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 Regeneration Next Initiative

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 hijacks a neural mechanism to invade the central nervous system.

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.
Authors
Yao, H; Price, TT; Cantelli, G; Ngo, B; Warner, MJ; Olivere, L; Ridge, SM; Jablonski, EM; Therrien, J; Tannheimer, S; McCall, CM; Chenn, A; Sipkins, DA
MLA Citation
Yao, Hisayuki, et al. “Leukaemia hijacks a neural mechanism to invade the central nervous system.Nature, vol. 560, no. 7716, Aug. 2018, pp. 55–60. Pubmed, doi:10.1038/s41586-018-0342-5.
URI
https://scholars.duke.edu/individual/pub1335790
PMID
30022166
Source
pubmed
Published In
Nature
Volume
560
Published Date
Start Page
55
End Page
60
DOI
10.1038/s41586-018-0342-5

Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche.

Specific tissue microenvironments, or niches, are critical for homing and maintenance of both stem cells and tumor cells in vivo. Little is known, however, about the molecular interactions between individual cells within these microenvironments. Recent studies that describe a newly identified hematopoietic stem and tumor cell vascular niche in the bone marrow (BM) suggest a critical role for vascular endothelial cell signaling and raise the possibility that bidirectional interactions of these cells with the vasculature regulate the niche dynamically. The mechanisms that govern hematopoietic stem cell (HSC)/tumor cell cross-talk with endothelial cells provide a promising new direction for future studies. Here we review recent advances that open new avenues of study in this field.
Authors
Colmone, A; Sipkins, DA
MLA Citation
Colmone, Angela, and Dorothy A. Sipkins. “Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche.Transl Res, vol. 151, no. 1, 2008, pp. 1–9. Pubmed, doi:10.1016/j.trsl.2007.09.003.
URI
https://scholars.duke.edu/individual/pub1025905
PMID
18061122
Source
pubmed
Published In
Translational Research : the Journal of Laboratory and Clinical Medicine
Volume
151
Published Date
Start Page
1
End Page
9
DOI
10.1016/j.trsl.2007.09.003

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.
Authors
Price, TT; Burness, ML; Sivan, A; Warner, MJ; Cheng, R; Lee, CH; Olivere, L; Comatas, K; Magnani, J; Kim Lyerly, H; Cheng, Q; McCall, CM; Sipkins, DA
MLA Citation
Price, Trevor T., et al. “Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.Sci Transl Med, vol. 8, no. 340, May 2016, p. 340ra73. Pubmed, doi:10.1126/scitranslmed.aad4059.
URI
https://scholars.duke.edu/individual/pub1132944
PMID
27225183
Source
pubmed
Published In
Sci Transl Med
Volume
8
Published Date
Start Page
340ra73
DOI
10.1126/scitranslmed.aad4059

Chemotherapy and the bone marrow stroma.

Authors
MLA Citation
Sipkins, Dorothy A. “Chemotherapy and the bone marrow stroma.Leuk Lymphoma, vol. 49, no. 1, Jan. 2008, pp. 17–18. Pubmed, doi:10.1080/10428190701784748.
URI
https://scholars.duke.edu/individual/pub1025906
PMID
18203006
Source
pubmed
Published In
Leuk Lymphoma
Volume
49
Published Date
Start Page
17
End Page
18
DOI
10.1080/10428190701784748

Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche

Authors
Price, TT; Lee, CH; Cheng, Q; Lyerly, HK; Fogler, WE; Magnani, JL; Sipkins, DA
MLA Citation
Price, Trevor T., et al. “Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche.” Tumor Biology, American Association for Cancer Research, 2015. Crossref, doi:10.1158/1538-7445.am2015-3212.
URI
https://scholars.duke.edu/individual/pub1127492
Source
crossref
Published In
Tumor Biology
Published Date
DOI
10.1158/1538-7445.am2015-3212