Publications by authors named "Jennifer A Geisler"

4 Publications

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Modeling Brain Metastases Through Intracranial Injection and Magnetic Resonance Imaging.

J Vis Exp 2020 06 7(160). Epub 2020 Jun 7.

The Comprehensive Cancer Center, The Ohio State University; Department of Radiation Oncology, The Ohio State University;

Metastatic spread of cancer is an unfortunate consequence of disease progression, aggressive cancer subtypes, and/or late diagnosis. Brain metastases are particularly devastating, difficult to treat, and confer a poor prognosis. While the precise incidence of brain metastases in the United States remains hard to estimate, it is likely to increase as extracranial therapies continue to become more efficacious in treating cancer. Thus, it is necessary to identify and develop novel therapeutic approaches to treat metastasis at this site. To this end, intracranial injection of cancer cells has become a well-established method in which to model brain metastasis. Previously, the inability to directly measure tumor growth has been a technical hindrance to this model; however, increasing availability and quality of small animal imaging modalities, such as magnetic resonance imaging (MRI), are vastly improving the ability to monitor tumor growth over time and infer changes within the brain during the experimental period. Herein, intracranial injection of murine mammary tumor cells into immunocompetent mice followed by MRI is demonstrated. The presented injection approach utilizes isoflurane anesthesia and a stereotactic setup with a digitally controlled, automated drill and needle injection to enhance precision, and reduce technical error. MRI is measured over time using a 9.4 Tesla instrument in The Ohio State University James Comprehensive Cancer Center Small Animal Imaging Shared Resource. Tumor volume measurements are demonstrated at each time point through use of ImageJ. Overall, this intracranial injection approach allows for precise injection, day-to-day monitoring, and accurate tumor volume measurements, which combined greatly enhance the utility of this model system to test novel hypotheses on the drivers of brain metastases.
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http://dx.doi.org/10.3791/61272DOI Listing
June 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Cancer Res 2021 Feb 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Prevention of Underage Drinking on California Indian Reservations Using Individual- and Community-Level Approaches.

Am J Public Health 2018 08 21;108(8):1035-1041. Epub 2018 Jun 21.

Roland S. Moore, Joel W. Grube, Juliet P. Lee, Bettina Friese, and Laura J. Finan are with Prevention Research Center, Pacific Institute for Research and Evaluation, Berkeley, CA. David A. Gilder and Cindy L. Ehlers are with the Scripps Research Institute, La Jolla, CA. Jennifer A. Geisler was with and Daniel J. Calac is with the Southern California Tribal Health Center.

Objectives: To evaluate combined individual- and community-level interventions to reduce underage drinking by American Indian/Alaska Native (AI/AN) youths on rural California Indian reservations.

Methods: Individual-level interventions included brief motivational interviewing and psychoeducation for Tribal youths. Community-level interventions included community mobilization and awareness activities, as well as restricting alcohol sales to minors. To test effects, we compared 7 waves of California Healthy Kids Survey data (2002-2015) for 9th- and 11th-grade AI/AN and non-AI/AN students in intervention area schools with California AI/AN students outside the intervention area (n = 617, n = 33 469, and n = 976, respectively).

Results: Pre- to postintervention mean past 30-day drinking frequency declined among current drinkers in the intervention group (8.4-6.3 days) relative to comparison groups. Similarly, heavy episodic drinking frequency among current drinkers declined in the intervention group (7.0-4.8 days) versus the comparison groups.

Conclusions: This study documented significant, sustained past 30-day drinking or heavy episodic drinking frequency reductions among AI/AN 9th- and 11th-grade current drinkers in rural California Indian reservation communities exposed to multilevel interventions. Public Health Implications. Multilevel community-partnered interventions can effectively reduce underage alcohol use in this population.
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http://dx.doi.org/10.2105/AJPH.2018.304447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050833PMC
August 2018

Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation.

Bone Res 2018 28;6. Epub 2018 Mar 28.

1Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210 USA.

Genome-wide association studies (GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast- and osteoclast (OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor (TF) network was revealed. Deletion of PU.1 in OCs in mice resulted in severe osteopetrosis. Functional genomic analysis indicated PU.1 and MITF orchestrated a TF network essential for OC differentiation. Several of these TFs were regulated by cooperative binding of PU.1 with BRD4 to form superenhancers. Further, PU.1 is essential for conformational changes in the superenhancer region of Nfatc1. In summary, our study demonstrates that combining GWASs with genome-wide binding studies and model organisms could decipher lineage-specific pathways contributing to complex disease states.
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http://dx.doi.org/10.1038/s41413-018-0011-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874256PMC
March 2018