It occurred to me that while I’ve told you that I’m a cancer researcher, you might not know what that actually means. There are many kinds of researchers who conduct many diverse types of cancer research, as detailed here. All are important and complimentary, and they often overlap. I am an academic (work at a University) laboratory researcher in the broad field of Cell Biology, with a focus on Cancer Biology and Cancer Treatment research, specifically working as a “wet lab” researcher. This means I conduct and supervise hands-on experimental research with cells in a dish, mouse models, and tissue/cell extracts (where we grind up or pulverize tissues and cells, separate them into their components like DNA, RNA, or protein, and analyze them using molecular biology or biochemistry). Other researchers use computational models and datasets to conduct their “dry lab” research.
Both types of research are important, and one informs and shapes the other. For example, I’ll use information found in large databases generated by dry labs that containing data from actual human cancers (e.g. cBioPortal for Cancer Genomics, Kaplan-Meier plotter, and The Human Cancer Metastasis Database) to find clues about how the gene product molecules I study might be driving cancer cell growth, survival, and invasion. The data I generate then feeds back into these databases, linking known functions in laboratory models along with data about where these gene product molecules are expressed and at what level in human cancers. In fact, all of the cancer research fields listed in the link feed into and fuel each other. Science these days is multi-disciplinary, meaning scientists from diverse fields bring their expertises to the table in order to do better, more advanced, more impactful science. Case in point – I’m working with Dr. Craig Duvall, Biomedical Engineer right now, applying his cutting-edge nanoparticle and carrier technologies to targeting the expression of cancer-driving genes in the cell culture and mouse models in my laboratory.
So, what is it exactly that I do…do?
These days, I split my time between the bench (doing actual experiments, which is why I became a scientist in the first place) and the office (doing endless paperwork as quickly and as efficiently as possible so I can get back to the bench). I also supervise a phenomenal medical student and co-mentor insanely smart graduate students, support and collaborate with a team of amazing junior and senior faculty, write grant proposals (more on that below), write up scientific findings into manuscripts for peer review and publication, prepare and deliver scientific talks, maintain compliance (biosafety, environmental safety, radiation safety, responsible care and use of laboratory animals, etc.), make sure the laboratory staff have what they need to perform their research, make sure equipment gets serviced and is operational, attend faculty meetings, scientific seminars, professional development meetings, student thesis committee meetings.
Lots of meetings…
As far as what I research, I use cell culture and mouse models of breast cancer, including metastatic breast cancer, to test new experimental therapeutics.
The goal is to discover more specific, effective, less toxic (looking at you, chemo) treatments for breast cancer. I’ll blog more about specific projects later, but what this normally involves is seeing if the new drug makes cancer cells in a petri dish stop growing and/or die, stops cancer cells in a dish from moving and invading, and if a new drug stops tumors in mice from growing or kills them, and, better yet, if the new drugs can actually shrink the tumors. For more information, see the copy of my NIH Biosketch, the mini-resume that we add to every grant application to prove our published expertise, pasted below.
How did I become a cancer researchers? Lots of school and training! I earned a B.A. in Biology from Maryville College in 1995. After graduating, I completed graduate studies at Vanderbilt University, earning a Ph.D. in Cell Biology in 2000. After graduate studies, I completed postdoctoral training in the laboratory of Jin Chen at Vanderbilt University Medical Center from 2000-2003, supported by an American Heart Association Postdoctoral Fellowship Award (I was studying tumor blood vessels, so it was legit!) and a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship award, before being promoted to Research Instructor. I was promoted to Research Assistant Professor in 2006, and during that time I earned a K01 career transition award from the National Institutes of Health/National Cancer Institute. (NIH/NCI – the major funding agency for biomedical cancer research in the united states). This led to my first NIH/NCI independent investigator R01 award in 2011. I was promoted to Assistant Professor of Medicine, Tenure Track, in 2015, and am still at Vanderbilt University Medical Center. I am currently supported by 2 NIH/NCI R01 grants as well as funds from my institution that allow me to generate preliminary data necessary to apply for more grants.
Have you spotted a theme? The theme is “grants” or “awards.” One of the most important jobs I have for my research laboratory is to successfully apply for grants – meaning I write up a proposal about the cool science I want to do, explaining how and why it will benefit patients with breast cancer and move the field forward, and I submit it to the funding agency and compete with a bunch of other super smart, top notch scientists for limited research dollars. These days, money is tough to come by. When I first entered the field as an independent scientist, the top 15% of NCI applications were funded (compared with a funding rate of 25% earlier). These days, it’s at 10%. My colleagues and I literally just missed out on getting a really innovative research proposal funded by 1%! I’m worried how Covid-19 will affect funding over the next 5-10 years, too, as are most of my colleagues. Why is that important? Well, if we want the U.S. to remain on the cutting edge of research and innovation, and if we want to keep discovering new and better ways to detect and treat cancer, we need to invest in science, especially academic science. If you are a cancer survivor, know a survivor, or just want to make the world a better place with less cancer, write your representatives Congress to let them know you want support and full funding of the National Institutes of Health and the National Cancer Institute.
OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
NAME: Dana M. Brantley-Sieders
eRA COMMONS USER NAME (credential, e.g., agency login): BRANTLDM
POSITION TITLE: Assistant Professor, Medicine/Rheumatology, Vanderbilt University School of Medicine
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
|INSTITUTION AND LOCATION||DEGREE (if applicable)||Completion Date MM/YYYY||FIELD OF STUDY|
|Maryville College, Maryville, Tennessee||B.A.||05/1995||Biology|
|Vanderbilt University School of Medicine||Ph.D.||06/2000||Cell Biology|
|Vanderbilt University Medical Center||Postdoctoral||07/2000||Cancer Biology|
A. Personal Statement
I have the expertise, leadership, training, and motivation to successfully carry out the proposed investigation of how EphA2 receptor tyrosine kinase contributes to breast cancer bone metastasis, particularly in terms of tumor-osteoclast interactions that mediate osteolysis in clinically relevant in vivo models that mimic human breast-to-bone metastasis. I have a broad background in cancer research, with specific training and expertise in mouse models of breast cancer and host-tumor interactions (genetically engineered mouse models and orthotopic allograft/xenograft models, including PDX), as well as three-dimensional cell culture and co-culture models, and data mining human tissue microarray and patient datasets to validate clinical relevance of findings in my laboratory model systems. I also have experience testing novel experimental therapeutics in clinically relevant models of breast cancer, including metastatic disease. My research includes analysis of breast cancer cell growth (multiple molecular subtypes), survival, invasion, and host-tumor interactions. Dr. Sterling, Dr. Pellecchia, and I have established a fruitful collaboration that will continue as a part of this exciting investigation
- Werfel, T.A., Wang, S., Jackson, M.A., Kavanaugh, T.E., Joly, M.M., Lee, L.H., Hicks, D.J., Sanchez, V., Ericsson, P.G., Kilchrist, K.V., Dimobi, S.C., Sarett, S.M., Brantley-Sieders, D.M., Cook, R.S., and Duvall, CL. (2018) Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res 78:1845-1858. PMID: 29358172. PMCID: PMC5882532.
- Sarett, S.M., Werfel, T.A., Lee, L., Jackson, M.A., Kilchrist, K.V., Brantley-Sieders, D., and Duvall, C.L. (2017) Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing. PNAS 114: E6490-E6497. doi: 10.1073/pnas.1621240114. Epub 2017 Jul 24. PMID: 28739942. PMCID: PMC5558996.
- Song, W., Hwang, Y., Youngblood, V.M., Cook, R.S., Balko, J.M., Chen, J., and Brantley-Sieders, D.M. (2017) Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers. Oncogene 36: 5620-30. PMID: 28581527. PMCID: PMC5629103.
- Shiuan, E., Inala, A., Wang, S., Song, W., Youngblood, V., Chen, J., and Brantley-Sieders, D.M. (2020). Host deficiency in ephrin-A1 inhibits breast cancer metastasis. [version 2; peer review: 3 approved]. F1000Research 2020, 9:217 (https://doi.org/10.12688/f1000research.22689.2). PMID: 32399207. PMCID: PMC7194498.
B. Positions and Honors
Positions and Employment
- Postdoctoral Fellowship, Vanderbilt University School of Medicine
- Research Instructor, Vanderbilt University School of Medicine
- 2006-2015 Research Assistant Professor of Medicine, Vanderbilt University School of Medicine
- 2015-present Assistant Professor of Medicine, Vanderbilt University School of Medicine
Other Experience and Professional Memberships
1998 Molecular Biology and Pathology of Neoplasia, Edward A. Smuckler Memorial Workshop,Keystone, Colorado
1998-present Member, American Association for Cancer Research
2002 Harvard Medical School Department of Continuing Medical Education and Massachusetts General Hospital Department of Radiation Oncology Seventeenth Annual Offering of Critical Issues in Tumor Microcirculation, Angiogenesis, and Metastasis; Biological Significance and Clinical Relevance Workshop, Cambridge, Massachusetts
2005 National Cancer Institute (NCI)-sponsored Organotypic Models Training Program; received training in orthotopic tumor cell transplantation in mice within several organs, including mammary gland fat pad, bone, lung, spleen, pancreas, bladder, and cecum in the laboratory of Dr. Isaiah J. Fidler, MD Anderson Cancer Center, Houston, Texas
2007-present Ad hoc reviewer for Nature, Cancer Research, PLoS One, Oncogene, Clinical Cancer Research, Neoplasia, European Journal of Cell Biology
2009-2016 Peer reviewer Department of Defense Breast Cancer Research Program
2012 Peer reviewer NCI TME study section
1997-1998 Department of Defense Breast Cancer Pre-doctoral Fellowship
1998-1999 Dissertation Enhancement Award, Vanderbilt University Graduate School
1998-1999 Coordinator for Developmental Biology Student Organization, Vanderbilt University
2000-2001 Public Health Service Vascular Biology Postdoctoral Fellowship
2001-2003 American Heart Association Postdoctoral Fellowship
2001-2002 American Heart Association Basic Cardiovascular Science Council
2003 NIH NRSA Postdoctoral Fellowship 1 F32 CA101419-01 (award offered, declined due to overlap with 2003 DOD award)
2003-2006 Department of Defense Breast Cancer Research Program Postdoctoral Fellowship DAMD17-03-1-0379
2006-2011 NCI Mentored Career Development Award K01CA117915
C. Contributions to Science
My early publications from graduate studies directly addressed how signaling pathways that regulate normal mammary epithelial morphogenesis (e.g. NF-kappaB transcription factors) can contribute to hyperplasia, a hallmark of neoplastic transformation. These publications provided the first evidence that NF-kappaB transcription factors are expressed and active in normal mammary epithelium during post-pubertal development, and that IkappaBalpha deletion in mammary epithelium, which promotes constitutive activation of NF-kappaB transcriptional activity, promotes pervasive intraductal hyperplasia in vivo. These studies laid the foundation for investigating the role of these transcription factors in breast cancer, and also provided training for me in animal models and mammary fat pad clearing and transplantation techniques that have formed a cornerstone of my independent research program and contributed to numerous collaborations, including those with Dr. Chen. I served as primary author for each of these studies and independently designed experiments, interpreted data, and prepared the manuscripts for publication. Funding from my Department of Defense Breast Cancer Pre-doctoral Fellowship award supported this work. I also contributed directly to collaborations that led to publication of work related to the role of NF-kappaB transcription factors to development and disease as a part of my graduate studies.
Brantley, D.M., Yull, F.E., Muraoka, R.S., Hicks, D.J., Cook, C.M., and Kerr, L.D. (2000) Dynamic expression and activity of NF-kappaB during post-natal mammary gland morphogenesis. Mech Dev 97:149-55. PMID: 11025216.
Brantley, D.M., Chen, C.-L., Muraoka, R.S., Bushdid, P. B., Bradberry, J. L., Kittrell, F., Medina, D., Matrisian, L. M., Kerr, L.D., and Yull, F. E. (2001) Nuclear factor-kappaB (NF-kappaB) regulates proliferation and branching in mouse mammary epithelium. Mol Biol Cell 12: 1445-55. PMID: 11359934. PMCID: PMC34596.
Bushdid PB, Brantley DM, Yull FE, Blaeuer GL, Hoffman LH, Niswander L, Kerr LD. (1998) Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Nature 392: 615-8. PMID: 9560159.
I continued to pursue the connection between signaling pathways that regulate development and contribute to tumorigenesis and progression during my post-doctoral training, providing the first evidence that EphA2 receptor tyrosine kinase regulates angiogenesis and tumor neovascularization. These publications showed that EphA2 regulates endothelial cell assembly and motility through a PI3K/Rac1-GTPase-dependent mechanism and regulates tumor angiogenesis in cooperation with the VEGF signaling pathway in vivo, providing novel insight on the molecular regulation of tumor angiogenesis and host-tumor interactions. I served as primary author for each of these studies and independently designed experiments, interpreted data, and prepared manuscripts for publication. Funding from my American Heart Association and Department of Defense Breast Cancer Postdoctoral Fellowship awards supported this work.
Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q., Brekken, R. A., Thorpe, P. E., Muraoka, R. S., Pozzi, A., Jackson, D., Lin, C., and Chen, J. (2002). Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21: 7011-26. PMID: 12370823.
Brantley-Sieders, D. M., Caughron, J., Hicks, D., Pozzi, A., Ruiz, J. C., and Chen, J. (2004). EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J Cell Sci 117: 2037-49. PMID: 15054110.
Brantley-Sieders, D.M., Fang, W.B., Hicks, D.J., Zhuang, G., Shyr, Y., and Chen, J. (2005) Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J 19: 1884-6. PMID: 16166198.
Brantley-Sieders, D.M., Fang, W.B., Hwang, Y., Hicks, D., and Chen, J. (2006) Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism by EphA2 receptor and Vascular Endothelial Growth Factor (VEGF) in mice. Cancer Res 66: 10315-24. PMID: 17079451.
As PI or co-investigator on several university- and NIH-funded grants, I laid the groundwork for an independent research program by showing that (1) EphA2 receptor tyrosine kinase is necessary for normal mammary epithelial morphogenesis, (2) EphA2 receptor tyrosine kinase promotes mammary tumorigenesis and metastasis in vivo in HER2-dependent models of breast cancer through physical and functional interaction with HER2 and activation of Ras/Erk and RhoA signaling, and, (3) demonstrating clinical relevance of these observations by interrogating patient mRNA datasets and human tissue microarrays to show that high levels of EphA2 correlate negatively with overall and recurrence-free survival in human breast cancer across multiple subtypes.
Brantley-Sieders, D.M., Zhuang, G., Hicks, D., Fang, W.B., Hwang, Y., Cates, J.M.M., Coffman, K., Jackson, D., Bruckheimer, E., Muraoka-Cook, R.S., and Chen, J. (2008) EphA2 receptor tyrosine kinase amplifies ErbB2 signaling, promoting tumorigenesis and metastatic progression of mammary adenocarcinoma. J Clin Invest 118: 64-78. PMID: 18079969. PMCID PMC2129239.
Vaught, D.B., Fang, W.B., Mazerik, J., Chen, J., and Brantley-Sieders, D.M. (2009) Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase. Mol Biol Cell 20: 2572-81. PMID: 19321667. PMCID: PMC2682598.
Brantley-Sieders, D.M., Jiang, A., Sarma, K., Badu-Nkansah, A., Walter, D.L., Shyr, Y., and Chen, J. (2011) Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One 6: e24426. PMID: 21935409. PMCID: PMC3174170.
Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J. (2010) Elevation of receptor tyrosine kinase EphA1 mediates resistance to trastuzumab therapy. Cancer Res 70: 299-308. PMID: 20028874. PMCID: PMC3859619.
My independent research career continues to focus on molecular mechanisms that regulate breast tumorigenesis, host-tumor interactions, and metastatic progression in clinically relevant cell culture and in vivo models. Work initiated in my mentor’s laboratory and supported by an NCI K01 Career Development Award pioneered a role for angiocrine factors regulated by EphA2 in tumor cell growth and invasion in culture and in vivo, providing the first evidence that inhibition of the tumor suppressive angiocrine factor, Slit2, by EphA2 receptor tyrosine kinase promotes tumor cell proliferation and invasion. These studies became the basis of my first independent NIH/NCI R01 grant (CA148934) and publications dissecting the molecular mechanisms through which EphA2 receptor and ephrin-A1 ligand cooperate with VEGF and Slit2 to modulate normal vascular remodeling and tumor angiogenesis in vivo. I served as primary author for the first study and senior author/PI for subsequent studies. I have also recently initiated a collaborative investigation of the role of Rictor/mTORC2 in mammary epithelial morphogenesis and breast cancer with Dr. Rebecca Cook.
Youngblood, V.Y., Wang, S., Song, W., Walter, D., Hwang, Y., Chen, J., and Brantley-Sieders, D.M. (2015)Elevated Slit2 activity impairs VEGF-induced angiogenesis and tumor neovascularization in EphA2-deficient endothelium. Mol Cancer Res. 13:524-37. PMID: 25504371. PMCID: PMC4416411.
Morrison, M.M., Young, C.D., Wang, S., Sobolik, T., Sanchez, V.M., Hicks, D.J., Cook, R.S., Brantley-Sieders, D.M. (2015) mTOR directs breast morphogenesis through the PKC-alpha-Rac1 signaling axis. PLoS Genet 11: e1005291. doi: 10.1371/journal.pgen.1005291. eCollection 2015 Jul. PMID: 26833123. PMCID: PMC4873477.
Morrison-Joly, M., Hicks, D.J., Jones, B., Sanchez, V., Estrada, M.V., Young, C., Williams, M., Rexer, B.N., Sarbassov, D.D., Muller, W.J., Brantley-Sieders, D., and Cook, R.S. (2016) Rictor/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res 76:4752-64. PMID: 27197158.
In addition to the contributions described above, with a team of collaborators, my experience in manipulation of the mouse mammary gland, including xenograft/allograft models, has directly promoted numerous studies elucidating the molecular mechanisms that regulate breast cancer growth/survival, metastatic progression, and host-tumor interactions. Moreover, these studies have benefitted the community at large (e.g. 2012 PLoS One community profiling study provided data for resource allocation requests by Susan G. Komen for the Cure Middle Tennessee Affiliate) and have forged collaborations that will be key in developing new research directions. I served as a collaborator on these studies, contributing to experimental design, interpretation of data, and manuscript preparation/application for funding (some projects).
Takahashi, K., Sumarriva, K., Kim, R., Jiang, R., Brantley-Sieders, D.M., Chen, J., Mernaugh, R.L., and Takahashi, T. (2016) Determination of the CD148-interacting region in thrombospondin-1. PLoS One 11: 5):e0154916. doi: 10.1371/journal.pone.0154916. eCollection 2016. PMID: 27149518. PMCID: PMC4858292.
Young, C.D., Zimmerman, L.J., Hoshino, D., Formisano, L., Hanker, A.B., Gatza, M.L., Morrison, M.M., Moore, P.D., Whitwell, C.A., Dave, B., Stricker, T., Bhola, N.E., Silva, G.O., Patel, P., Brantley-Sieders, D.M., Levin, M., Horiates, M., Palma, N.A., Wang, K., Stephens, P.J., Perou, C.M., Weaver, A.M., O’Shaughnessy, J.A., Chang, J.C., Park, B., Liebler, D.C., Cook, R.S., and Arteaga, C.L. (2015) Activating PIK3CA mutations induce an EGFR/ERK paracrine signaling axis in basal-like breast cancer. Mol Cell Proteomics 14: 1959-76. PMID: 25953087. PMCID: PMC4587316.
Stanford, J.C., Young, C., Hicks, D., Owens, P., Williams, A., Vaught, D.B., Morrison, M.M., Lim, J., Williams, M., Brantley-Sieders, D.M., Balko, J.M., Tonetti, D., Earp, H.S. 3rd, and Cook, R.S. (2014) Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest 124: 4737-52. PMID: 25250573. PMCID: PMCID: PMC4347249.
Brantley-Sieders DM, Fan KH, Deming-Halverson SL, Shyr Y, Cook RS. (2012) Local breast cancer spatial patterning: a tool for community health resource allocation to address local disparities in breast cancer mortality. PLoS One 7:e45238. PMID: 23028869. PMCID: PMC3460936.
Complete List of Published Work in MyBibliography:
*Gap in publications 2018-2019 due to personal breast cancer diagnosis and medical leave.
D. Research Support
Ongoing Research Support
NIH/NCI (Multi-PI Duvall, Brantley-Sieders, Cook) 07/01/2018-06/30/2023
NextGen RNAi delivery to breast tumors for selective mTORC2 blockade.
The goal of this study is to optimize advanced nanocarrier technologies for application to targeting the conventionally undruggable cancer driver mTORC2 in breast cancer, including the impact of systemic rictor-targeting RNAi delivery, alone or in combination with chemo and molecularly targeted therapies, on tumor growth/survival, progression, metastasis, and the tumor microenvironment.
Role: Multi-PI with Craig Duvall and Rebecca Cook – no overlap
Completed Research Support
5K01 CA117915 (Brantley Sieders) 07/14/06-06/30/11
The Role of EphA2 Receptor Signaling in Host-Tumor Interactions
The goal of this study is to determine if native, membrane tethered ephrin-A1 ligand activates endothelial expressed EphA2 RTK, linking specific domains of the receptor to initiation of endothelial cell migration and neovascularization.
3K01 CA117915-S1 (Brantley-Sieders) 07/01/09-06/30/11
The Role of EphA2 Receptor Signaling in Host-Tumor Interactions
NIH/NCI (Brantley-Sieders) 04/01/2011-03/31/2017
EphA2 receptor in endothelial cell-mediated tumor progression
The goal of this study is to determine how angiocrine factors secreted by tumor endothelilum enhance tumor cell growth and motility, as well as angiogenesis.
NIH/NCI (Chen and Brantley-Sieders) 07/14/2014-05/31/2019
Ephrin-A1 in lipogenesis and breast cancer metastatic progression
The goal of this study is to determine how ligand-independent signaling of EphA receptors in the absence of eprhin-A1 promotes HER2-dependent breast tumor progression, metastasis, and lipid metabolism.
Role: Co-PI with Jin Chen – no overlap