Jennifer Freedman

Positions:

Associate Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2001

Emory University

Grants:

Publications:

Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk.

Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E-09), rs2285521 in GGA2 (P = 4.43E-08), and rs198459 in MYRF (P = 1.60E-06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E-08, P = 6.21E-08, and P = 7.93E-04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E-05, P = 2.70E-04, and P = 2.90E-05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.
Authors
Yang, W; Liu, H; Zhang, R; Freedman, JA; Han, Y; Hung, RJ; Brhane, Y; McLaughlin, J; Brennan, P; Bickeboeller, H; Rosenberger, A; Houlston, RS; Caporaso, NE; Landi, MT; Brueske, I; Risch, A; Christiani, DC; Amos, CI; Chen, X; Patierno, SR; Wei, Q
MLA Citation
Yang, Wenjun, et al. “Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk.Npj Precis Oncol, vol. 6, no. 1, June 2022, p. 48. Pubmed, doi:10.1038/s41698-022-00281-9.
URI
https://scholars.duke.edu/individual/pub1526275
PMID
35773316
Source
pubmed
Published In
Npj Precis Oncol
Volume
6
Published Date
Start Page
48
DOI
10.1038/s41698-022-00281-9

Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences.

Aggressive breast cancer variants, like triple negative and inflammatory breast cancer, contribute to disparities in survival and clinical outcomes among African American (AA) patients compared to White (W) patients. We previously identified the dominant role of anti-apoptotic protein XIAP in regulating tumor cell adaptive stress response (ASR) that promotes a hyperproliferative, drug resistant phenotype. Using The Cancer Genome Atlas (TCGA), we identified 46-88 ASR genes that are differentially expressed (2-fold-change and adjusted p-value < 0.05) depending on PAM50 breast cancer subtype. On average, 20% of all 226 ASR genes exhibited race-related differential expression. These genes were functionally relevant in cell cycle, DNA damage response, signal transduction, and regulation of cell death-related processes. Moreover, 23% of the differentially expressed ASR genes were associated with AA and/or W breast cancer patient survival. These identified genes represent potential therapeutic targets to improve breast cancer outcomes and mitigate associated health disparities.
Authors
Al Abo, M; Gearhart-Serna, L; Van Laere, S; Freedman, JA; Patierno, SR; Hwang, E-SS; Krishnamurthy, S; Williams, KP; Devi, GR
MLA Citation
Al Abo, Muthana, et al. “Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences.Npj Breast Cancer, vol. 8, no. 1, June 2022, p. 73. Pubmed, doi:10.1038/s41523-022-00431-z.
URI
https://scholars.duke.edu/individual/pub1524865
PMID
35697736
Source
pubmed
Published In
Npj Breast Cancer
Volume
8
Published Date
Start Page
73
DOI
10.1038/s41523-022-00431-z

A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation.

Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under intravital imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican (VCAN) as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis.
Authors
Allen, TA; Cullen, MM; Hawkey, N; Mochizuki, H; Nguyen, L; Schechter, E; Borst, L; Yoder, JA; Freedman, JA; Patierno, SR; Cheng, K; Eward, WC; Somarelli, JA
MLA Citation
Allen, Tyler A., et al. “A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation.Front Oncol, vol. 11, 2021, p. 641187. Pubmed, doi:10.3389/fonc.2021.641187.
URI
https://scholars.duke.edu/individual/pub1498525
PMID
34631514
Source
pubmed
Published In
Frontiers in Oncology
Volume
11
Published Date
Start Page
641187
DOI
10.3389/fonc.2021.641187

Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), the hepatic correlate of the metabolic syndrome, is a major risk factor for hepatobiliary cancer (HBC). Although chronic inflammation is thought to be the root cause of all these diseases, the mechanism whereby it promotes HBC in NAFLD remains poorly understood. Herein, we aim to evaluate the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis. METHODS: We use murine NAFLD models, liver biopsies from patients with NAFLD, human liver cancer registry data, and studies in liver cancer cell lines. RESULTS: Our results confirm the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis, supporting a model whereby chronic inflammation suppresses hepatocyte expression of ESRP2, an RNA splicing factor that directly targets and activates NF2, a tumor suppressor that is necessary to constrain YAP/TAZ activation. The resultant loss of NF2 function permits sustained YAP/TAZ activity that drives hepatocyte proliferation and de-differentiation. CONCLUSION: Herein, we report on a novel mechanism by which chronic inflammation leads to sustained activation of YAP/TAZ activity; this imposes a selection pressure that favors liver cells with mutations enabling survival during chronic oncogenic stress. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) increases the risk of hepatobiliary carcinogenesis. However, the underlying mechanism remains unknown. Our study demonstrates that chronic inflammation suppresses hepatocyte expression of ESRP2, an adult RNA splicing factor that activates NF2. Thus, inactive (fetal) NF2 loses the ability to activate Hippo kinases, leading to the increased activity of downstream YAP/TAZ and promoting hepatobiliary carcinogenesis in chronically injured livers.
Authors
Hyun, J; Al Abo, M; Dutta, RK; Oh, SH; Xiang, K; Zhou, X; Maeso-Díaz, R; Caffrey, R; Sanyal, AJ; Freedman, JA; Patierno, SR; Moylan, CA; Abdelmalek, MF; Diehl, AM
MLA Citation
Hyun, Jeongeun, et al. “Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease.J Hepatol, vol. 75, no. 3, Sept. 2021, pp. 623–33. Pubmed, doi:10.1016/j.jhep.2021.04.033.
URI
https://scholars.duke.edu/individual/pub1481815
PMID
33964370
Source
pubmed
Published In
J Hepatol
Volume
75
Published Date
Start Page
623
End Page
633
DOI
10.1016/j.jhep.2021.04.033

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.
Authors
George, DJ; Halabi, S; Heath, EI; Sartor, AO; Sonpavde, GP; Das, D; Bitting, RL; Berry, W; Healy, P; Anand, M; Winters, C; Riggan, C; Kephart, J; Wilder, R; Shobe, K; Rasmussen, J; Milowsky, MI; Fleming, MT; Bearden, J; Goodman, M; Zhang, T; Harrison, MR; McNamara, M; Zhang, D; LaCroix, BL; Kittles, RA; Patierno, BM; Sibley, AB; Patierno, SR; Owzar, K; Hyslop, T; Freedman, JA; Armstrong, AJ
MLA Citation
George, Daniel J., et al. “A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.Cancer, vol. 127, no. 16, Aug. 2021, pp. 2954–65. Pubmed, doi:10.1002/cncr.33589.
URI
https://scholars.duke.edu/individual/pub1481831
PMID
33951180
Source
pubmed
Published In
Cancer
Volume
127
Published Date
Start Page
2954
End Page
2965
DOI
10.1002/cncr.33589