Benjamin Alman

Positions:

James R. Urbaniak, M.D., Professor of Orthopedic Surgery

Orthopaedics
School of Medicine

Professor of Orthopaedic Surgery

Orthopaedics
School of Medicine

Chair of Orthopaedic Surgery

Orthopaedics
School of Medicine

Professor in Cell Biology

Cell Biology
School of Medicine

Professor in Pediatrics

Pediatrics
School of Medicine

Professor in the Department of Pathology

Pathology
School of Medicine

Core Faculty in Innovation & Entrepreneurship

Duke Innovation & Entrepreneurship
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Co-Director of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1986

Jefferson Medical College of Thomas Jefferson University

Grants:

Rejuvenating fracture repair: The role of the macrophage and Beta-catenin

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Stable Isotope Resolved Metabolomics to Interrogate the Interactions between Stroma and Desmoid Tumors

Administered By
Orthopaedics
Role
Principal Investigator
Start Date
End Date

IPA - Janet Prvu Bettger

Administered By
Orthopaedics
Role
Principal Investigator
Start Date
End Date

Collaboration for a Cure: Identifying new Therapeutic Targets for Desmoid Tumors

Administered By
Orthopaedics
Role
Principal Investigator
Start Date
End Date

Targeting Tumor Initiating Cell in Undifferentiated Pleomorphic Sarcoma

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis.

Cellular heterogeneity is frequently observed in cancer, but the biological significance of heterogeneous tumor clones is not well defined. Using multicolor reporters and CRISPR-Cas9 barcoding, we trace clonal dynamics in a mouse model of sarcoma. We show that primary tumor growth is associated with a reduction in clonal heterogeneity. Local recurrence of tumors following surgery or radiation therapy is driven by multiple clones. In contrast, advanced metastasis to the lungs is driven by clonal selection of a single metastatic clone (MC). Using RNA sequencing (RNA-seq) and in vivo assays, we identify candidate suppressors of metastasis, namely, Rasd1, Reck, and Aldh1a2. These genes are downregulated in MCs of the primary tumors prior to the formation of metastases. Overexpression of these suppressors of metastasis impair the ability of sarcoma cells to colonize the lungs. Overall, this study reveals clonal dynamics during each step of tumor progression, from initiation to growth, recurrence, and distant metastasis.
Authors
Tang, YJ; Huang, J; Tsushima, H; Ban, GI; Zhang, H; Oristian, KM; Puviindran, V; Williams, N; Ding, X; Ou, J; Jung, S-H; Lee, C-L; Jiao, Y; Chen, BJ; Kirsch, DG; Alman, BA
MLA Citation
Tang, Yuning J., et al. “Tracing Tumor Evolution in Sarcoma Reveals Clonal Origin of Advanced Metastasis..” Cell Rep, vol. 28, no. 11, Sept. 2019, pp. 2837-2850.e5. Pubmed, doi:10.1016/j.celrep.2019.08.029.
URI
https://scholars.duke.edu/individual/pub1368140
PMID
31509746
Source
pubmed
Published In
Cell Reports
Volume
28
Published Date
Start Page
2837
End Page
2850.e5
DOI
10.1016/j.celrep.2019.08.029

Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma.

Enchondroma and chondrosarcoma are the most common benign and malignant cartilaginous neoplasms. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are present in the majority of these tumors. We performed RNA-seq analysis on chondrocytes from Col2a1Cre;Idh1LSL/+ animals and found that genes implied in cholesterol synthesis pathway were significantly upregulated in the mutant chondrocytes. We examined the phenotypic effect of inhibiting intracellular cholesterol biosynthesis on enchondroma formation by conditionally deleting SCAP (sterol regulatory element-binding protein cleavage-activating protein), a protein activating intracellular cholesterol synthesis, in IDH1 mutant mice. We found fewer enchondromas in animals lacking SCAP. Furthermore, in chondrosarcomas, pharmacological inhibition of intracellular cholesterol synthesis significantly reduced chondrosarcoma cell viability in vitro and suppressed tumor growth in vivo. Taken together, these data suggest that intracellular cholesterol synthesis is a potential therapeutic target for enchondromas and chondrosarcomas.
Authors
Zhang, H; Wei, Q; Tsushima, H; Puviindran, V; Tang, YJ; Pathmanapan, S; Poon, R; Ramu, E; Al-Jazrawe, M; Wunder, J; Alman, BA
MLA Citation
Zhang, Hongyuan, et al. “Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma..” Jci Insight, vol. 5, Apr. 2019. Pubmed, doi:10.1172/jci.insight.127232.
URI
https://scholars.duke.edu/individual/pub1387942
PMID
31039139
Source
pubmed
Published In
Jci Insight
Volume
5
Published Date
DOI
10.1172/jci.insight.127232

Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management.

A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available.
Authors
Birnkrant, DJ; Bushby, K; Bann, CM; Alman, BA; Apkon, SD; Blackwell, A; Case, LE; Cripe, L; Hadjiyannakis, S; Olson, AK; Sheehan, DW; Bolen, J; Weber, DR; Ward, LM; DMD Care Considerations Working Group,
MLA Citation
Birnkrant, David J., et al. “Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management..” Lancet Neurol, vol. 17, no. 4, Apr. 2018, pp. 347–61. Pubmed, doi:10.1016/S1474-4422(18)30025-5.
URI
https://scholars.duke.edu/individual/pub1300157
PMID
29395990
Source
pubmed
Published In
Lancet Neurol
Volume
17
Published Date
Start Page
347
End Page
361
DOI
10.1016/S1474-4422(18)30025-5

Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.

The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease. Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (MET(Δ14)) lacking a cytoplasmic juxtamembrane domain. Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization. In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the MET(Δ14) mutations, had a stabilizing effect on the mature protein. Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone.
Authors
Gray, MJ; Kannu, P; Sharma, S; Neyt, C; Zhang, D; Paria, N; Daniel, PB; Whetstone, H; Sprenger, H-G; Hammerschmidt, P; Weng, A; Dupuis, L; Jobling, R; Mendoza-Londono, R; Dray, M; Su, P; Wilson, MJ; Kapur, RP; McCarthy, EF; Alman, BA; Howard, A; Somers, GR; Marshall, CR; Manners, S; Flanagan, AM; Rathjen, KE; Karol, LA; Crawford, H; Markie, DM; Rios, JJ; Wise, CA; Robertson, SP
MLA Citation
Gray, Mary J., et al. “Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia..” Am J Hum Genet, vol. 97, no. 6, Dec. 2015, pp. 837–47. Pubmed, doi:10.1016/j.ajhg.2015.11.001.
URI
https://scholars.duke.edu/individual/pub1112673
PMID
26637977
Source
pubmed
Published In
Am J Hum Genet
Volume
97
Published Date
Start Page
837
End Page
847
DOI
10.1016/j.ajhg.2015.11.001

Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease.

Skeletal metastasis is a serious complication of many primary cancers. A common feature of tumor cells that metastasize to the bone marrow microenvironment is that they initiate a cascade of events, recruiting and presumably/potentially altering the phenotype of bone marrow mesenchymal stromal cells (MSC) to produce an environment that allows for tumor growth and in some cases, drug-resistant dormancy of latent cancer cells. Consequently the MSC population can contribute to metastatic disease through several distinct mechanisms by differentiating into cancer-associated fibroblasts (CAFs). Understanding the expression and epigenetic changes that occur as normal MSCs become associated with metastatic tumors would reveal possible therapeutic targets for treating skeletal metastasis.
Authors
Gordon, JAR; Lisle, JW; Alman, BA; Lian, JB
MLA Citation
Gordon, Jonathan A. R., et al. “Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease..” J Cell Physiol, vol. 229, no. 12, Dec. 2014, pp. 1884–86. Pubmed, doi:10.1002/jcp.24692.
URI
https://scholars.duke.edu/individual/pub1032558
PMID
24905746
Source
pubmed
Published In
J Cell Physiol
Volume
229
Published Date
Start Page
1884
End Page
1886
DOI
10.1002/jcp.24692