Scholars@Duke
Darren Tyson

Darren Tyson

Associate Research Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
darren.tyson@duke.edu
308 Research Drive, LSRC C136, Durham, NC 27710

Selected Publications

Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.

Journal Article Nature · November 2025 Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets ... Full text Link to item Cite

Intercellular signaling reinforces single-cell level phenotypic transitions and facilitates robust re-equilibrium of heterogeneous cancer cell populations.

Journal Article Cell Commun Signal · August 28, 2025 BACKGROUND: Cancer cells within tumors exhibit a wide range of phenotypic states driven by non-genetic mechanisms, such as epithelial-to-mesenchymal transition (EMT), in addition to extensively studied genetic alterations. Conversions among cancer cell sta ... Full text Link to item Cite

Addressing persistent challenges in digital image analysis of cancer tissue: resources developed from a hackathon.

Journal Article Mol Oncol · June 2025 The National Cancer Institute (NCI) supports numerous research consortia that rely on imaging technologies to study cancerous tissues. To foster collaboration and innovation in this field, the Image Analysis Working Group (IAWG) was created in 2019. As mul ... Full text Link to item Cite

Intercellular signaling reinforces single-cell level phenotypic transitions and facilitates robust re-equilibrium of heterogeneous cancer cell populations.

Journal Article bioRxiv · March 26, 2025 BACKGROUND: Cancer cells within tumors exhibit a wide range of phenotypic states driven by non-genetic mechanisms in addition to extensively studied genetic alterations. Conversions among cancer cell states can result in intratumoral heterogeneity which co ... Full text Link to item Cite

Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.

Journal Article bioRxiv · November 15, 2024 Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively1,2. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets ... Full text Link to item Cite

Purinergic Ca2+ Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma.

Journal Article Cancers (Basel) · June 30, 2024 Drug tolerance is a major cause of relapse after cancer treatment. Despite intensive efforts, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug toleranc ... Full text Link to item Cite

Involvement of Epithelial-Mesenchymal Transition Genes in Small Cell Lung Cancer Phenotypic Plasticity.

Journal Article Cancers (Basel) · February 25, 2023 Small cell lung cancer (SCLC) is an aggressive cancer recalcitrant to treatment, arising predominantly from epithelial pulmonary neuroendocrine (NE) cells. Intratumor heterogeneity plays critical roles in SCLC disease progression, metastasis, and treatment ... Full text Link to item Cite

Utilizing Three-Dimensional Culture Methods to Improve High-Throughput Drug Screening in Anaplastic Thyroid Carcinoma.

Journal Article Cancers (Basel) · April 7, 2022 Anaplastic thyroid carcinoma (ATC) is the most aggressive endocrine neoplasm, with a median survival of just four to six months post-diagnosis. Even with surgical and chemotherapeutic interventions, the five-year survival rate is less than 5%. Although com ... Full text Link to item Cite

Thunor: visualization and analysis of high-throughput dose-response datasets.

Journal Article Nucleic Acids Res · July 2, 2021 High-throughput cell proliferation assays to quantify drug-response are becoming increasingly common and powerful with the emergence of improved automation and multi-time point analysis methods. However, pipelines for analysis of these datasets that provid ... Full text Link to item Cite

An in vitro model of tumor heterogeneity resolves genetic, epigenetic, and stochastic sources of cell state variability.

Journal Article PLoS Biol · June 2021 Tumor heterogeneity is a primary cause of treatment failure and acquired resistance in cancer patients. Even in cancers driven by a single mutated oncogene, variability in response to targeted therapies is well known. The existence of additional genomic al ... Full text Link to item Cite

ACDC: Automated Cell Detection and Counting for Time-Lapse Fluorescence Microscopy.

Journal Article Appl Sci (Basel) · September 2, 2020 Advances in microscopy imaging technologies have enabled the visualization of live-cell dynamic processes using time-lapse microscopy imaging. However, modern methods exhibit several limitations related to the training phases and to time constraints, hinde ... Full text Link to item Cite

Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers.

Journal Article PLoS Comput Biol · October 2019 Adopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three corresp ... Full text Link to item Cite

Ursprung: Provenance for large-scale analytics environments

Conference Proceedings of the ACM SIGMOD International Conference on Management of Data · June 25, 2019 Modern analytics has produced wonders, but reproducing and verifying these wonders is difficult. Data provenance helps to solve this problem by collecting information on how data is created and accessed. Although provenance collection techniques have been ... Full text Cite

Quantifying Drug Combination Synergy along Potency and Efficacy Axes.

Journal Article Cell Syst · February 27, 2019 Two goals motivate treating diseases with drug combinations: reduce off-target toxicity by minimizing doses (synergistic potency) and improve outcomes by escalating effect (synergistic efficacy). Established drug synergy frameworks obscure such distinction ... Full text Link to item Cite

A Nonquiescent "Idling" Population State in Drug-Treated, BRAF-Mutated Melanoma.

Journal Article Biophys J · March 27, 2018 Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated mel ... Full text Link to item Cite

A drift-diffusion checkpoint model predicts a highly variable and growth-factor-sensitive portion of the cell cycle G1 phase.

Journal Article PLoS One · 2018 Even among isogenic cells, the time to progress through the cell cycle, or the intermitotic time (IMT), is highly variable. This variability has been a topic of research for several decades and numerous mathematical models have been proposed to explain it. ... Full text Link to item Cite

A Predictive Mathematical Modeling Approach for the Study of Doxorubicin Treatment in Triple Negative Breast Cancer.

Journal Article Sci Rep · July 18, 2017 Doxorubicin forms the basis of chemotherapy regimens for several malignancies, including triple negative breast cancer (TNBC). Here, we present a coupled experimental/modeling approach to establish an in vitro pharmacokinetic/pharmacodynamic model to descr ... Full text Link to item Cite

Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer.

Journal Article Cancer Res · June 15, 2017 PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB ... Full text Link to item Cite

Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.

Journal Article Sci Rep · February 16, 2017 Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therape ... Full text Link to item Cite

Altered TGF-α/β signaling drives cooperation between breast cancer cell populations.

Journal Article FASEB J · October 2016 The role of tumor heterogeneity in regulating disease progression is poorly understood. We hypothesized that interactions between subpopulations of cancer cells can affect the progression of tumors selecting for a more aggressive phenotype. We developed an ... Full text Link to item Cite

Abstract 302: ECM/Integrin signaling promotes resistance to the combination of HER2 and PI3K inhibitors in HER2+, PIK3CA-mutant breast cancer

Journal Article Cancer Research · July 15, 2016 AbstractHER2 amplification and activating mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, often co-occur in breast cancer. We generated a transgenic mouse model of HER2-overexpressing (HER2 ... Full text Cite

Abstract 776: Multiscale treatment response model for triple-negative breast cancer linking drug pharmacokinetics to tumor cell population dynamics

Journal Article Cancer Research · July 15, 2016 AbstractIntroductionThe goal of this study is to establish a predictive model of cytotoxic therapy that incorporates in vitro drug pharmacokinetics and cell-scale therapy res ... Full text Cite

An unbiased metric of antiproliferative drug effect in vitro.

Journal Article Nat Methods · June 2016 In vitro cell proliferation assays are widely used in pharmacology, molecular biology, and drug discovery. Using theoretical modeling and experimentation, we show that current metrics of antiproliferative small molecule effect suffer from time-dependent bi ... Full text Link to item Cite

Abstract A43: BRAF-mutated melanomas exhibit distinct metabolic programs that may determine therapeutic response

Journal Article Molecular Cancer Research · January 1, 2016 AbstractNearly 60% of melanomas have an activating mutation in the BRAF kinase. Targeted inhibition of mutant BRAF has prolonged overall survival, but responses are highly variable. To investigate the respon ... Full text Cite

Abstract 3747: Identification of NSCLC biomarkers underlying quantifiable drug-induced clonal fitness

Journal Article Cancer Research · August 1, 2015 AbstractLung cancer accounts for nearly 20% of all cancer-related deaths worldwide. Subsets of non-small-cell lung cancer (NSCLC; >80% of all lung cancers) harboring activating epidermal growth factor ... Full text Cite

Quantifying heterogeneity and dynamics of clonal fitness in response to perturbation.

Journal Article J Cell Physiol · July 2015 The dynamics of heterogeneous clonal lineages within a cell population, in aggregate, shape both normal and pathological biological processes. Studies of clonality typically relate the fitness of clones to their relative abundance, thus requiring long-term ... Full text Link to item Cite

Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.

Journal Article JAMA Otolaryngol Head Neck Surg · June 2015 IMPORTANCE: The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation. OBJECT ... Full text Link to item Cite

Derivation and experimental comparison of cell-division probability densities.

Journal Article J Theor Biol · October 21, 2014 Experiments have shown that, even in a homogeneous population of cells, the distribution of division times is highly variable. In addition, a homogeneous population of cells will exhibit a heterogeneous response to drug therapy. We present a simple stochas ... Full text Link to item Cite

Abstract 1845: Sensitivity of PC9 cells to erlotinib is affected by extracellular matrix

Journal Article Cancer Research · October 1, 2014 AbstractTyrosine kinase inhibitors of epidermal growth factor receptor, such as erlotinib and gefinitib, have been effective in the initial treatment of non-small cell lung cancer. With time, however, initia ... Full text Cite

Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer.

Journal Article Clin Cancer Res · May 1, 2014 PURPOSE: Human papilloma virus (HPV)-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) have different molecular and biologic characteristics and clinical behavior compared with HPV-negative (HPV-) OPSCC. PIK3CA mutations are more common in H ... Full text Link to item Cite

What lies beneath: looking beyond tumor genetics shows the complexity of signaling networks underlying drug sensitivity.

Other Sci Signal · September 24, 2013 The identification of "driver mutations" in cancers initiated rapid development of targeted drugs for the clinic. Despite promising outcomes initially in patients, the ultimate success of oncogene-targeted drugs has been hampered by the redundancy and rema ... Full text Link to item Cite

Abstract 4626: Quantifying erlotinib response variability in EGFR-addicted cells.

Journal Article Cancer Research · April 15, 2013 AbstractPatients with activating epidermal growth factor receptor (EGFR) mutations display drastic initial responses to erlotinib, but tumor reduction and progression-free survival vary widely. An open quest ... Full text Cite

Abstract 3403: A stochastically arising subpopulation of B-RafV600E-expressing melanoma continues division in the presence of vemurafenib.

Journal Article Cancer Research · April 15, 2013 AbstractPatients with melanomas expressing B-RafV600E benefit from treatment with B-Raf-targeted therapeutics, such as vemurafenib. Initial responses to these agents are occasionally profound, but the durati ... Full text Cite

The contribution of age structure to cell population responses to targeted therapeutics.

Journal Article J Theor Biol · October 21, 2012 Cells grown in culture act as a model system for analyzing the effects of anticancer compounds, which may affect cell behavior in a cell cycle position-dependent manner. Cell synchronization techniques have been generally employed to minimize the variation ... Full text Link to item Cite

Network analysis of the focal adhesion to invadopodia transition identifies a PI3K-PKCα invasive signaling axis.

Journal Article Sci Signal · September 11, 2012 In cancer, deregulated signaling can produce an invasive cellular phenotype. We modeled the invasive transition as a theoretical switch between two cytoskeletal structures: focal adhesions and extracellular matrix-degrading invadopodia. We constructed mole ... Full text Link to item Cite

Fractional proliferation: a method to deconvolve cell population dynamics from single-cell data.

Journal Article Nat Methods · September 2012 We present an integrated method that uses extended time-lapse automated imaging to quantify the dynamics of cell proliferation. Cell counts are fit with a quiescence-growth model that estimates rates of cell division, entry into quiescence and death. The m ... Full text Link to item Cite

Inhibition of phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model.

Journal Article Mol Cancer · July 25, 2012 BACKGROUND: We previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibiti ... Full text Link to item Cite

Composite thin film and electrospun biomaterials for urologic tissue reconstruction.

Journal Article Biotechnol Bioeng · January 2011 A replacement material for autologous grafts for urinary tract reconstruction would dramatically reduce the complications of surgery for these procedures. However, acellular materials have not proven to work sufficiently well, and cell-seeded materials are ... Full text Link to item Cite

Periprostatic adipose tissue as a modulator of prostate cancer aggressiveness.

Journal Article J Urol · October 2009 PURPOSE: Adipose tissue has been suggested to contribute to the pathogenesis of various disease states, including prostate cancer. We investigated the association of cytokines and growth factors secreted by periprostatic adipose tissue with pathological fe ... Full text Link to item Cite

Loss of annexin A1 disrupts normal prostate glandular structure by inducing autocrine IL-6 signaling.

Journal Article Carcinogenesis · July 2009 Annexin A1 (ANXA1) expression is commonly reduced in premalignant lesions and prostate cancer, but a causal relationship of ANAX1 loss with carcinogenesis has not been established. ANXA1 levels have been shown to inversely correlate with interleukin 6 (IL- ... Full text Link to item Cite

Long-term impact of a robot assisted laparoscopic prostatectomy mini fellowship training program on postgraduate urological practice patterns.

Journal Article J Urol · February 2009 PURPOSE: Robot assisted laparoscopic prostatectomy has stimulated a great deal of interest among urologists. We evaluated whether a mini fellowship for robot assisted laparoscopic prostatectomy would enable postgraduate urologists to incorporate this new p ... Full text Link to item Cite

Transmembrane Receptor Oligomerization

Chapter · January 1, 2009 This chapter provides a brief description on how oligomerization is utilized by the major cell transmembrane receptor classes. The cell-surface receptors possessing intrinsic tyrosine kinase activity (RTK) minimally require a dimeric state for their full a ... Full text Cite

Trait variability of cancer cells quantified by high-content automated microscopy of single cells.

Journal Article Methods Enzymol · 2009 Mapping quantitative cell traits (QCT) to underlying molecular defects is a central challenge in cancer research because heterogeneity at all biological scales, from genes to cells to populations, is recognized as the main driver of cancer progression and ... Full text Link to item Cite

Annexin A2 positively contributes to the malignant phenotype and secretion of IL-6 in DU145 prostate cancer cells.

Journal Article Int J Cancer · January 1, 2009 Several groups, including ours, have reported that annexin A2 (ANXA2) expression is reduced in most prostate cancer (CaP). More recently, however, we reported that ANXA2 is expressed in some high-grade tumors, but the biologic consequence of this is curren ... Full text Link to item Cite

Bone marrow stem cells for urologic tissue engineering.

Journal Article World J Urol · August 2008 OBJECTIVES: Experiments in rats and dogs have demonstrated the potential of bone marrow-derived mesenchymal stem cells (MSCs) for urinary tract tissue engineering. However, the small graft size in rats and a failure to identify the MSCs in engineered tissu ... Full text Link to item Cite

Encrustation of nanostructured Ti in a simulated urinary tract environment

Journal Article Materials Science and Engineering C · April 1, 2008 The use of materials for medical applications in the urinary tract is hampered by the formation of calcium-based crystalline deposits, generally referred to as encrustation, that act as precursors to urinary stones. Anecdotal evidence suggests that titaniu ... Full text Cite

Proteomics of cancer of hormone-dependent tissues.

Journal Article Adv Exp Med Biol · 2008 Serum and tissue biomarkers have begun to play an increasingly important role in the detection and management of many cancers of hormone-sensitive tissues. Specifically, the introduction of serum PSA measurements into clinical practice has dramatically alt ... Full text Link to item Cite

Culture requirements of prostatic epithelial cell lines for acinar morphogenesis and lumen formation in vitro: role of extracellular calcium.

Journal Article Prostate · November 1, 2007 BACKGROUND: Three-dimensional (3D) culture of benign prostatic epithelial cell lines can recapitulate acinar morphogenesis in vitro, but the broad applicability of this approach has not been described. The present studies examine the culture conditions imp ... Full text Link to item Cite

The impact of altered annexin I protein levels on apoptosis and signal transduction pathways in prostate cancer cells.

Journal Article Prostate · September 15, 2006 BACKGROUND: Although reduced expression levels of annexin I (ANX I) protein is a common finding in all stages of prostate cancer a causative relationship between ANX I dysregulation and prostate cancer development has yet to be established. METHODS: Annexi ... Full text Link to item Cite

Proteomics for the identification of new prostate cancer biomarkers.

Journal Article Urol Oncol · 2006 Molecular profiling studies of human prostate cancer provide great opportunities to identify new prostate cancer biomarkers to improve prostate cancer detection and treatment. Proteomics has distinct advantages over genomic and ribonucleic acid expression ... Full text Link to item Cite

Human embryonic kidney cells (HEK-293 cells): characterization and dose-response relationship for modulated release of nerve growth factor for nerve regeneration.

Journal Article Plast Reconstr Surg · February 2004 The development of engineered constructs to bridge nerve gaps may hold the key to improved functional outcomes in the repair of injured peripheral nerves. These constructs must be rendered bioactive by providing the growth factors required for successful p ... Full text Link to item Cite

PC12 cell activation by epidermal growth factor receptor: role of autophosphorylation sites.

Journal Article Int J Dev Neurosci · April 2003 PC12 cells have been used as a model system for neuronal differentiation due to their ability to alter their phenotype to a sympathetic neuron-like cell in response to nerve growth factor or fibroblast growth factor. Under some conditions, epidermal growth ... Full text Link to item Cite

Induction of transcriptional activity of the cyclic adenosine monophosphate response element binding protein by parathyroid hormone and epidermal growth factor in osteoblastic cells.

Journal Article J Bone Miner Res · August 2002 Previously, we have shown that parathyroid hormone (PTH) transactivation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) requires both serine 129 (S129) and serine 133 (S133) in rat osteosarcoma cells UMR 106-01 (UMR) cells ... Full text Link to item Cite

PTH induction of transcriptional activity of the cAMP response element-binding protein requires the serine 129 site and glycogen synthase kinase-3 activity, but not casein kinase II sites.

Journal Article Endocrinology · February 2002 We have previously shown that PTH induction of c-fos expression in the rat osteoblastic cell line UMR 106-01 requires the phosphorylation of cAMP response element-binding protein (CREB) at serine 133. Here we show that this event is not sufficient for indu ... Full text Link to item Cite

Role of GATA motifs in tissue factor pathway inhibitor gene expression in malignant cells.

Journal Article Thromb Res · February 1, 2001 Tissue factor pathway inhibitor (TFPI) is the primary physiologic inhibitor of tissue factor-induced clotting. The TFPI gene contains three GATA motifs in the region flanking its transcription initiation sites. GATA motifs present in promoters of other gen ... Full text Link to item Cite

Parathyroid hormone regulation of the rat collagenase-3 promoter by protein kinase A-dependent transactivation of core binding factor alpha1.

Journal Article J Biol Chem · February 18, 2000 Previously we showed that the activator protein-1 site and the runt domain binding site in the collagenase-3 promoter act cooperatively in response to parathyroid hormone (PTH) in the rat osteoblastic osteosarcoma cell line, UMR 106-01. Our results of the ... Full text Link to item Cite

Increased osteoblastic c-fos expression by parathyroid hormone requires protein kinase A phosphorylation of the cyclic adenosine 3',5'-monophosphate response element-binding protein at serine 133.

Journal Article Endocrinology · March 1999 PTH induces c-fos expression rapidly and transiently in osteoblastic cells and requires the activity of the cAMP response element-binding protein (CREB). Here we provide evidence that protein kinase A (PKA) is the enzyme responsible for phosphorylating CRE ... Full text Link to item Cite

Parathyroid hormone induction of c-fos expression requires phosphorylation of creb at serine 133 by protein kinase A

Journal Article FASEB Journal · December 1, 1998 c-fos is induced in response to parathyroid horinonr (PTH) in a (AMP-depetident manner in the rat osteosarroina cell line UMR 106-01. PTH treatment leads to the phosphorylation of the cAMP response element binding prutrinf(CREB) at M-rine 133 (pCRKB) which ... Cite

Parathyroid hormone versus phorbol ester stimulation of activator protein-1 gene family members in rat osteosarcoma cells.

Journal Article Calcif Tissue Int · July 1997 We have previously shown that in the rat osteoblastic osteosarcoma cell line-UMR 106-01-PTH induces maximal collagenase mRNA levels at 4 hours. Since this response to PTH requires de novo protein synthesis, it may be mediated by the combined temporal expre ... Full text Link to item Cite

Parathyroid hormone stimulates the c-FOS promoter through creb phosphorylation and binding to the major cre

Journal Article FASEB Journal · December 1, 1996 The major CRE in the c-fos gene is necessary for its activation in response to parathyroid hormone (PTH) treatment in UMR 106-01 rat osteosarcoma cells as determined through transient transfection of mouse c-fos 5'-deletion constructs. This CRE binds prote ... Cite