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:

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 <i>intravital</i> 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 (<i>VCAN</i>) 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.Frontiers in Oncology, vol. 11, Jan. 2021, p. 641187. Epmc, doi:10.3389/fonc.2021.641187.
URI
https://scholars.duke.edu/individual/pub1498525
PMID
34631514
Source
epmc
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

Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.

BACKGROUND: Prostate cancer is a clinically and molecularly heterogeneous disease, with highest incidence and mortality among men of African ancestry. To date, prostate cancer patient-derived xenograft (PCPDX) models to study this disease have been difficult to establish because of limited specimen availability and poor uptake rates in immunodeficient mice. Ancestrally diverse PCPDXs are even more rare, and only six PCPDXs from self-identified African American patients from one institution were recently made available. METHODS: In the present study, we established a PCPDX from prostate cancer tissue from a patient of estimated 90% West African ancestry with metastatic castration resistant disease, and characterized this model's pathology, karyotype, hotspot mutations, copy number, gene fusions, gene expression, growth rate in normal and castrated mice, therapeutic response, and experimental metastasis. RESULTS: This PCPDX has a mutation in TP53 and loss of PTEN and RB1. We have documented a 100% take rate in mice after thawing the PCPDX tumor from frozen stock. The PCPDX is castrate- and docetaxel-resistant and cisplatin-sensitive, and has gene expression patterns associated with such drug responses. After tail vein injection, the PCPDX tumor cells can colonize the lungs of mice. CONCLUSION: This PCPDX, along with others that are established and characterized, will be useful pre-clinically for studying the heterogeneity of prostate cancer biology and testing new therapeutics in models expected to be reflective of the clinical setting.
Authors
Patierno, BM; Foo, W-C; Allen, T; Somarelli, JA; Ware, KE; Gupta, S; Wise, S; Wise, JP; Qin, X; Zhang, D; Xu, L; Li, Y; Chen, X; Inman, BA; McCall, SJ; Huang, J; Kittles, RA; Owzar, K; Gregory, S; Armstrong, AJ; George, DJ; Patierno, SR; Hsu, DS; Freedman, JA
MLA Citation
Patierno, Brendon M., et al. “Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.Prostate Cancer Prostatic Dis, 2021. Pubmed, doi:10.1038/s41391-021-00460-y.
URI
https://scholars.duke.edu/individual/pub1466481
PMID
34645983
Source
pubmed
Published In
Prostate Cancer Prostatic Dis
Published Date
DOI
10.1038/s41391-021-00460-y

Differential alternative RNA splicing and transcription events between tumors from African American and White patients in The Cancer Genome Atlas.

Individuals of African ancestry suffer disproportionally from higher incidence, aggressiveness, and mortality for particular cancers. This disparity likely results from an interplay among differences in multiple determinants of health, including differences in tumor biology. We used The Cancer Genome Atlas (TCGA) SpliceSeq and TCGA aggregate expression datasets and identified differential alternative RNA splicing and transcription events (ARS/T) in cancers between self-identified African American (AA) and White (W) patients. We found that retained intron events were enriched among race-related ARS/T. In addition, on average, 12% of the most highly ranked race-related ARS/T overlapped between any two analyzed cancers. Moreover, the genes undergoing race-related ARS/T functioned in cancer-promoting pathways, and a number of race-related ARS/T were associated with patient survival. We built a web-application, CanSplice, to mine genomic datasets by self-identified race. The race-related targets have the potential to aid in the development of new biomarkers and therapeutics to mitigate cancer disparity.
Authors
MLA Citation
Al Abo, Muthana, et al. “Differential alternative RNA splicing and transcription events between tumors from African American and White patients in The Cancer Genome Atlas.Genomics, vol. 113, no. 3, May 2021, pp. 1234–46. Epmc, doi:10.1016/j.ygeno.2021.02.020.
URI
https://scholars.duke.edu/individual/pub1476027
PMID
33705884
Source
epmc
Published In
Genomics
Volume
113
Published Date
Start Page
1234
End Page
1246
DOI
10.1016/j.ygeno.2021.02.020