Dorothy Sipkins

Positions:

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Associate Research Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1999

Stanford University, School of Medicine

Ph.D. 1999

Stanford University, School of Medicine

Internship and Residency, Internal Medicine

Massachusetts General Hospital

Hematology-Oncology Fellowship, Hematology Oncology

Dana-Farber Cancer Institute

Grants:

Targeting sphingosine kinase 2 for the treatment of multiple myeloma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Defining the Rules of Breast Cancer Cell Traffic Through Bone

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Targeting Dormant Breast Cancer Micrometastases to Prevent Disease Relapse

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Role of Osteopontin in Induction of Leukemia Dormancy in the Bone Marrow

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Studying the Effects of Combined E-Selectin/CXCR4 Inhibition on Breast Cancer Cell Metastasis, Growth and Immune Regulation

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
GlycoMimetics, Inc
Role
Principal Investigator
Start Date
End Date

Publications:

Leukaemia: a model metastatic disease.

In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells uniquely possess the innate ability for migration and invasion. Dedifferentiated, malignant leukocytes retain the benign leukocytes' capacity for cell motility and survival in the circulation, while acquiring the potential for rapid and uncontrolled cell division. For these reasons, leukaemias, although not traditionally considered as metastatic diseases, are in fact models of highly efficient metastatic spread. Accordingly, they are often aggressive and challenging diseases to treat. In this Perspective, we discuss the key molecular processes that facilitate metastasis in a variety of leukaemic subtypes, the clinical significance of leukaemic invasion into specific tissues and the current pipeline of treatments targeting leukaemia metastasis.
Authors
Whiteley, AE; Price, TT; Cantelli, G; Sipkins, DA
MLA Citation
Whiteley, Andrew E., et al. “Leukaemia: a model metastatic disease.Nat Rev Cancer, vol. 21, no. 7, July 2021, pp. 461–75. Pubmed, doi:10.1038/s41568-021-00355-z.
URI
https://scholars.duke.edu/individual/pub1482284
PMID
33953370
Source
pubmed
Published In
Nat Rev Cancer
Volume
21
Published Date
Start Page
461
End Page
475
DOI
10.1038/s41568-021-00355-z

The bone marrow microenvironment and its impact in acute and chronic B cell malignancies

The bone marrow (BM) hosts normal hematopoiesis by providing the cellular and molecular environment necessary for hematopoietic stem cell maintenance, expansion, and differentiation into the various hematopoietic lineages. This highly organized factory requires cross talk between hematopoietic and stromal elements in distinct microanatomical sites (niches), promoting the expansion of normal hematopoietic elements and the deletion of defective and potentially harmful cells [1]. The neoplastic cells from patients with lymphoid malignancies take advantage of the BM microenvironment by parasitizing niches that normally are restricted to hematopoietic progenitors [2]. Interactions with the marrow microenvironment contribute to malignant B cell growth and drug resistance, leading to a gradual replacement of normal hematopoiesis. In lymphoid malignancies, the BM also is a common site for residual disease and relapses after conventional therapies [3]. Therefore, there is growing interest in understanding the biology of the BM microenvironment. Over the last two decades, there has been substantial progress in identifying key cellular and molecular players in cross talk between malignant lymphocytes and the marrow microenvironment. In this chapter, we will highlight established pathways and current therapeutic approaches to target the microenvironment in acute and chronic B cell malignancies.
Authors
Burger, JA; Sipkins, DA
MLA Citation
Burger, J. A., and D. A. Sipkins. “The bone marrow microenvironment and its impact in acute and chronic B cell malignancies.” Bone Marrow Lymphoid Infiltrates: Diagnosis and Clinical Impact, 2013, pp. 35–45. Scopus, doi:10.1007/978-1-4471-4174-7_3.
URI
https://scholars.duke.edu/individual/pub1092722
Source
scopus
Published Date
Start Page
35
End Page
45
DOI
10.1007/978-1-4471-4174-7_3

Specialized Bone Marrow Endothelium Defines Microdomains for Tumor and Stem Cell Engraftment.

<jats:title>Abstract</jats:title> <jats:p>The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation and regeneration, yet relatively little is known about the architecture of microenvironments that support malignant proliferation. Using dynamic in vivo confocal and multi-photon imaging, we show that the bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant SDF-1 in discrete, discontinuous areas that localize the homing and early engraftment of both leukemic and normal primitive hematopoietic cells. Real-time imaging of cell-cell interactions in SCID mice bone marrow was performed after injection of fluorescently-labeled leukemic and other malignant cell lines. Progressive scanning and optical sectioning through the marrow revealed the existence of unique, spatially-restricted vascular domains to which the majority of marrow-homing tumor cells rolled and arrested. Serial imaging of mice on days 3 – 14 demonstrated that leukemic (Nalm-6 pre-B ALL) extravasation and early proliferation were restricted to these vascular beds. To define the molecular basis of these homing interactions, in vivo labeling of key vascular cell adhesion molecules and chemokines using fluorescent antibodies was performed. We observed that while ICAM-1, VCAM-1, PECAM-1 and P-selectin were expressed diffusely throughout the marrow vasculature, the expression of E-selectin and the chemokine receptor CXCR4 ligand SDF-1 was distinctly limited to vessels that supported leukemic cell engraftment. In vivo co-localization experiments confirmed Nalm-6 binding was restricted to vascular beds expressing both E-selectin and SDF-1. In functional studies, disruption of E-selection had a modest effect on leukemic homing (&lt;20% diminution), while pharmacologic blockade of CXCR4 decreased Nalm-6 binding to vessels by approximately 80%. To explore the normal function of this vascular niche, we next examined whether benign primitive hematopoietic cells might preferentially home to these same vascular microdomains. Fluorescently-labeled stem and progenitor cells (HSPC) isolated from donor balb/c mice were injected into recipient mice and imaging was performed at multiple time points. HSPC were found to adhere to the BM microvasculature in the same restricted domains. At 70 days post-injection, HSPC had extravasated, were persistent in these perivascular areas and had undergone cell division as assessed by dye dilution. Our findings show that these microdomains serve as vascular portals around which leukemic and hematopoietic stem cells engraft, suggesting that this molecularly distinct vasculature provides both a cancer and normal stem cell niche. Specialized vascular structures therefore appear to delineate a stem cell microenvironment that is exploited by malignancy.</jats:p>
Authors
Sipkins, DA; Wei, X; Wu, JW; Means, TK; Luster, AD; Lin, CP; Scadden, DT
MLA Citation
Sipkins, Dorothy A., et al. “Specialized Bone Marrow Endothelium Defines Microdomains for Tumor and Stem Cell Engraftment.Blood, vol. 104, no. 11, American Society of Hematology, 2004, pp. 663–663. Crossref, doi:10.1182/blood.v104.11.663.663.
URI
https://scholars.duke.edu/individual/pub1025903
Source
crossref
Published In
Blood
Volume
104
Published Date
Start Page
663
End Page
663
DOI
10.1182/blood.v104.11.663.663

Stem cell factor expression in B cell malignancies is influenced by the niche.

Our group has previously demonstrated that expression of the cytokine stem cell factor (SCF) by leukemic blasts is a frequent finding in pre-B acute lymphoblastic leukemia (ALL). Whether SCF expression is a feature of other B cell malignancies and whether cross-talk from the local microenvironment modulates malignant cell SCF production are, however, unknown. Here we show using immunohistochemistry that SCF is expressed by a wide variety of indolent and aggressive B cell malignancies involving the bone marrow (BM) or lymph nodes (LNs). In diseases such as follicular lymphoma (FL), however, where lymphoma cells uniquely associate with the BM endosteal niche, BM lymphoma does not express SCF, while LN involvement is SCF positive. In contrast, cases of FL with high-grade transformation in the BM are SCF positive. These data suggest that lymphoma cell interaction with the endosteal niche inhibits SCF production, and that FL cells become independent of this microenvironment effect following transformation.
Authors
Fox, MF; Pontier, A; Gurbuxani, S; Sipkins, DA
MLA Citation
Fox, Matthew F., et al. “Stem cell factor expression in B cell malignancies is influenced by the niche.Leuk Lymphoma, vol. 54, no. 10, Oct. 2013, pp. 2274–80. Pubmed, doi:10.3109/10428194.2013.777067.
URI
https://scholars.duke.edu/individual/pub1025908
PMID
23418895
Source
pubmed
Published In
Leuk Lymphoma
Volume
54
Published Date
Start Page
2274
End Page
2280
DOI
10.3109/10428194.2013.777067

ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging.

The expression of leukocyte adhesion molecules in the intact brains of mice with experimental autoimmune encephalitis (EAE) was visualized by Magnetic Resonance Imaging (MRI) through the use of a new, target-specific MR contrast agent. Antibody-conjugated paramagnetic liposomes (ACPLs) were designed to achieve in vivo targeting of molecules expressed on vascular endothelium, while providing sufficient signal enhancement at these sites for detection by MRI. ACPLs targeted to intercellular adhesion molecule-1 (ICAM-1), an endothelial leukocyte receptor upregulated on cerebral microvasculature during EAE, were administered to diseased mice. Fluorescence microscopy confirmed that fluorescently-tagged ACPLs were localized to central nervous system (CNS) microvasculature in a pattern consistent with ICAM-1 upregulation described immunohistochemically. High resolution MRI of mouse brains ex vivo demonstrated that ACPL binding conferred significant enhancement of signal intensity (SI) as compared to control images. These results suggest that ACPLs can be used as MRI contrast agents to visualize specific molecules expressed on vascular endothelium during disease.
Authors
Sipkins, DA; Gijbels, K; Tropper, FD; Bednarski, M; Li, KC; Steinman, L
MLA Citation
Sipkins, D. A., et al. “ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging.J Neuroimmunol, vol. 104, no. 1, Apr. 2000, pp. 1–9. Pubmed, doi:10.1016/s0165-5728(99)00248-9.
URI
https://scholars.duke.edu/individual/pub1025892
PMID
10683508
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
104
Published Date
Start Page
1
End Page
9
DOI
10.1016/s0165-5728(99)00248-9