Xiaowei Xu

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (94)484.16 Total impact

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    ABSTRACT: Over-expression of the HER2/neu receptor occurs in 20 to 30 percent of breast tumors and is linked to poorer prognosis. The HER2/neu expression status determines whether or not patient will receive trastuzumab-based treatment. In clinical practice, over-expression of HER2/neu is routinely identified using Immunohistochemistry (IHC) or Fluorescence in Situ Hybridization (FISH), both of which are invasive approaches requiring tissue samples. Serum assays for the Extra Cellular Domain of HER2/neu receptor (HER2 ECD) have been reported but the use is very limited due to serum interference factors (e.g. human anti-animal immunoglobulin antibodies) that lead to false test results and inconsistency with tissue Her2 status. We have developed an ELISA based approach using an MBB buffer to eliminate false results and to obtain more accurate assessment of HER2 ECD levels. Using this refined assay we retroactively measured HER2/neu levels from breast cancer patients and controls. Abnormal HER2 ECD levels were detected in about 32% of invasive breast cancer patients but not in controls or patients with benign diseases. In addition, we also showed that patients with elevated serum HER2 levels appeared to have worse survival regardless of treatments. In a small group of 12 Ductal Carcinoma in situ (DCIS) patients who received HER2/neu peptide vaccination and surgery, only one patient showed constantly rising HER2 levels after treatment and this patient had recurrence of HER2 positive tumor within 5 years. Our studies indicate that once the serum interference issue is resolved, serum HER2 ECD can have potential clinical utility to supplement the tissue based tests.
    Journal of molecular biomarkers & diagnosis. 11/2014; 4(3):151.
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    ABSTRACT: Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors.
    The American journal of surgical pathology 03/2014; · 4.06 Impact Factor
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    ABSTRACT: Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAFV600E melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.
    The Journal of clinical investigation 02/2014; · 15.39 Impact Factor
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    ABSTRACT: Epithelial stem cells (EpSCs) in the hair follicle bulge are required for hair follicle growth and cycling. The isolation and propagation of human EpSCs for tissue engineering purposes remains a challenge. Here we develop a strategy to differentiate human iPSCs (hiPSCs) into CD200(+)/ITGA6(+) EpSCs that can reconstitute the epithelial components of the hair follicle and interfollicular epidermis. The hiPSC-derived CD200(+)/ITGA6(+) cells show a similar gene expression signature as EpSCs directly isolated from human hair follicles. Human iPSC-derived CD200(+)/ITGA6(+) cells are capable of generating all hair follicle lineages including the hair shaft, and the inner and outer root sheaths in skin reconstitution assays. The regenerated hair follicles possess a KRT15(+) stem cell population and produce hair shafts expressing hair-specific keratins. These results suggest an approach for generating large numbers of human EpSCs for tissue engineering and new treatments for hair loss, wound healing and other degenerative skin disorders.
    Nature Communications 01/2014; 5:3071. · 10.74 Impact Factor
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    ABSTRACT: Melanoma has a propensity for lymph node metastasis. However, the incidence of lymphatic invasion detected by histology alone in primary melanoma is disproportionately low in comparison to the incidence of positive sentinel lymph nodes (SLN). With the discovery of lymphatic endothelial cell markers, such as podoplanin and LYVE-1, lymphatic vessels can be reliably detected in formalin-fixed paraffin-embedded (FFPE) tissues. There is a now consensus that lymphatic invasion detected by immunohistochemical stains in primary melanoma is much more common than previously reported by histological examination alone. Immunohistochemical stains show that lymphangiogenesis and lymphatic invasion in primary melanoma may occur intratumorally or peritumorally, and lymphatic invasion is common across the range of tumor thicknesses in primary vertical growth phase (VGP) melanomas. A number of studies have shown that lymphatic invasion in primary melanoma is associated with a positive sentinel lymph node biopsy and a worse clinical outcome. Although not currently a part of the standard of care for staging of melanoma, the detection of lymphatic invasion in primary melanoma using immunohistochemical markers may be helpful in planning of therapy in some cases and may find a routine role in primary melanoma microscopic attributes in future.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1102:275-286. · 1.29 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is an important developmental process hijacked by cancer cells for their dissemination. Here, we show that Exo70, a component of the exocyst complex, undergoes isoform switching mediated by ESRP1, a pre-mRNA splicing factor that regulates EMT. Expression of the epithelial isoform of Exo70 affects the levels of key EMT transcriptional regulators such as Snail and ZEB2 and is sufficient to drive the transition to epithelial phenotypes. Differential Exo70 isoform expression in human tumors correlates with cancer progression, and increased expression of the epithelial isoform of Exo70 inhibits tumor metastasis in mice. At the molecular level, the mesenchymal-but not the epithelial-isoform of Exo70 interacts with the Arp2/3 complex and stimulates actin polymerization for tumor invasion. Our findings provide a mechanism by which the exocyst function and actin dynamics are modulated for EMT and tumor invasion.
    Developmental Cell 12/2013; 27(5):560-573. · 12.86 Impact Factor
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    ABSTRACT: Melanoma microsatellitosis is classified as stage IIIB/C disease and is associated with a poor prognosis. Prognostic factors within this group, however, have not been well characterized. We performed a retrospective analysis of 1,621 patients undergoing sentinel lymph node (SLN) biopsy at our institution (1996-2011) to compare patients with (n = 98) and patients without (n = 1,523) microsatellites. Univariate and multivariate logistic and Cox regression analyses were used to identify factors associated with SLN positivity and melanoma-specific survival (MSS) in patients with microsatellites. Patients with microsatellites were older and had lesions with higher Clark level and greater thickness that more frequently had mitoses, ulceration, and lymphovascular invasion (LVI) (all p < 0.0001). In microsatellite patients, the SLN positivity rate was 43 %. Lesional ulceration (odds ratio [OR] = 2.9, 95 % confidence interval [CI] 1.5-8.6), absent tumor infiltrating lymphocytes (OR = 2.8, 95 % CI 1.1-7.1), and LVI (OR = 3.3, 95 % CI 1.7-10) were significantly associated with SLN positivity by multivariate analysis. With a median follow-up of 4.5 years in survivors, ulceration (hazards ratio [HR] = 3.4, 95 % CI 1.5-7.8) and >1 metastatic LN (HR = 2.7, 95 % CI 1.1-6.6) were significantly associated with decreased MSS by multivariate analysis. In patients without these prognostic factors, the 5-year MSS was 90 % (n = 49) compared with 50 % (n = 23) among patients with ulceration only, 51 % (n = 12) in those with >1 metastatic LN only, or 25 % in those with both (n = 14, p < 0.01). Microsatellitosis was frequently associated with multiple adverse pathologic features. In the absence of ulceration and >1 metastatic LN; however, the outcome for patients with microsatellites compared favorably to stage IIIB patients overall.
    Annals of Surgical Oncology 11/2013; · 4.12 Impact Factor
  • Society for Melanoma Research 2013 Congress Meeting, Philadelphia; 11/2013
  • Society for Melanoma Research 2013 Congress Meeting, Philadelphia; 11/2013
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    ABSTRACT: Tumor-associated macrophages (TAMs) play essential roles in tumor progression and metastasis. Tumor cells recruit myeloid progenitors and monocytes to the tumor site, where they differentiate into TAMs; however, this process is not well studied in humans. Here we show that human CD7, a T cell and NK cell receptor, is highly expressed by monocytes and macrophages. Expression of CD7 decreases in M-CSF differentiated macrophages and in Melanoma-conditioned Medium Induced Macrophages (MCMI/Mφ) in comparison to monocytes. A ligand for CD7, SECTM1 (Secreted and transmembrane protein 1), is highly expressed in many tumors, including melanoma cells. We show that SECTM1 binds to CD7 and significantly increases monocyte migration by activation of the PI3K pathway. In human melanoma tissues, tumor-infiltrating macrophages expressing CD7 are present. These melanomas, with CD7-positive inflammatory cell infiltrations, frequently highly express SECTM1, including an N-terminal, soluble form, which can be detected in the sera of metastatic melanoma patients but not in normal sera. Taken together, our data demonstrate that CD7 is present on monocytes and tumor macrophages, and that its ligand, SECTM1, is frequently expressed in corresponding melanoma tissues, possibly acting as a chemoattractant for monocytes to modulate the melanoma microenvironment.Journal of Investigative Dermatology accepted article preview online, 24 October 2013; doi:10.1038/jid.2013.437.
    Journal of Investigative Dermatology 10/2013; · 6.19 Impact Factor
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    ABSTRACT: The role for sentinel lymph node biopsy (SLNB) in patients with thin melanoma (≤1 mm) remains controversial. We examined a large cohort of patients with thin melanoma to better define predictors of SLN positivity. From 1995 to 2011, 781 patients with thin primary melanoma and evaluable clinicopathologic data underwent SLNB at our institution. Predictors of SLN positivity were determined using univariate and multivariate regression analyses, and patients were risk-stratified using a classification and regression tree (CART) analysis. In the study cohort (n = 781), 29 patients (3.7 %) had nodal metastases. In the univariate analysis, mitotic rate [odds ratio (OR) = 8.11, p = 0.005], Clark level (OR 4.04, p = 0.003), and thickness (OR 3.33, p = 0.011) were significantly associated with SLN positivity. In the multivariate analysis, MR (OR 7.01) and level IV-V (OR 3.45) remained significant predictors of SLN positivity. CART analysis initially stratified lesions by mitotic rate; nonmitogenic lesions (n = 273) had a 0.7 % SLN positivity rate versus 5.6 % in mitogenic lesions (n = 425). Mitogenic lesions were further stratified by Clark level; patients with level II-III had a 2.9 % SLN positivity rate (n = 205) versus 8.2 % with level IV-V (n = 220). With median follow-up of 6.3 years, five SLN-negative patients developed nodal recurrence and four SLN-positive patients died of disease. SLN positivity is low in patients with thin melanoma (3.7 %) and exceedingly so in nonmitogenic lesions (0.7 %). Appreciable rates of SLN positivity can be identified in patients with mitogenic lesions, particularly with concurrent level IV-V regardless of thickness. These factors may guide appropriate selection of patients with thin melanoma for SLNB.
    Annals of Surgical Oncology 10/2013; · 4.12 Impact Factor
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    ABSTRACT: Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
    Cell Reports 09/2013; · 7.21 Impact Factor
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    ABSTRACT: Cyclin D1-CDK4/6 dysregulation is a major contributor to melanomagenesis. Clinical evidence has revealed that p16(INK4A), an allosteric inhibitor of CDK4/6, is inactivated in over half of human melanomas and numerous animal models have demonstrated that p16(INK4A) deletion promotes melanoma. FBXO4, a specificity factor for the E3 ligase that directs timely cyclin D1 proteolysis, has not been studied in melanoma. We demonstrate that Fbxo4 deficiency induces Braf-driven melanoma that this phenotype depends on cyclin D1 accumulation in mice, underscoring the importance of this ubiquitin ligase in tumor suppression. Furthermore, we have identified a substrate-binding mutation, FBXO4 I377M, that selectively disrupts cyclin D1 degradation while preserving proteolysis of the other known FBXO4 substrate, TRF1. The I377M mutation and Fbxo4 deficiency result in nuclear accumulation of cyclin D1, a key transforming neoplastic event. Collectively, these data provide evidence that FBXO4 dysfunction, as a mechanism for cyclin D1 overexpression, is a contributor to human malignancy.
    Molecular and cellular biology 09/2013; · 6.06 Impact Factor
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    ABSTRACT: Dynamic shape changes of the plasma membrane are fundamental to many processes, ranging from morphogenesis and cell migration to phagocytosis and viral propagation. Here, we demonstrate that Exo70, a component of the exocyst complex, induces tubular membrane invaginations toward the lumen of synthetic vesicles in vitro and generates protrusions on the surface of cells. Biochemical analyses using Exo70 mutants and independent molecular dynamics simulations based on Exo70 structure demonstrate that Exo70 generates negative membrane curvature through an oligomerization-based mechanism. In cells, the membrane-deformation function of Exo70 is required for protrusion formation and directional cell migration. Exo70 thus represents a membrane-bending protein that may couple actin dynamics and plasma membrane remodeling for morphogenesis.
    Developmental Cell 08/2013; 26(3):266-78. · 12.86 Impact Factor
  • JAMA dermatology (Chicago, Ill.). 07/2013;
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    ABSTRACT: Tumor infiltrating lymphocytes (TIL) and histological regression in primary melanoma are generally considered indicators of the local immune response but their roles as prognostic factors have been variably reported. We examined the prognostic role of these variables in patients with high risk (T4) primary melanomas in a large series of patients with long-term follow-up. From a prospectively maintained cohort of patients diagnosed between 1971 and 2004, 161 patients were retrospectively identified with primary thick melanomas (>4 mm), no clinical evidence of regional nodal disease (RND) at diagnosis and complete histopathologic data. Univariate and multivariate Cox regression models were performed to identify clinical and histopathologic predictors of disease-specific survival (DSS) and to identify subgroups with differential survival. Factors significantly associated with decreased DSS by univariate analysis included male gender, age ≥ 60 years, axial anatomic location, presence of ulceration, RND, absence of TIL, and presence of regression. In the final multivariate model, TIL and regression, as interacting variables, and RND status remained significantly associated with DSS. In the presence of TIL, concomitant regression was associated with significantly worse survival (p ≤ 0.0001). In the absence of TIL, there was no effect of regression on survival (p = 0.324). Primary TIL and regression status and RND status are independently associated with melanoma-specific survival in patients with T4 melanomas; presence of TIL in the primary melanoma with concomitant radial growth phase regression is associated with a poor prognosis and may reflect an ineffective local regional immune response.
    Annals of Surgical Oncology 07/2013; · 4.12 Impact Factor
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    ABSTRACT: Death due to melanoma in childhood (up to 20 y of age) is a rare event, with an average of 18 cases reported annually in the United States. In this study we evaluated 2 subgroups of high-risk melanocytic neoplasms in childhood, specifically atypical Spitz tumors (ASTs) with chromosomal copy number changes and conventional melanomas. We analyzed the clinical, histologic, and molecular features of all cases and performed the Fisher exact test, logistic regression, and multivariate analysis to evaluate features associated with aggressive clinical behavior in these cases. Among the ASTs, all of which had 1 or more chromosomal copy number aberrations, the presence of homozygous 9p21 deletions and a positive sentinel lymph node were each found to be correlated with tumor extension beyond the sentinel lymph node, with P-values of 0.046 and 0.01, respectively. Two patients with ASTs that had homozygous 9p21 deletions developed brain metastasis, one of whom died of disease. Among the 21 conventional melanomas, 3 patients developed distant metastasis and died of disease. Chromosomal copy number aberrations evaluated by fluorescence in situ hybridization were present in the majority of the cases (16/18). Among conventional melanomas, we did not identify any clinical, histologic, or molecular features associated with aggressive behavior. The presence of 8q24 gains was seen almost exclusively in 6 amelanotic small cell melanomas in children of whom 1 died of disease. Characteristic chromosomal copy number aberrations may occur in specific subtypes of melanocytic neoplasms in children and may help with the classification and prognostication of these rare tumors.
    The American journal of surgical pathology 06/2013; · 4.06 Impact Factor
  • JAMA dermatology (Chicago, Ill.). 06/2013; 149(6):751-6.
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    ABSTRACT: The prognosis of patients with metastatic melanoma has improved significantly with targeted therapeutic agents and immunotherapies. Detection of early melanoma recurrence after treatment will be beneficial to switch patients who fail on one therapy to different modalities. Circulating tumor cells (CTCs) are cancer cells released by a tumor into the peripheral blood. These cells hold potential as prognostic, predictive, and pharmacodynamic biomarkers for treatment. In this issue, Khoja et al. report that melanoma CTCs can be detected using Melcam and high molecular weight melanoma-associated antibody. They found that in 101 stage IV melanoma patients, CTC numbers ranged between 0 and 36/7.5 ml blood; 26% of the patients had 2 CTCs at baseline. The CTC number (2 CTCs) at baseline was significantly prognostic for median overall survival (OS) in univariate and multivariate analysis. Patients receiving treatment where CTC numbers remained 2 CTCs during their treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, hazard ratio 0.34, 95% confidence interval 0.14-0.81, log-rank test P=0.015). The implications of this work are substantial in counseling patients about their prognosis and in helping to assess responses to systemic therapies.
    Journal of Investigative Dermatology 06/2013; 133(6):1460-1462. · 6.19 Impact Factor
  • JAMA dermatology (Chicago, Ill.). 04/2013;

Publication Stats

3k Citations
484.16 Total Impact Points

Institutions

  • 2011–2014
    • University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
    • Chonnam National University
      • Department of Dermatology
      Gwangju, Gwangju, South Korea
  • 2002–2014
    • Hospital of the University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Surgery
      Philadelphia, Pennsylvania, United States
  • 2013
    • Moffitt Cancer Center
      Tampa, Florida, United States
  • 2012
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2003–2012
    • Wistar Institute
      • Melanoma Research Center
      Philadelphia, Pennsylvania, United States
  • 2010
    • Yale University
      New Haven, Connecticut, United States
    • Fudan University
      • Cancer Hospital
      Shanghai, Shanghai Shi, China