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

Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice.

The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice.
Authors
Vi, L; Baht, GS; Soderblom, EJ; Whetstone, H; Wei, Q; Furman, B; Puviindran, V; Nadesan, P; Foster, M; Poon, R; White, JP; Yahara, Y; Ng, A; Barrientos, T; Grynpas, M; Mosely, MA; Alman, BA
MLA Citation
Vi, Linda, et al. “Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice..” Nat Commun, vol. 9, no. 1, Dec. 2018. Pubmed, doi:10.1038/s41467-018-07666-0.
URI
https://scholars.duke.edu/individual/pub1361295
PMID
30518764
Source
pubmed
Published In
Nature Communications
Volume
9
Published Date
Start Page
5191
DOI
10.1038/s41467-018-07666-0

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis.

Both the WNT/β-catenin and hedgehog signaling pathways are important in the regulation of limb development, chondrocyte differentiation, and degeneration of articular cartilage in osteoarthritis (OA). It is not clear how these signaling pathways interact in interzone cell differentiation and synovial joint morphogenesis. Here, we determined that constitutive activation of hedgehog signaling specifically within interzone cells induces joint morphological changes by selectively inhibiting β-catenin-induced Fgf18 expression. Stabilization of β-catenin or treatment with FGF18 rescued hedgehog-induced phenotypes. Hedgehog signaling induced expression of a dominant negative isoform of TCF7L2 (dnTCF7L2) in interzone progeny, which may account for the selective regulation of β-catenin target genes observed. Knockdown of TCF7L2 isoforms in mouse chondrocytes rescued hedgehog signaling-induced Fgf18 downregulation, while overexpression of the human dnTCF7L2 orthologue (dnTCF4) in human chondrocytes promoted the expression of catabolic enzymes associated with OA. Similarly, expression of dnTCF4 in human chondrocytes positively correlated with the aggrecanase ADAMTS4. Consistent with our developmental findings, activation of β-catenin also attenuated hedgehog-induced or surgically induced articular cartilage degeneration in mouse models of OA. Thus, our results demonstrate that hedgehog inhibits selective β-catenin target gene expression to direct interzone progeny fates and articular cartilage development and disease. Moreover, agents that increase β-catenin activity have the potential to therapeutically attenuate articular cartilage degeneration as part of OA.
Authors
Rockel, JS; Yu, C; Whetstone, H; Craft, AM; Reilly, K; Ma, H; Tsushima, H; Puviindran, V; Al-Jazrawe, M; Keller, GM; Alman, BA
MLA Citation
Rockel, Jason S., et al. “Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis..” J Clin Invest, vol. 126, no. 5, May 2016, pp. 1649–63. Pubmed, doi:10.1172/JCI80205.
URI
https://scholars.duke.edu/individual/pub1146587
PMID
27018594
Source
pubmed
Published In
J Clin Invest
Volume
126
Published Date
Start Page
1649
End Page
1663
DOI
10.1172/JCI80205

Optimal therapy for desmoid tumors: current options and challenges for the future.

Desmoid tumors, or aggressive fibromatosis, are rare, locally infiltrative neoplasms caused by mutations that activate β-catenin. Although these tumors do not metastasize, they are difficult to manage due to variability in tumor presentation and behavior. A variety of treatment options exist, including surgery, radiotherapy, chemotherapy, hormone therapy, isolated limb perfusion, cryoablation and tyrosine kinase inhibitors. Treatment-induced morbidity and poor local control rates, combined with spontaneous stabilization of some desmoid tumors, have allowed watchful waiting to recently emerge as a front-line management option. This has emphasized the need to better understand tumor behavior in order to differentiate between tumors that may stabilize and those that may progress. Here, we review the most recent findings in desmoid tumor biology and treatment options for this enigmatic disease.
Authors
Al-Jazrawe, M; Au, M; Alman, B
MLA Citation
Al-Jazrawe, Mushriq, et al. “Optimal therapy for desmoid tumors: current options and challenges for the future..” Expert Rev Anticancer Ther, vol. 15, no. 12, 2015, pp. 1443–58. Pubmed, doi:10.1586/14737140.2015.1096203.
URI
https://scholars.duke.edu/individual/pub1110569
PMID
26472625
Source
pubmed
Published In
Expert Rev Anticancer Ther
Volume
15
Published Date
Start Page
1443
End Page
1458
DOI
10.1586/14737140.2015.1096203