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Academic Background

Associate Professor of Biological Chemistry, Harvard Medical School, Boston

Senior Research Associate, Department of Orthopaedic Surgery, Children's Hospital Medical Center, Boston

Post-doctoral training: National Institutes of Health; Harvard Medical School, Children's Hospital.

Ph.D., Boston University School of Medicine

Molecular Mechanisms Regulating Skeletal Development and Metastasis of Cancer Cells to Bone

Bone tissue functions as a mechanically responsive structural component of the body and as a major organ essential for maintaining calcium and phosphate homeostasis. The skeleton is the target of numerous human genetic disorders and recently mouse models have identified new regulatory pathways that affect the skeleton. As a normal process of aging and hormonal changes after the menopause, skeletal mass can decrease by as much as 30% leading to bone fracture and compromised quality of life in the elderly population. Historically the laboratory has addressed molecular mechanisms regulating formation and mineralization of bone by osteoblasts and turnover of bone tissue by osteoclasts, the bone resorbing cells. We are defining the key regulatory events for the progressive differentiation of osteoprogenitor stem cells to osteogenic cells by identifying transcription factor complexes that control expression of tissue-specific genes. Our studies are showing that early events of skeletal development are recapitulated in the adult skeleton for the normal maintenance of bone mass.

The skeleton is also a target of metastatic cancers and recent studies from our laboratory and others are demonstrating that signaling pathways which mediate responsiveness of the bone forming and bone resorbing cells of the skeleton for organogenesis are also pathways that are activated in cancer cells which metastasize to bone.

Areas of current investigation for graduate and MD/PhD students and postdoctoral fellows include:

1.   Combinatorial Control Mechanisms for Skeletal Development

This laboratory is defining a regulatory network of developmental factors with a focus on three major pathways critical for skeletal pattern formation, early embryonic bone development, and osteoblast differentiation:  the bone morphogenetic protein (BMP) family, the Wnt signaling pathway and Hox homeodomain factors.  The integration of these signaling pathways for tissue-specific gene expression is being characterized for two genes, the transcription factor Runx2/Cbfa1 established as essential for skeletal development and a bone-specific Runx2 target gene, osteocalcin, that represents one of the major non-collagenous bone matrix proteins (Choi et al., 2001; Lengner et al., 2002).  The Runx2/Cbfa transcription factor is essential for osteogenic differentiation and functions as a master regulatory gene through multiple properties (Fig. 1). Runx2 can change the phenotype of a cell, e.g., from a non-osseous adipocyte to an osteoblast, as well as control recruitment of stem cells into the chondrogenic and osteogenic phenotype (Lengner et al., 2005).  Characterizing the functional activities of this protein has provided new paradigms for understanding gene regulation.  First, Runx2 expression is regulated in stem cells by early development cues including Hox genes, BMP/TGFb, and Wnt proteins (Balint et al., 2003, Zaidi et al., 2002; Gaur et al., 2005, 2006; Bodine et al., 2004).  Secondly, this transcription factor is a scaffolding protein that is targeted to specific subnuclear domains for the assembly of multimeric complexes on target genes (reviewed in Lian et al., 2004).  Third, Runx2 recruits chromatin remodeling proteins and assembles complexes at Runx2 regulatory elements in genes to either activate or repress gene transcription (Javed et al., 1999; Young et al., 2005).  By mutational analyses of different protein interacting domains of Runx2, we are identifying the coregulatory proteins essential for osteoblast differentiation in vitro and for skeletal development in vivo (Zaidi et al., 2004; Afzal et al., 2005). Experimental approaches include cell culture models for chondrocyte and osteoblast differentiation using human embryonic and mesenchymal stem cells, gene regulation studies and characterization of mouse phenotypes. 

2.  Tissue Specific Gene Regulatory Mechanisms

The osteocalcin gene encodes a calcium binding ECM protein that is developmentally regulated during bone formation by a plethora of hormones, growth factors, and cell signaling proteins involved in calcium homeostasis and bone remodeling. The integration of independent signals must converge on the promoter to account for complex physiologic control of the gene during bone formation and turnover. Thus, the promoter of the osteocalcin gene provides a molecular blueprint for understanding developmental and hormonal regulation of gene expression required for bone formation (Hassan et al., 2004; Javed et al., 1999; Gutierrez et al., 2004). Identification of tissue-specific regulatory sequences and their cognate binding factors have allowed us to develop strategies for cell based therapy to target therapeutic genes specifically to bone. Examples of osteocalcin tissue-specific regulatory elements undergoing characterization include the steroid response elements, runt homology (Runx/Cbfa), homeodomain (HD), Hox, C/EBP, ATF and AP-1 protein binding sites.  The HD proteins (Msx, Dlx) and Hoxa10 regulate osteocalcin at different stages of cell differentiation (Fig. 2). Transcriptional control of the gene is evaluated at multiple levels including chromatin modifications and recruitment of transcription factors and their coregulatory proteins by chromatin immunoprecipitation studies.  Enforced expression and siRNA knockdown studies of regulatory factors strategies are used to establish their function in vitro and in vivo using transgenic mouse models. Such analyses have revealed new insights into understanding the complex interplay of physiologic mediators of tissue differentiation. This program of research provides a student with fundamental techniques requisite for characterizing gene regulation and expression in a biological context.

3.  Cancer Cell Biology in the Bone Microenvironment

The end stage of breast and prostate cancer is metastasis to bone, with very poor prognosis with nearly 70% mortality within a year.  Cancer cells cause destruction of the bone, resulting in fractures and severe pain.  Understanding the mechanisms which induce metastasis of the primary cancer cell to the bone environment needs to be addressed.  We have identified high expression levels of the Runx2 transcription factor in metastatic breast and prostate cancer cell lines.  Runx target genes in the cancer cell include the entire class of matrix metalloproteinases characterized for their role in tissue invasion, the vascular endothelial growth factor, a potent angiogenic factor involved as a primary event in tumor growth and several cell growth and osteoblastic genes expressed in the bone environment that allow for tumor growth (Fig. 3) (Pratap et al., 2005).  The cancer cell responds to TGFb and BMP growth factors in the bone extracellular matrix and stimulates bone resorbing cells.  In recent studies, we have shown metastatic cancer cell lines in which Runx2 activity has been blocked through genetic mutations, that the osteolytic disease of breast cancer cells can be prevented in the mouse (Barnes et al., 2004; Javed et al., 2005). The presence of mutant Runx2 protein in metastatic cells inhibits cell invasion (in vitro assays) and genes associated with tumor growth (Fig. 3).  We are now turning our attention to mechanisms responsible for activation of Runx2 in the primary tumor that would lead to the metastatic event in vivo.  Experimental approaches include generation of human cancer cell lines with mutants of Runx2, assessing tumor growth by in vivo imaging of tumors in breast, prostate and bone tissues, and examining gene expression profiles of the tumors are assayed.

4.  Gene Therapy and Tissue Engineering for Skeletal Diseases

Genetic disorders of the skeleton require expression of the normal proteins, specifically in bone cells.   Here the osteocalcin gene promoter provides the appropriate method for targeting expressed genes to mature osteoblasts.  Using OC-EGFP mice, we are characterizing a population of mesenchymal stem cells from these mice that differentiate into bone cells expressing GFP in donor mice.  Numerous donor mice carrying mutated genes that mimic human genetic disorders are available for addressing the critical number of mesenchymal stem cells differentiated to osteoblasts that can provide a sufficient level of normal protein to correct the skeletal disorder.  A second example where tissue engineering is being developed relates to the problem of non-union fractures where scar tissue rather than new bone formation occurs.  By using autologous cells expressing osteogenic factors, bone formation can be induced.  Lastly, we are culturing human embryonic stem cells and promoting their differentiation to chondrogenic and osteogenic lineages and testing these in mouse models.  These powerful properties are being exploited for treatment of skeletal diseases that require rebuilding of skeletal tissue by promoting lineage allocation of stem cells or marrow progenitor cells. 

Figures

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One or more keywords matched the following items that are connected to Lian, Jane
Item TypeName
Academic Article Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites.
Academic Article Intranuclear organization of RUNX transcriptional regulatory machinery in biological control of skeletogenesis and cancer.
Academic Article Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts.
Academic Article Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo.
Academic Article Combinatorial organization of the transcriptional regulatory machinery in biological control and cancer.
Academic Article Networks and hubs for the transcriptional control of osteoblastogenesis.
Academic Article Organization of transcriptional regulatory machinery in nuclear microenvironments: implications for biological control and cancer.
Academic Article Nuclear microenvironments in biological control and cancer.
Academic Article Prostate carcinoma and radiation therapy: therapeutic treatment resistance and strategies for targeted therapeutic intervention.
Academic Article Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells.
Academic Article The subnuclear organization of histone gene regulatory proteins and 3' end processing factors of normal somatic and embryonic stem cells is compromised in selected human cancer cell types.
Academic Article Prostate cancer regulatory networks.
Academic Article Ectopic runx2 expression in mammary epithelial cells disrupts formation of normal acini structure: implications for breast cancer progression.
Academic Article Transcription factor-mediated epigenetic regulation of cell growth and phenotype for biological control and cancer.
Academic Article The cancer-related Runx2 protein enhances cell growth and responses to androgen and TGFbeta in prostate cancer cells.
Academic Article Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.
Academic Article Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer.
Academic Article Live cell imaging of the cancer-related transcription factor RUNX2 during mitotic progression.
Academic Article Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility.
Academic Article Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma.
Academic Article Molecular targets for radiation oncology in prostate cancer.
Academic Article miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells.
Academic Article Transcriptional induction of the osteocalcin gene during osteoblast differentiation involves acetylation of histones h3 and h4.
Academic Article Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.
Academic Article Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease.
Academic Article The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion.
Academic Article Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling.
Academic Article Targeted deletion of Wwox reveals a tumor suppressor function.
Academic Article Genetic and epigenetic regulation in nuclear microenvironments for biological control in cancer.
Academic Article Organization, integration, and assembly of genetic and epigenetic regulatory machinery in nuclear microenvironments: implications for biological control in cancer.
Academic Article Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network.
Academic Article Metastatic bone disease: role of transcription factors and future targets.
Academic Article Mitotic bookmarking of genes: a novel dimension to epigenetic control.
Academic Article A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes.
Academic Article The histone deacetylase inhibitor, vorinostat, reduces tumor growth at the metastatic bone site and associated osteolysis, but promotes normal bone loss.
Academic Article An architectural genetic and epigenetic perspective.
Academic Article Genomic promoter occupancy of runt-related transcription factor RUNX2 in Osteosarcoma cells identifies genes involved in cell adhesion and motility.
Academic Article miRNA signatures associate with pathogenesis and progression of osteosarcoma.
Academic Article Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells.
Academic Article Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.
Academic Article Targeting deregulated epigenetic control in cancer.
Academic Article MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma.
Concept Lung Neoplasms
Concept Prostatic Neoplasms
Concept Mammary Neoplasms, Animal
Concept Bone Neoplasms
Concept Neoplasms, Glandular and Epithelial
Concept Bone Marrow Neoplasms
Concept Thyroid Neoplasms
Concept Mammary Neoplasms, Experimental
Concept Breast Neoplasms
Concept Neoplasms
Academic Article Standardizing analysis of circulating microRNA: clinical and biological relevance.
Academic Article Integrin ?v?6 promotes an osteolytic program in cancer cells by upregulating MMP2.
Academic Article Bookmarking target genes in mitosis: a shared epigenetic trait of phenotypic transcription factors and oncogenes?
Academic Article MicroRNAs in the control of metastatic bone disease.
Academic Article hsa-mir-30c promotes the invasive phenotype of metastatic breast cancer cells by targeting NOV/CCN3.
Academic Article Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease.
Academic Article Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response.
Academic Article Runx2-Smad signaling impacts the progression of tumor-induced bone disease.
Academic Article Epigenetic pathways regulating bone homeostasis: potential targeting for intervention of skeletal disorders.
Academic Article Targeting of Runx2 by miR-135 and miR-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease.
Academic Article Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion.
Academic Article Expression of the IL-11 Gene in Metastatic Cells Is Supported by Runx2-Smad and Runx2-cJun Complexes Induced by TGF?1.
Academic Article The SWI/SNF ATPases Are Required for Triple Negative Breast Cancer Cell Proliferation.
Academic Article Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells.
Academic Article Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes.
Academic Article Oncogenic epigenetic control.
Academic Article Oncofetal Epigenetic Bivalency in Breast Cancer Cells: H3K4 and H3K27 Tri-Methylation as a Biomarker for Phenotypic Plasticity.
Academic Article Thyroid Hormone Receptor-? (TR?) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer.
Academic Article MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells.
Academic Article Dissection of Individual Prostate Lobes in Mouse Models of Prostate Cancer to Obtain High Quality RNA.
Academic Article Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells.
Academic Article RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.
Academic Article WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.
Academic Article The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation.
Academic Article Identifying Nuclear Matrix-Attached DNA Across the Genome.
Academic Article A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice.
Academic Article A perspective on malignancy in the marrow.
Academic Article Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition.
Academic Article Selective expression of long non-coding RNAs in a breast cancer cell progression model.
Academic Article Intranuclear and higher-order chromatin organization of the major histone gene cluster in breast cancer.
Academic Article The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer.
Academic Article Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer.
Academic Article Suppression of Breast Cancer Stem Cells and Tumor Growth by the RUNX1 Transcription Factor.
Academic Article Nuclear organization mediates cancer-compromised genetic and epigenetic control.
Academic Article Mitotic Gene Bookmarking: An Epigenetic Program to Maintain Normal and Cancer Phenotypes.
Academic Article Loss of RUNX1 is associated with aggressive lung adenocarcinomas.
Academic Article Thyroid Hormone Receptor ? Suppression of RUNX2 Is Mediated by Brahma-Related Gene 1-Dependent Chromatin Remodeling.
Academic Article Development of a predictive miRNA signature for breast cancer risk among high-risk women.
Academic Article Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer.
Academic Article Nanoparticle-based targeted cancer strategies for non-invasive prostate cancer intervention.
Academic Article Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity.
Academic Article tsRNA signatures in cancer.
Academic Article RUNX1-dependent mechanisms in biological control and dysregulation in cancer.
Academic Article Towards a more precise and individualized assessment of breast cancer risk.
Academic Article The Thyroid Hormone Receptor-RUNX2 Axis: A Novel Tumor Suppressive Pathway in Breast Cancer.
Academic Article Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer.
Academic Article RUNX1 and RUNX2 transcription factors function in opposing roles to regulate breast cancer stem cells.
Concept Triple Negative Breast Neoplasms
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