Gayathri Devi

Overview:

Dr. Devi’s research interests include functional genomics, anti-cancer drug discovery and development, mechanisms of cancer cell signaling, tumor immunity and applications thereof for overcoming therapeutic resistance in cancer.

The lab has established prostate, inflammatory breast cancer and ovarian cellular and tumor models.

Positions:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1998

University of Nebraska, College of Medicine

Grants:

Resveratrol, Carbohydrate Restriction and Prostate Cancer Progression

Administered By
Surgery, Urology
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

GLI1 Inhibition to Enhance Chemo- and Targeted-Therapies in Inflammatory Breast Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
North Carolina Central University
Role
Principal Investigator
Start Date
End Date

Role of XIAP in Therapeutic Resistance in Inflammatory Breast Cancer

Administered By
Surgery
Awarded By
Dept. of the Army -- USAMRAA
Role
Principal Investigator
Start Date
End Date

Publications:

Analysis of polycyclic aromatic hydrocarbon intake in the US adult population from NHANES 2005-2014 identifies vulnerable subpopulations, suggests interaction between tobacco smoke exposure and sociodemographic factors.

Polycyclic aromatic hydrocarbons (PAHs) are a toxic and ubiquitous class of environmental chemicals, products of fuel combustion from human and natural sources. The objective of this study was to identify vulnerable populations for high PAH exposure and variability, to better understand where to target PAH exposure reduction initiatives. Urinary metabolite data were collected from 9517 individuals from the U.S. CDC National Health and Nutrition Examination Survey years 2005-2014 for four parental PAHs naphthalene, fluorene, phenanthrene, and pyrene. We utilized these urinary biomarkers to estimate PAH intake, and regression models were fit for multiple demographic and lifestyle variables, to determine variable effects, interactions, odds of high versus low PAH intake. Smoking and secondhand smoke exposure accounted for the largest PAH intake rate variability (25.62%), and there were strongest interactions between race/ethnicity and smoking or SHS exposure, reflected in a much greater contribution of smoking to PAH intake in non-Hispanic Whites as compared to other races/ethnicities. Increased odds of high PAH intake were seen in older age groups, obese persons, college graduates, midrange incomes, smokers, and those who were SHS exposed. Among the non-smoking population, effects of other demographic factors lessened, suggesting a highly interactive nature. Our results suggest that there are demographic subpopulations with high PAH intake as a result of different smoking behaviors and potentially other exposures. This has human health, environmental justice, and regulatory implications wherein smoking cessation programs, SHS exposure regulations, and public health initiatives could be better targeted towards vulnerable subpopulations to meaningfully reduce PAH exposures.
Authors
Gearhart-Serna, LM; Tacam, M; Slotkin, TA; Devi, GR
URI
https://scholars.duke.edu/individual/pub1487567
PMID
34216610
Source
pubmed
Published In
Environ Res
Volume
201
Published Date
Start Page
111614
DOI
10.1016/j.envres.2021.111614

Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.
Authors
Schirmer, AU; Driver, LM; Zhao, MT; Wells, CI; Pickett, JE; O'Bryne, SN; Eduful, BJ; Yang, X; Howard, L; You, S; Devi, GR; DiGiovanni, J; Freedland, SJ; Chi, J-T; Drewry, DH; Macias, E
MLA Citation
Schirmer, Amelia U., et al. “Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.Mol Ther, Aug. 2021. Pubmed, doi:10.1016/j.ymthe.2021.08.029.
URI
https://scholars.duke.edu/individual/pub1494995
PMID
34450249
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Published Date
DOI
10.1016/j.ymthe.2021.08.029

Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy.

XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients' age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2- status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2- but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP.
Authors
Devi, GR; Finetti, P; Morse, MA; Lee, S; de Nonneville, A; Van Laere, S; Troy, J; Geradts, J; McCall, S; Bertucci, F
MLA Citation
Devi, Gayathri R., et al. “Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy.Cancers (Basel), vol. 13, no. 11, June 2021. Pubmed, doi:10.3390/cancers13112807.
URI
https://scholars.duke.edu/individual/pub1484291
PMID
34199946
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13112807

Hymenolepis diminuta-based helminth therapy in C3(1)-TAg mice does not alter breast tumor onset or progression.

Background and objectives: An individual's risk of breast cancer is profoundly affected by evolutionary mismatch. Mismatches in Western society known to increase the risk of breast cancer include a sedentary lifestyle and reproductive factors. Biota alteration, characterized by a loss of biodiversity from the ecosystem of the human body as a result of Western society, is a mismatch known to increase the risk of a variety of inflammation-related diseases, including colitis-associated colon cancer. However, the effect of biota alteration on breast cancer has not been evaluated. Methodology: In this study, we utilized the C3(1)-TAg mouse model of breast cancer to evaluate the role of biota alteration in the development of breast cancer. This model has been used to recapitulate the role of exercise and pregnancy in reducing the risk of breast cancer. C3(1)-TAg mice were treated with Hymenolepis diminuta, a benign helminth that has been shown to reverse the effects of biota alteration in animal models. Results: No effect of the helminth H. diminuta was observed. Neither the latency nor tumor growth was affected by the therapy, and no significant effects on tumor transcriptome were observed based on RNAseq analysis. Conclusions and implications: These findings suggest that biota alteration, although known to affect a variety of Western-associated diseases, might not be a significant factor in the high rate of breast cancer observed in Western societies. Lay summary: An almost complete loss of intestinal worms in high-income countries has led to increases in allergic disorders, autoimmune conditions, and perhaps colon cancer. However, in this study, results using laboratory mice suggest that loss of intestinal worms might not be associated with breast cancer.
Authors
Sauer, S; Beinart, D; Finn, SMB; Kumar, SL; Cheng, Q; Hwang, SE; Parker, W; Devi, GR
MLA Citation
Sauer, Scott, et al. “Hymenolepis diminuta-based helminth therapy in C3(1)-TAg mice does not alter breast tumor onset or progression.Evol Med Public Health, vol. 9, no. 1, 2021, pp. 131–38. Pubmed, doi:10.1093/emph/eoab007.
URI
https://scholars.duke.edu/individual/pub1476488
PMID
33738103
Source
pubmed
Published In
Evolution, Medicine, and Public Health
Volume
9
Published Date
Start Page
131
End Page
138
DOI
10.1093/emph/eoab007

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation.

BACKGROUND: Thrombosis is a known consequence of intraportal islet transplantation, particularly for xenogeneic islets. To define the origins of thrombosis after islet xenotransplantation and relate it to early inflammation, we examined porcine islets transplanted into non-human primates using a dual-transplant model to directly compare islet characteristics. METHODS: α1,3-Galactosyltransferase gene-knockout (GTKO) islets with and without expression of the human complement regulatory transgene CD46 (hCD46) were studied. Biologically inert polyethylene microspheres were used to examine the generic pro-thrombotic effects of particle embolization. Immunohistochemistry was performed 1 and 24 hours after transplantation. RESULTS: Xeno-islet transplantation activated both extrinsic and intrinsic coagulation pathways. The intrinsic pathway was also initiated by microsphere embolization, while extrinsic pathway tissue factor (TF) and platelet aggregation were more specific to engrafted islets. hCD46 expression significantly reduced TF, platelet, fibrin, and factor XIIIa accumulation in and around islets but did not alter intrinsic factor activation. Layers of TF+ cells emerged around islets within 24 hours, particularly co-localized with vimentin, and identified as CD3+ and CD68+ cells inflammatory cells. CONCLUSIONS: These findings detail the origins of thrombosis following islet xenotransplantation, relate it to early immune activation, and suggest a role for transgenic hCD46 expression in its mitigation. Layers of TF-positive inflammatory cells and fibroblasts around islets at 24 hours may have important roles in the progressive events of thrombosis, inflammatory cell recruitment, rejection, and the ultimate outcome of transplanted grafts. These suggest that the strategies targeting these elements could yield more progress toward successful xenogeneic islet engraftment and survival.
Authors
Song, M; Fitch, ZW; Samy, KP; Martin, BM; Gao, Q; Patrick Davis, R; Leopardi, FV; Huffman, N; Schmitz, R; Devi, GR; Collins, BH; Kirk, AD
MLA Citation
Song, Mingqing, et al. “Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation.Xenotransplantation, vol. 28, no. 3, May 2021, p. e12680. Pubmed, doi:10.1111/xen.12680.
URI
https://scholars.duke.edu/individual/pub1474591
PMID
33619844
Source
pubmed
Published In
Xenotransplantation
Volume
28
Published Date
Start Page
e12680
DOI
10.1111/xen.12680