Benjamin Alman

Positions:

James R. Urbaniak, M.D., Distinguished 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:

Yolk-sac-derived macrophages progressively expand in the mouse kidney with age.

Renal macrophages represent a highly heterogeneous and specialized population of myeloid cells with mixed developmental origins from the yolk-sac and hematopoietic stem cells (HSC). They promote both injury and repair by regulating inflammation, angiogenesis, and tissue remodeling. Recent reports highlight differential roles for ontogenically distinct renal macrophage populations in disease. However, little is known about how these populations change over time in normal, uninjured kidneys. Prior reports demonstrated a high proportion of HSC-derived macrophages in the young adult kidney. Unexpectedly, using genetic fate-mapping and parabiosis studies, we found that yolk-sac-derived macrophages progressively expand in number with age and become a major contributor to the renal macrophage population in older mice. This chronological shift in macrophage composition involves local cellular proliferation and recruitment from circulating progenitors and may contribute to the distinct immune responses, limited reparative capacity, and increased disease susceptibility of kidneys in the elderly population.
Authors
Ide, S; Yahara, Y; Kobayashi, Y; Strausser, SA; Ide, K; Watwe, A; Xu-Vanpala, S; Privratsky, JR; Crowley, SD; Shinohara, ML; Alman, BA; Souma, T
MLA Citation
Ide, Shintaro, et al. “Yolk-sac-derived macrophages progressively expand in the mouse kidney with age.Elife, vol. 9, Apr. 2020. Pubmed, doi:10.7554/eLife.51756.
URI
https://scholars.duke.edu/individual/pub1438043
PMID
32301704
Source
pubmed
Published In
Elife
Volume
9
Published Date
DOI
10.7554/eLife.51756

Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair.

Osteoclasts are multinucleated cells of the monocyte/macrophage lineage that degrade bone. Here, we used lineage tracing studies-labelling cells expressing Cx3cr1, Csf1r or Flt3-to identify the precursors of osteoclasts in mice. We identified an erythromyeloid progenitor (EMP)-derived osteoclast precursor population. Yolk-sac macrophages of EMP origin produced neonatal osteoclasts that can create a space for postnatal bone marrow haematopoiesis. Furthermore, EMPs gave rise to long-lasting osteoclast precursors that contributed to postnatal bone remodelling in both physiological and pathological settings. Our single-cell RNA-sequencing data showed that EMP-derived osteoclast precursors arose independently of the haematopoietic stem cell (HSC) lineage and the data from fate tracking of EMP and HSC lineages indicated the possibility of cell-cell fusion between these two lineages. Cx3cr1+ yolk-sac macrophage descendants resided in the adult spleen, and parabiosis experiments showed that these cells migrated through the bloodstream to the remodelled bone after injury.
Authors
Yahara, Y; Barrientos, T; Tang, YJ; Puviindran, V; Nadesan, P; Zhang, H; Gibson, JR; Gregory, SG; Diao, Y; Xiang, Y; Qadri, YJ; Souma, T; Shinohara, ML; Alman, BA
MLA Citation
Yahara, Yasuhito, et al. “Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair.Nat Cell Biol, vol. 22, no. 1, Jan. 2020, pp. 49–59. Pubmed, doi:10.1038/s41556-019-0437-8.
URI
https://scholars.duke.edu/individual/pub1426871
PMID
31907410
Source
pubmed
Published In
Nat Cell Biol
Volume
22
Published Date
Start Page
49
End Page
59
DOI
10.1038/s41556-019-0437-8

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

Effects of chondroitin sulfate proteoglycan 4 (NG2/CSPG4) on soft-tissue sarcoma growth depend on tumor developmental stage.

Sarcomas, and the mesenchymal precursor cells from which they arise, express chondroitin sulfate proteoglycan 4 (NG2/CSPG4). However, NG2/CSPG4's function and its capacity to serve as a therapeutic target in this tumor type are unknown. Here, we used cells from human tumors and a genetically engineered autochthonous mouse model of soft-tissue sarcomas (STSs) to determine NG2/CSPG4's role in STS initiation and growth. Inhibiting NG2/CSPG4 expression in established murine and human STSs decreased tumor volume by almost two-thirds and cell proliferation rate by 50%. NG2/CSPG4 antibody immunotherapy in human sarcomas established as xenografts in mice similarly decreased tumor volume, and expression of a lentivirus blocking NG2/CSPG4 expression inhibited tumor cell proliferation and increased the latency of engraftment. Gene profiling showed that Ng2/Cspg4 deletion altered the expression of genes regulating cell proliferation and apoptosis. Surprisingly, Ng2/Cspg4 deletion at the time of tumor initiation resulted in larger tumors. Gene expression profiling indicated substantial down-regulation of insulin-like growth factor binding protein (Igfbp) genes when Ng2/Cspg4 is depleted at tumor initiation, but not when Ng2/Cspg4 is depleted after tumor initiation. Such differences may have clinical significance, as therapeutic targeting of a signaling pathway such as NG2/CSPG4 may have different effects on cell behavior with tumor progression. NG2/CSPG4 depletion has divergent effects, depending on the developmental stage of sarcoma. In established tumors, IGF signaling is active, and NG2 inhibition targets cell proliferation and apoptosis.
Authors
Hsu, S-HC; Nadesan, P; Puviindran, V; Stallcup, WB; Kirsch, DG; Alman, BA
MLA Citation
Hsu, Shu-Hsuan Claire, et al. “Effects of chondroitin sulfate proteoglycan 4 (NG2/CSPG4) on soft-tissue sarcoma growth depend on tumor developmental stage.J Biol Chem, vol. 293, no. 7, Feb. 2018, pp. 2466–75. Pubmed, doi:10.1074/jbc.M117.805051.
URI
https://scholars.duke.edu/individual/pub1288214
PMID
29196603
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
293
Published Date
Start Page
2466
End Page
2475
DOI
10.1074/jbc.M117.805051