syngeneic model that reflects the immunosuppressive milieu typical of most PDAC tumors. As mouse cells do not produce the CA19-9 antigen, we generated a CA19-9-expressing PDAC cell line by overexpressing enzymes essential for CA19-9 production. Subsequent in vivo testing confirmed the anti-tumor activity of murine AbLIFT15.28z CAR T cells in both primary and metastatic tumor settings, significantly reducing tumor burden and prolonging animal survival in an immunocompetent setting (median survival, unmodified T cell vs CAR T cell: orthotopic tumor model – 24 vs 47 days, n=8-12; lung metastatic tumor model – 44 days vs undefined (75% of mice survived for over 250 days), n=8 per group). These findings demonstrate the feasibility and potency of CAR T cells targeting CA19-9, providing a rationale for further clinical development. Citation Format: Feiyan Mo, Austin L. Good, Dannielle D. Engle, Avery D. Posey, Ben Z. Stanger. The CA19-9 glycan is a viable target for CAR T cell therapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A104.

  PublisherDOI

• Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-01

  preprintOpen access

  Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

  PublisherOA PDFDOI

• Abstract B092: Investigating combination therapies to overcome RAS inhibitor resistance in pancreatic cancer

  Cancer Research · 2025-09-28

  articleSenior author

  Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal malignancies, largely due to limited therapeutic options and the rapid development of treatment resistance. Recent progress in the development of RAS targeting agents, including mutant-specific and pan-RAS inhibitors, has expanded potential treatment strategies for tumors harboring oncogenic KRAS mutations. However, clinical and preclinical evidence indicates that resistance to these agents emerges rapidly, limiting their long-term efficacy. This study aims to investigate the mechanisms underlying resistance to RAS inhibitors and to identify rational combination strategies that enhance therapeutic durability in PDA. Using advanced organoid and in vivo models, we are characterizing resistance to clinically relevant RAS inhibitors and evaluating the therapeutic potential of combining RAS inhibition with other targeted agents. We will also examine the influence of treatment timing, drug synergy, and tumor microenvironmental factors, including immune interactions, on treatment response. Ultimately, this research seeks to inform the development of more effective combination strategies for PDA by elucidating resistance mechanisms and identifying therapeutic vulnerabilities. Insights from this work may support future translational efforts in a disease with pressing unmet clinical needs. Citation Format: Vasiliki Pantazopoulou, Casie Kubota, Satoshi Ogawa, Kassidy Curtis, Araceli Herrera Morales, Dannielle Engle. Investigating combination therapies to overcome RAS inhibitor resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B092.

  PublisherDOI

• Experimental models of pancreas cancer: what has been the impact for precision medicine?

  Journal of Clinical Investigation · 2025-08-15 · 6 citations

  reviewOpen accessSenior author

  Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, including patient performance status, metastatic disease at diagnosis, intrinsic drug resistance, and a highly complex tumor microenvironment. Emerging targeted therapies, such as RAS inhibitors, offer promise for personalized treatment. These developments have prompted precision medicine-focused clinical trials using molecular subtyping for patient stratification. Effective development of precision medicine therapies depends heavily on robust preclinical models capable of accurately recapitulating the complexities of the pancreatic tumor microenvironment. Two-dimensional, air-liquid interface, and patient-derived organoid cultures combined with in vivo genetically engineered mouse models and patient-derived xenografts represent valuable experimental systems. This Review critically examines the strengths and limitations of these experimental model systems. We highlight their relevance and utility for advancing precision medicine strategies in pancreas cancer.

  PublisherOA PDFDOI

• Abstract B009: Fibulin-3 drives tumor progression and microenvironment remodeling in CA19-9-induced pancreatic ductal adenocarcinoma

  Cancer Research · 2025-09-28

  articleSenior author

  Abstract Glycosylation is a complex post-translational modification essential for development, growth, and survival. Altered glycosylation is a hallmark of cancer, yet the roles of many glycoproteins remain unclear, hampering translation of glycoprotein-related vulnerabilities into therapeutic strategies. Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies, with a five-year survival rate under 13%. For decades, serum levels of CA19-9, a terminal tetra-saccharide glycan, conjugating many secreted and cell surface proteins, has been the single-most effective biomarker to track PDA progression in patients. Recent studies have identified Fibulin-3 (Fbln3) as a secreted, CA19-9–modified matricellular glycoprotein that drives EGFR hyperactivation in the pancreatic epithelium, which is essential for PDA development. However, the functional role of Fbln3 in PDA has remained largely unexplored. Here, we show that Fbln3 promotes PDA progression and tumor microenvironment (TME) remodeling. Fbln3 expression is significantly upregulated in both human and mouse PDA tissues. Overexpression and knockdown of Fbln3 modulate PDA growth rates both in vitro and in vivo. In CA19-9–expressing KRASG12D mutant PDA organoids, Fbln3 enhances activation of key oncogenic pathways, including EGFR, NFκB, and TGFβ signaling. Notably, Fbln3 regulates the expression of IL1A and TGF, cytokines known to impact both autocrine and paracrine signaling. In syngeneic orthotopic tumor models, Fbln3 promotes the expansion of antigen-presenting cancer associated fibroblasts and reduces infiltration of CD8+ T cells, contributing to an immunosuppressive microenvironment. Taken together, these findings demonstrate that CA19-9-modified Fbln3 drives pancreatic tumor progression and TME remodeling by regulating IL1A and TGFb production, highlighting the need to further investigate its potential as a therapeutic target. Citation Format: Hyemin Song, Jasper Hsu, Satoshi Ogawa, Kristina Peck, Kassidy Curtis, Chelsea Bottomely, McKenna Stamp, Dannielle D. Engle. Fibulin-3 drives tumor progression and microenvironment remodeling in CA19-9-induced pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B009.

  PublisherDOI

• Abstract 1600: Interception of pro-tumorigenic glycan signaling in pancreatic cancer

  Cancer Research · 2024-03-22

  articleSenior author

  Abstract Pancreatic cancer is a deadly malignancy. We have setup a pipeline to interrogate cancer cell intrinsic and extrinsic mechanisms contributing to treatment response. Using a combination of mouse and human organoids models together with in vivo investigation, we have systematically dissected key signaling hubs driving pro-tumorigenic cancer cell intrinsic features as well as remodeling of the tumor microenvironment (TME). We found that the glycan epitope, CA19-9, drives pancreatic inflammation, cancer, and metastasis. CA19-9 drives pro-tumorigenic intrinsic features in part through CA19-9 modification of the secreted glycoprotein Fibulin 3. We have also discovered direct and indirect mechanisms through which CA19-9 causes remodeling of the TME. Specifically, CA19-9 elevation causes expansion of all cancer associated fibroblast (CAF) subtypes, including an increase in antigen presenting CAFs and resulting increase in regulatory T cells. Further, there are dramatic increases in tumor associated macrophages (TAMs) derived from both inflammatory monocytes as well as tissue resident macrophages. To delineate the mechanisms by which these TME changes are mediated, we use novel co-culture model incorporating macrophages, organoids, and fibroblasts (MOrF). Blocking CA19-9 signaling in vitro and in vivo reverses these TME alterations. These changes to the TME are mediated through indirect effectors as well as previously unknown CA19-9 modified proteins. Overall, we elucidate previously unexplored mechanisms driving pancreatic tumorigenesis while also uncovered vulnerabilities for therapeutic exploitation. Citation Format: Jasper Hsu, Hyemin Song, Kristina Peck, Chelsea Bottomley, McKenna Stamp, Shira Okhovat, Dannielle D. Engle. Interception of pro-tumorigenic glycan signaling in pancreatic 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 1600.

  PublisherDOI

Recent grants

• Exploring Glycobiology and Discovering Biomarkers for Pancreatic Cancer

  NIH · $747k · 2019–2022

• NIH Grant K99CA204725

  NIH · $256k · 2018

Frequent coauthors

• David A. Tuveson

  Cold Spring Harbor Laboratory

  82 shared

• Hervé Tiriac

  University of California, San Diego

  75 shared

• Kenneth H. Yu

  Kettering University

  54 shared

• Ralph H. Hruban

  Cancer Research Center

  33 shared

• Hans Clevers

  University Medical Center Utrecht

  33 shared

• Vasiliki Pantazopoulou

  Salk Institute for Biological Studies

  31 shared

• Satoshi Ogawa

  30 shared

• Richard A. Burkhart

  University of Baltimore

  29 shared

Awards & honors

• Prebys Research Hero, 2024
• Lustgarten Foundation-AACR Career Development Award for Panc…
• Tobacco-Related Disease Research Program New Investigator Aw…
• NIH NCI Career Transition K99/R00 Award, 2016 - 2018
• California Breast Cancer Research Program Fellowship, 2009 -…