Wei Chen

Overview:

My general area of interest relates to how cancer develops and how to identify cancer therapeutic agents. In particular I hope to identify molecular signals that underlie the changes necessary for directing normal tissue to a malignant state in cancer. Therefore, I have been studying how extracellular signals are deciphered by seven trans-membrane receptors and their regulatory proteins to control cell proliferation and differentiation. My major research focuses on studying GPCR, Smoothened, TGF-beta and Frizzled receptor trafficking and signaling as well as their roles in tumor biology. Abnormalities in the receptors or other proteins they interact with either directly or indirectly result in malignancies. Moreover, as a result of our research, we have established a state-of-the-art high throughput, high content screening platform in my laboratory to identify novel small molecules that modulate the activity of these receptors. We have found many new small molecules that block Hedgehog pathway. These chemical compounds may have the potential to become new therapeutic agents to treat many refractory cancers of the pancreas, liver, breast, prostate, and skin.

Positions:

Associate Professor in Medicine

Medicine, Gastroenterology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

University of Toledo

Grants:

Targeting the WNT/beta-catenin pathway in triple negative breast cancer

Administered By
Medicine, Gastroenterology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Publications:

β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion.

Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta-cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and co-immunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta-cells may prove useful for the development of efficacious antidiabetic drugs.
Authors
Barella, LF; Rossi, M; Zhu, L; Cui, Y; Mei, FC; Cheng, X; Chen, W; Gurevich, VV; Wess, J
MLA Citation
Barella, Luiz F., et al. “β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion.J Clin Invest, vol. 130, June 2019, pp. 3732–37. Pubmed, doi:10.1172/JCI126309.
URI
https://scholars.duke.edu/individual/pub1402624
PMID
31184597
Source
pubmed
Published In
J Clin Invest
Volume
130
Published Date
Start Page
3732
End Page
3737
DOI
10.1172/JCI126309

Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.

PURPOSE: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. METHODS AND MATERIALS: Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. RESULTS: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. CONCLUSIONS: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.
Authors
Horton, JK; Blitzblau, RC; Yoo, S; Geradts, J; Chang, Z; Baker, JA; Georgiade, GS; Chen, W; Siamakpour-Reihani, S; Wang, C; Broadwater, G; Groth, J; Palta, M; Dewhirst, M; Barry, WT; Duffy, EA; Chi, J-TA; Hwang, ES
MLA Citation
Horton, Janet K., et al. “Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.Int J Radiat Oncol Biol Phys, vol. 92, no. 4, July 2015, pp. 846–55. Pubmed, doi:10.1016/j.ijrobp.2015.03.007.
URI
https://scholars.duke.edu/individual/pub1075477
PMID
26104938
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
92
Published Date
Start Page
846
End Page
855
DOI
10.1016/j.ijrobp.2015.03.007

Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.
Authors
Osada, T; Chen, M; Yang, XY; Spasojevic, I; Vandeusen, JB; Hsu, D; Clary, BM; Clay, TM; Chen, W; Morse, MA; Lyerly, HK
MLA Citation
Osada, Takuya, et al. “Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.Cancer Res, vol. 71, no. 12, June 2011, pp. 4172–82. Pubmed, doi:10.1158/0008-5472.CAN-10-3978.
URI
https://scholars.duke.edu/individual/pub764958
PMID
21531761
Source
pubmed
Published In
Cancer Res
Volume
71
Published Date
Start Page
4172
End Page
4182
DOI
10.1158/0008-5472.CAN-10-3978

Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice.

Rac, a small, GTP-binding protein in the Rho family, regulates several cellular functions, including the activation of NADPH oxidase, a major intracellular producer of reactive oxygen species (ROS). Hepatic stellate cells (HSCs) isolated from mice that are genetically deficient in NADPH oxidase produce less ROS, and their activation during chronic liver injury is abrogated, resulting in decreased liver fibrosis. Therefore, we hypothesized that HSC ROS production and activation would be enhanced, and fibrosis worsened, by increasing Rac expression in HSCs. To achieve this, we used transgenic mice that express constitutively active human Rac1 under the control of the alpha-smooth muscle actin (alpha-sma) promoter, because alpha-sma expression is induced spontaneously during HSC activation. Transgene expression was upregulated progressively during culture of primary Rac-transgenic HSCs, and this increased HSC ROS production as well as expression of activation markers and collagen. Similarly, Rac mice treated with carbon tetrachloride (CCl(4)) accumulated greater numbers of activated HSCs and had more liver damage, hepatocyte apoptosis, and liver fibrosis-as well as higher mortality-than CCl(4)-treated wild-type mice. In conclusion, sustained activation of Rac in HSCs perpetuates their activation and exacerbates toxin-induced liver injury and fibrosis, prompting speculation that Rac may be a therapeutic target in patients with cirrhosis.
Authors
Choi, SS; Sicklick, JK; Ma, Q; Yang, L; Huang, J; Qi, Y; Chen, W; Li, Y-X; Goldschmidt-Clermont, PJ; Diehl, AM
MLA Citation
Choi, Steve S., et al. “Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice.Hepatology, vol. 44, no. 5, Nov. 2006, pp. 1267–77. Pubmed, doi:10.1002/hep.21375.
URI
https://scholars.duke.edu/individual/pub733060
PMID
17058265
Source
pubmed
Published In
Hepatology (Baltimore, Md.)
Volume
44
Published Date
Start Page
1267
End Page
1277
DOI
10.1002/hep.21375

A metabolomic study of the PPARδ agonist GW501516 for enhancing running endurance in Kunming mice.

Exercise can increase peroxisome proliferator-activated receptor-δ (PPARδ) expression in skeletal muscle. PPARδ regulates muscle metabolism and reprograms muscle fibre types to enhance running endurance. This study utilized metabolomic profiling to examine the effects of GW501516, a PPARδ agonist, on running endurance in mice. While training alone increased the exhaustive running performance, GW501516 treatment enhanced running endurance and the proportion of succinate dehydrogenase (SDH)-positive muscle fibres in both trained and untrained mice. Furthermore, increased levels of intermediate metabolites and key enzymes in fatty acid oxidation pathways were observed following training and/or treatment. Training alone increased serum inositol, glucogenic amino acids, and branch chain amino acids. However, GW501516 increased serum galactose and β-hydroxybutyrate, independent of training. Additionally, GW501516 alone raised serum unsaturated fatty acid levels, especially polyunsaturated fatty acids, but levels increased even more when combined with training. These findings suggest that mechanisms behind enhanced running capacity are not identical for GW501516 and training. Training increases energy availability by promoting catabolism of proteins, and gluconeogenesis, whereas GW501516 enhances specific consumption of fatty acids and reducing glucose utilization.
Authors
Chen, W; Gao, R; Xie, X; Zheng, Z; Li, H; Li, S; Dong, F; Wang, L
MLA Citation
Chen, Wei, et al. “A metabolomic study of the PPARδ agonist GW501516 for enhancing running endurance in Kunming mice.Sci Rep, vol. 5, May 2015, p. 9884. Pubmed, doi:10.1038/srep09884.
URI
https://scholars.duke.edu/individual/pub1102507
PMID
25943561
Source
pubmed
Published In
Scientific Reports
Volume
5
Published Date
Start Page
9884
DOI
10.1038/srep09884