Honors & Awards
Advanced Proteome Informatics of Cancer Training Program (T32), Dept of Computational Medicine & Bioinformatics, University of Michigan (2016-2018)
Doctor of Philosophy, University of Michigan Ann Arbor (2020)
B.S., University of California, Santa Cruz, Applied Physics (2009)
M.S., San Jose State University, Biomedical Engineering (2012)
Ph.D., University of Michigan, Molecular & Cellular Pathology (2019)
Current Research and Scholarly Interests
My passion is translating bioinformatics integrative workflows and engineering platforms from multi-omics data to better discovery of new therapies. Experienced in statistical analyses and mathematical modeling early in my career and currently working on single-cell sequencing analyses (scRNA-seq), genomics (WES), and epigenomics (targeted chromatin ligation), data integration methods, and algorithm development.
Next-generation sequencing identifies recurrent copy number variations in invasive breast carcinomas from Ghana
NATURE PUBLISHING GROUP. 2020: 1537–45
African and African-American (AA) women have higher incidence of triple-negative breast cancers (TNBC) with high histological grade and aggressive clinical behavior, but the reasons are not fully understood. We recently found that the oncogenic protein EZH2 is overexpressed in Ghanaian breast cancer patients, with 16% of the tumors expressing cytoplasmic EZH2. Understanding the molecular underpinnings of these aggressive tumors may lead to the identification of potential targetable oncogenic drivers. We characterized the copy number variations of 11 Ghanaian breast tumor patients by targeted multiplexed PCR-based DNA next-generation sequencing (NGS) over 130 cancer-relevant genes. While the DNA quality was not optimal for mutation analysis, 90% of the tumors had frequent recurrent copy number alterations (CNAs) of 17 genes: SDHC, RECQL4, TFE3, BCL11A, BCL2L1, PDGFRA, DEK, SMUG1, AKT3, SMARCA4, VHL, KLF6, CCNE1, G6PD, FGF3, ABL1, and CCND1, with the top oncogenic functions being mitotic G1-G1/S-phase regulation, gene transcription, apoptosis, and PI3K/AKT pathway. The most common recurrent high-level CNAs were gains of RECQL4 and SDHC, in 50% and 60% of cases, respectively. Network analyses revealed a significant predicted interaction among 12 of the 17 (70.6%) genes with high-level CNAs (p = 5.7E-07), which was highly correlated with EZH2 expression (r = 0.4-0.75). By immunohistochemistry, RECQL4 and SDHC proteins were upregulated in 53 of 86 (61.6%) and 48 of 86 (56%) of Ghanaian invasive carcinoma tissue samples. In conclusion, our data show that invasive carcinomas from Ghana exhibit recurrent CNAs in 17 genes, with functions in oncogenic pathways, including PI3K/AKT and G1-G1/S regulation, which may have implications for the biology and treatment of invasive carcinomas in African and AA women.
View details for DOI 10.1038/s41379-020-0515-2
View details for Web of Science ID 000553605900009
View details for PubMedID 32152520
View details for PubMedCentralID PMC7390688
Cancer Cell Invasion of Mammary Organoids with Basal-In Phenotype
ADVANCED HEALTHCARE MATERIALS
This paper describes mammary organoids with a basal-in phenotype where the basement membrane is located on the interior surface of the organoid. A key materials consideration to induce this basal-in phenotype is the use of a minimal gel scaffold that the epithelial cells self-assemble around and encapsulate. When MDA-MB-231 breast cancer cells are co-cultured with epithelial cells from day 0 under these conditions, cells self-organize into patterns with distinct cancer cell populations both inside and at the periphery of the epithelial organoid. In another type of experiment, the robust formation of the basement membrane on the epithelial organoid interior enables convenient studies of MDA-MB-231 invasion in a tumor progression-relevant direction relative to epithelial cell-basement membrane positioning. That is, the study of cancer invasion through the epithelium first, followed by the basement membrane to the basal side, is realized in an experimentally convenient manner where the cancer cells are simply seeded on the outside of preformed organoids, and their invasion into the organoid is monitored. Interestingly, invasion is more prominent when tumor cells are added to day 7 organoids with less developed basement membranes compared to day 16 organoids with more defined ones.
View details for DOI 10.1002/adhm.202000810
View details for Web of Science ID 000542702600001
View details for PubMedID 32583612
Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors
2020; 11 (1): 1723
Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific increases related to epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways. MBC subtypes exhibit distinct upregulated profiles, including translation and ribosomal events in spindle, inflammation- and apical junction-related proteins in squamous, and extracellular matrix proteins in sarcomatoid subtypes. Comparison of the proteomes of human spindle MBC with mouse spindle (CCN6 knockout) MBC tumors reveals a shared spindle-specific signature of 17 upregulated proteins involved in translation and 19 downregulated proteins with roles in cell metabolism. These data identify potential subtype specific MBC biomarkers and therapeutic targets.
View details for DOI 10.1038/s41467-020-15283-z
View details for Web of Science ID 000526532500001
View details for PubMedID 32265444
View details for PubMedCentralID PMC7138853
A reproducible scaffold-free 3D organoid model to study neoplastic progression in breast cancer
JOURNAL OF CELL COMMUNICATION AND SIGNALING
2019; 13 (1): 129–43
While 3D cellular models are useful to study biological processes, gel-embedded organoids have large variability. This paper describes high-yield production of large (~1 mm diameter), scaffold-free, highly-spherical organoids in a one drop-one organoid format using MCF10A cells, a non-tumorigenic breast cell line. These organoids display a hollow lumen and secondary acini, and express mammary gland-specific and progenitor markers, resembling normal human breast acini. When subjected to treatment with TGF-β, the hypoxia-mimetic reagent CoCl2, or co-culture with mesenchymal stem/stromal cells (MSC), the organoids increase collagen I production and undergo large phenotypic and morphological changes of neoplastic progression, which were reproducible and quantifiable. Advantages of this scaffold-free, 3D breast organoid model include high consistency and reproducibility, ability to measure cellular collagen I production without noise from exogenous collagen, and capacity to subject the organoid to various stimuli from the microenvironment and exogenous treatments with precise timing without concern of matrix binding. Using this system, we generated organoids from primary metaplastic mammary carcinomas of MMTV-Cre;Ccn6fl/fl mice, which retained the high grade spindle cell morphology of the primary tumors. The platform is envisioned to be useful as a standardized 3D cellular model to study how microenvironmental factors influence breast tumorigenesis, and to potential therapeutics.
View details for DOI 10.1007/s12079-018-0498-7
View details for Web of Science ID 000464883300012
View details for PubMedID 30515709
View details for PubMedCentralID PMC6381373
Ccn6/Wisp3 Regulates the IGF2BP2/HMGA2 Signaling Axis in Metaplastic Carcinomas of the Breast
Breast cancer research and treatment
2018; 172 (3): 577-586
View details for DOI 10.1007/s10549-018-4960-2
Repair of dentin defects from DSPP knockout mice by PILP mineralization
JOURNAL OF MATERIALS RESEARCH
2016; 31 (3): 321–27
Dentinogenesis imperfecta type II (DGI-II) lacks intrafibrillar mineral with severe compromise of dentin mechanical properties. A Dspp knockout (Dspp-/-) mouse, with a phenotype similar to that of human DGI-II, was used to determine if poly-L-aspartic acid [poly(ASP)] in the "polymer-induced liquid-precursor" (PILP) system can restore its mechanical properties. Dentin from six-week old Dspp-/- and wild-type mice was treated with CaP solution containing poly(ASP) for up to 14 days. Elastic modulus and hardness before and after treatment were correlated with mineralization from Micro x-ray computed tomography (Micro-XCT). Transmission electron microscopy (TEM)/Selected area electron diffraction (SAED) were used to compare matrix mineralization and crystallography. Mechanical properties of the Dspp-/- dentin were significantly less than wild-type dentin and recovered significantly (P < 0.05) after PILP-treatment, reaching values comparable to wild-type dentin. Micro-XCT showed mineral recovery similar to wild-type dentin after PILP-treatment. TEM/SAED showed repair of patchy mineralization and complete mineralization of defective dentin. This approach may lead to new strategies for hard tissue repair.
View details for DOI 10.1557/jmr.2015.406
View details for Web of Science ID 000371705900002
View details for PubMedID 27239097
View details for PubMedCentralID PMC4884014
Strain-guided mineralization in the bone-PDL-cementum complex of a rat periodontium.
2015; 3: 20–31
OBJECTIVE: The objective of this study was to investigate the effect of mechanical strain by mapping physicochemical properties at periodontal ligament (PDL)-bone and PDL-cementum attachment sites and within the tissues per se.DESIGN: Accentuated mechanical strain was induced by applying a unidirectional force of 0.06N for 14 days on molars in a rat model. The associated changes in functional space between tooth and bone, mineral formation and resorbing events at the PDL-bone and PDL-cementum attachment sites were identified by using micro-X-ray computed tomography (micro-XCT), atomic force microscopy (AFM), dynamic histomorphometry, Raman microspectroscopy, AFM-based nanoindentation technique, and were correlated with histochemical stains specific to low and high molecular weight GAGs, including biglycan, and osteoclast distribution through tartrate-resistant acid phosphatase (TRAP) staining.RESULTS: Unique chemical and mechanical qualities including heterogenous bony fingers with hygroscopic Sharpey's fibers contributing to a higher organic (amide III - 1240 cm-1) to inorganic (phosphate - 960 cm-1) ratio, with lower average elastic modulus of 8 GPa versus 12 GPa in unadapted regions were identified. Furthermore, an increased presence of elemental Zn in cement lines and mineralizing fronts of PDL-bone was observed. Adapted regions containing bony fingers exhibited woven bone-like architecture and these regions rich in biglycan (BGN) and bone sialoprotein (BSP) also contained high-molecular weight polysaccharides predominantly at the site of polarized bone growth.CONCLUSIONS: From a fundamental science perspective the shift in local properties due to strain amplification at the soft-hard tissue attachment sites is governed by semiautonomous cellular events at the PDL-bone and PDL-cementum sites. Over time, these strain-mediated events can alter the physicochemical properties of tissues per se, and consequently the overall biomechanics of the bone-PDL-tooth complex. From a clinical perspective, the shifts in magnitude and duration of forces on the periodontal ligament can prompt a shift in physiologic mineral apposition in cementum and alveolar bone albeit of an adapted quality owing to the rapid mechanical translation of the tooth.
View details for PubMedID 26636129
Mineral Density Volume Gradients in Normal and Diseased Human Tissues
2015; 10 (4): e0121611
Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095 mg/cc, bone: 570-1415 mg/cc, cementum: 1240-1340 mg/cc, dentin: 1480-1590 mg/cc, cementum affected by periodontitis: 1100-1220 mg/cc, hypomineralized carious dentin: 345-1450 mg/cc, hypermineralized carious dentin: 1815-2740 mg/cc, and dental calculus: 1290-1770 mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.
View details for DOI 10.1371/journal.pone.0121611
View details for Web of Science ID 000352588500024
View details for PubMedID 25856386
View details for PubMedCentralID PMC4391782
Simulation and verification of macroscopic isotropy of hollow alginate-based microfibers
ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY
2015; 43 (6): 390–97
A simulation of tensile strength of various alginate-based hollow microfibers using FEA analysis has been conducted with the hypothesis of macroscopic isotropy and linear elastic-plastic behavior. Results of student t-tests indicated that there was no significant difference between the experimental and simulated tensile strengths (p = 0.37, α = 0.05), while there was a significant reduction in elasticity as a result of chitosan coating (p = 0.024, α = 0.05). The hypothesis of macroscopic isotropy was verified by highly correlated (R(2) ≥ 0.92) theoretical and experimental elongation at break measurements, findings that could be extended to the failure analysis of alginate microfibers used in regenerative medicine.
View details for DOI 10.3109/21691401.2014.897629
View details for Web of Science ID 000361301800005
View details for PubMedID 24684489
Fickian-Based Empirical Approach for Diffusivity Determination in Hollow Alginate-Based Microfibers Using 2D Fluorescence Microscopy and Comparison with Theoretical Predictions
2014; 7 (12): 7670–88
Hollow alginate microfibers (od = 1.3 mm, id = 0.9 mm, th = 400 µm, L = 3.5 cm) comprised of 2% (w/v) medium molecular weight alginate cross-linked with 0.9 M CaCl₂ were fabricated to model outward diffusion capture by 2D fluorescent microscopy. A two-fold comparison of diffusivity determination based on real-time diffusion of Fluorescein isothiocyanate molecular weight (FITC MW) markers was conducted using a proposed Fickian-based approach in conjunction with a previously established numerical model developed based on spectrophotometric data. Computed empirical/numerical (Dempiricial/Dnumerical) diffusivities characterized by small standard deviations for the 4-, 70- and 500-kDa markers expressed in m²/s are (1.06 × 10-9 ± 1.96 × 10-10)/(2.03 × 10-11), (5.89 × 10-11 ± 2.83 × 10-12)/(4.6 × 10-12) and (4.89 × 10-12 ± 3.94 × 10-13)/(1.27 × 10-12), respectively, with the discrimination between the computation techniques narrowing down as a function of MW. The use of the numerical approach is recommended for fluorescence-based measurements as the standard computational method for effective diffusivity determination until capture rates (minimum 12 fps for the 4-kDa marker) and the use of linear instead of polynomial interpolating functions to model temporal intensity gradients have been proven to minimize the extent of systematic errors associated with the proposed empirical method.
View details for DOI 10.3390/ma7127670
View details for Web of Science ID 000346796800005
View details for PubMedID 28788268
View details for PubMedCentralID PMC5456451
The narwhal (Monodon monoceros) cementum-dentin junction: A functionally graded biointerphase
PROCEEDINGS OF THE INSTITUTION OF MECHANICAL ENGINEERS PART H-JOURNAL OF ENGINEERING IN MEDICINE
2014; 228 (8): 754–67
In nature, an interface between dissimilar tissues is often bridged by a graded zone, and provides functional properties at a whole organ level. A perfect example is a "biological interphase" between stratified cementum and dentin of a narwhal tooth. This study highlights the graded structural, mechanical, and chemical natural characteristics of a biological interphase known as the cementum-dentin junction layer and their effect in resisting mechanical loads. From a structural perspective, light and electron microscopy techniques illustrated the layer as a wide 1000-2000 μm graded zone consisting of higher density continuous collagen fiber bundles from the surface of cementum to dentin, that parallels hygroscopic 50-100 μm wide collagenous region in human teeth. The role of collagen fibers was evident under compression testing during which the layer deformed more compared to cementum and dentin. This behavior is reflected through site-specific nanoindentation indicating a lower elastic modulus of 2.2 ± 0.5 GPa for collagen fiber bundle compared to 3 ± 0.4 GPa for mineralized regions in the layer. Similarly, microindentation technique illustrated lower hardness values of 0.36 ± 0.05 GPa, 0.33 ± 0.03 GPa, and 0.3 ± 0.07 GPa for cementum, dentin, and cementum-dentin layer, respectively. Biochemical analyses including Raman spectroscopy and synchrotron-source microprobe X-ray fluorescence demonstrated a graded composition across the interface, including a decrease in mineral-to-matrix and phosphate-to-carbonate ratios, as well as the presence of tidemark-like bands with Zn. Understanding the structure-function relationships of wider tissue interfaces can provide insights into natural tissue and organ function.
View details for DOI 10.1177/0954411914547553
View details for Web of Science ID 000342058800002
View details for PubMedID 25205746
Biomechanics of a bone-periodontal ligament-tooth fibrous joint
JOURNAL OF BIOMECHANICS
2013; 46 (3): 443–49
This study investigates bone-tooth association under compression to identify strain amplified sites within the bone-periodontal ligament (PDL)-tooth fibrous joint. Our results indicate that the biomechanical response of the joint is due to a combinatorial response of the constitutive properties of organic, inorganic, and fluid components. Second maxillary molars within intact maxillae (N=8) of 5-month-old rats were loaded with a μ-XCT-compatible in situ loading device at various permutations of displacement rates (0.2, 0.5, 1.0, 1.5, 2.0 mm/min) and peak reactionary load responses (5, 10, 15, 20 N). Results indicated a nonlinear biomechanical response of the joint, in which the observed reactionary load rates were directly proportional to displacement rates (velocities). No significant differences in peak reactionary load rates at a displacement rate of 0.2mm/min were observed. However, for displacement rates greater than 0.2mm/min, an increasing trend in reactionary rate was observed for every peak reactionary load with significant increases at 2.0mm/min. Regardless of displacement rates, two distinct behaviors were identified with stiffness (S) and reactionary load rate (LR) values at a peak load of 5 N (S(5 N)=290-523 N/mm) being significantly lower than those at 10 N (LR(5 N)=1-10 N/s) and higher (S(10 N-20 N)=380-684 N/mm; LR(10 N-20 N)=1-19 N/s). Digital image correlation revealed the possibility of a screw-like motion of the tooth into the PDL-space, i.e., predominant vertical displacement of 35 μm at 5 N, followed by a slight increase to 40 μm at 10 N and 50 μm at 20 N of the tooth and potential tooth rotation at loads above 10 N. Narrowed and widened PDL spaces as a result of tooth displacement indicated areas of increased apparent strains within the complex. We propose that such highly strained regions are "hot spots" that can potentiate local tissue adaptation under physiological loading and adverse tissue adaptation under pathological loading conditions.
View details for DOI 10.1016/j.jbiomech.2012.11.010
View details for Web of Science ID 000315317100002
View details for PubMedID 23219279
View details for PubMedCentralID PMC3690590
Age-Related Adaptation of Bone-PDL-Tooth Complex: Rattus-Norvegicus as a Model System
2012; 7 (4): e35980
Functional loads on an organ induce tissue adaptations by converting mechanical energy into chemical energy at a cell-level. The transducing capacity of cells alters physico-chemical properties of tissues, developing a positive feedback commonly recognized as the form-function relationship. In this study, organ and tissue adaptations were mapped in the bone-tooth complex by identifying and correlating biomolecular expressions to physico-chemical properties in rats from 1.5 to 15 months. However, future research using hard and soft chow over relevant age groups would decouple the function related effects from aging affects. Progressive curvature in the distal root with increased root resorption was observed using micro X-ray computed tomography. Resorption was correlated to the increased activity of multinucleated osteoclasts on the distal side of the molars until 6 months using tartrate resistant acid phosphatase (TRAP). Interestingly, mononucleated TRAP positive cells within PDL vasculature were observed in older rats. Higher levels of glycosaminoglycans were identified at PDL-bone and PDL-cementum entheses using alcian blue stain. Decreasing biochemical gradients from coronal to apical zones, specifically biomolecules that can induce osteogenic (biglycan) and fibrogenic (fibromodulin, decorin) phenotypes, and PDL-specific negative regulator of mineralization (asporin) were observed using immunohistochemistry. Heterogeneous distribution of Ca and P in alveolar bone, and relatively lower contents at the entheses, were observed using energy dispersive X-ray analysis. No correlation between age and microhardness of alveolar bone (0.7 ± 0.1 to 0.9 ± 0.2 GPa) and cementum (0.6 ± 0.1 to 0.8 ± 0.3 GPa) was observed using a microindenter. However, hardness of cementum and alveolar bone at any given age were significantly different (P<0.05). These observations should be taken into account as baseline parameters, during development (1.5 to 4 months), growth (4 to 10 months), followed by a senescent phase (10 to 15 months), from which deviations due to experimentally induced perturbations can be effectively investigated.
View details for DOI 10.1371/journal.pone.0035980
View details for Web of Science ID 000305340200033
View details for PubMedID 22558292
View details for PubMedCentralID PMC3340399