Bio

Bio

Wenhui was born in Southeast China and then immigrated to the San Francisco Bay Area as a teenager. He attended the University of California, Davis under a Regent Scholarship, and graduated with highest honors in Biochemistry and Molecular Biology. Wenhui subsequently pursued training in medicine and translational research in the Medical Scientist Training Program (MSTP) at Tufts University. In the Laboratory of Dr. Charlotte Kuperwasser, Wenhui studied the regulation and function of transcription factors in triple-negative breast cancer with the goal of improving cancer diagnosis and therapeutics. Additionally, he pursued clinical research examining image-guided ablative therapy as a front-line treatment option for renal cancer under the mentorship of Dr. Ronald Arellano at Massachusetts General Hospital. Outside of his clinical and academic interests, Wenhui enjoys food, taking walks, listening to NPR, and spending time with family and friends.

Clinical Focus

  • Residency

Honors & Awards

  • Best Scientific Abstract, Society of Interventional Oncology (2020)
  • Best Oral Abstract, World Congress of Interventional Oncology (2018)
  • Trainee Travel Award, Radiological Society of North America (2018)
  • Outstanding Young Investigator Award, Central Society of Clinical and Translational Research (2015)
  • Research Scholar, American Federation for Medical Research - Midwestern section (2015)
  • Charlton Poster Prize, Tufts University (2014)
  • National Institutes of Health (NIH) Ruth L. Kirschstein T32 Training Fellowship, National Institutes of Health (2011-2019)
  • National Institutes of Health (NIH) Academy Fellowship, National Institutes of Health (2010)
  • Ronald and Lydia Baskin Research Prize, University of California, Davis (2010)
  • Thomas A. Bardos Science Award, American Association for Cancer Research (2010)
  • Regent Scholarship, University of California, Davis (2006-2010)

Publications

All Publications

  • Impact of Body Mass Index on Perioperative Complications and Oncologic Outcomes in Patients Undergoing Thermal Ablation for Renal Cell Carcinoma. Journal of vascular and interventional radiology : JVIR Zhou, W., Herwald, S. E., Uppot, R. N., Arellano, R. S. 2020

    Abstract

    PURPOSE: To determine effect of body mass index (BMI) on safety and cancer-related outcomes of thermal ablation for renal cell carcinoma (RRC).MATERIALS AND METHODS: This retrospective study evaluated 427 patients (287 men and 140 women; mean [SD] age, 72 [12] y) who were treated with thermal ablation for RCC between October 2006 and December 2017. Patients were stratified by BMI into 3 categories: normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (? 30 kg/m2). Of 427 patients, 71 (16%) were normal weight, 157 (37%) were overweight, and 199 (47%) were obese. Complication rates, local recurrence, and residual disease were compared in the 3 cohorts.RESULTS: No differences in technical success between normal-weight, overweight, and obese patients were identified (P= .72). Primary technique efficacy rates for normal-weight, overweight, and obese patients were 91%, 94%, and 93% (P= .71). There was no significant difference in RCC specific-free survival, disease-free survival, and metastasis-free survival between obese, overweight, and normal-weight groups (P= .72, P= .43, P= .99). Complication rates between the 3 cohorts were similar (normal weight 4%, overweight 2%, obese 3%; P= .71).CONCLUSIONS: CT-guided renal ablation is safe, feasible, and effective regardless of BMI.

    View details for DOI 10.1016/j.jvir.2020.07.028

    View details for PubMedID 33308948

  • Thermal Ablation of Renal Cell Carcinoma in Morbidly Obese Patients: Assessment of Technical Results, Procedural Safety, and Oncological Outcomes. AJR. American journal of roentgenology Zhou, W., Herwald, S. E., Uppot, R. N., Arellano, R. S. 2020

    Abstract

    Please see the Author Video associated with this article. BACKGROUND. Obesity is a worldwide problem that impacts patient health as well as the morbidity associated with surgical procedures. Thus, morbidly obese patients may not be suitable candidates for curative surgery. For this patient population, thermal ablation may be an effective alternative to nephrectomy. OBJECTIVE. To determine the feasibility, oncological outcomes, and survival of morbidly obese patients with renal cell carcinoma treated with thermal ablation. MATERIALS AND METHODS. A retrospective analysis was performed of 107 patients treated with CT-guided renal ablation for clinical stageT1renal cell carcinoma between February 2005 and December 2017. Patients were stratified into two cohorts on body mass index of ? 40 kg/m2 (morbidly obese) and body mass index of 18.5 to 24.9 kg/m2 normal-weight). Anesthetic and radiation dosages, procedure time, residual disease, and local recurrence and adverse events were analyzed between the two groups. Kaplan-Meier statistics evaluated cancer-related outcomes for each group. RESULTS. 34 patients were morbidly, and 73 patients were normal-weight. Morbid obesity was associated with longer procedural duration (p = 0.001), sedative doses (p = 0.002) and radiation exposure (p = 0.001), compared to normal-weight patients. Hematomas were more prevalent in the morbidly obese than normal body mass index patients (p = 0.01), but treatment efficacy and local recurrences were comparable to normal-weight individuals (p = 0.81, p = 0.12, respectively). Cancer-related outcomes were equivalent between the two groups based on five years of imaging observation data. CONCLUSION. CT-guided thermal ablation remains technically feasible, well-tolerated and effective in morbidly obese patients with renal cell carcinoma, with the caveat of increased risk of perinephric hematoma, anesthesia dosage and radiation exposure. CLINICAL IMPACT: CT-guided thermal ablation can be considered a safe and effective treatment for morbidly obese patients with renal cell carcinoma.

    View details for DOI 10.2214/AJR.20.23803

    View details for PubMedID 32755206

  • Molecular regulation of Snai2 in development and disease JOURNAL OF CELL SCIENCE Zhou, W., Gross, K. M., Kuperwasser, C. 2019; 132 (23)

    Abstract

    The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease.

    View details for DOI 10.1242/jcs.235127

    View details for Web of Science ID 000500368400008

    View details for PubMedID 31792043

  • Loss of Slug Compromises DNA Damage Repair and Accelerates Stem Cell Aging in Mammary Epithelium CELL REPORTS Gross, K. M., Zhou, W., Breindel, J. L., Ouyang, J., Jin, D. X., Sokol, E. S., Gupta, P. B., Huber, K., Zou, L., Kuperwasser, C. 2019; 28 (2): 394-+

    Abstract

    DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell activity, including luminobasal differentiation, and are protected from mammary cancer, we reasoned that Slug might regulate DNA damage checkpoints in mammary epithelial cells. Here, we show that Slug facilitates efficient execution of RPA32-mediated DNA damage response (DDR) signaling. Slug deficiency leads to delayed phosphorylation of ataxia telangiectasia mutated and Rad3-related protein (ATR) and its effectors RPA32 and CHK1. This leads to impaired RAD51 recruitment to DNA damage sites and persistence of unresolved DNA damage. In vivo, Slug/Snai2 loss leads to increased DNA damage and premature aging of mammary epithelium. Collectively, our work demonstrates that the mammary stem cell regulator Slug controls DDR checkpoints by dually inhibiting differentiation and facilitating DDR repair, and its loss causes unresolved DNA damage and accelerated aging.

    View details for DOI 10.1016/j.celrep.2019.06.043

    View details for Web of Science ID 000474580800010

    View details for PubMedID 31291576

  • Radiofrequency Ablation, Cryoablation, and Microwave Ablation for T1a Renal Cell Carcinoma: A Comparative Evaluation of Therapeutic and Renal Function Outcomes JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Zhou, W., Herwald, S. E., McCarthy, C., Uppot, R. N., Arellano, R. S. 2019; 30 (7): 1035?42

    Abstract

    To compare the therapeutic and renal function outcomes of radiofrequency (RF) ablation, cryoablation, and microwave (MW) ablation for treatment of T1a renal cell carcinoma (RCC).A retrospective assessment of 297 patients (mean age 72 years range 24-90 years) with biopsy-proven RCC treated with image-guided percutaneous thermal ablation was performed between October 2006 and December 2016. Mean tumor size was 2.4 cm; mean radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, hilar tumor touching the main renal artery or vein, and location relative to polar lines; Preoperative Aspects and Dimensions Used for an Anatomical; and c-centrality scores were 6.0, 7.0, and 2.8, respectively. Assessments of adverse events, treatment efficacy, and therapeutic outcomes were performed among RF ablation, cryoablation, and MW ablation. The 2-year disease-free, metastatic-free, and cancer-specific survival rates were tabulated. Estimated glomerular filtration rate was used to assess for treatment related changes in renal function.A total of 297 T1aN0M0 biopsy-proven RCCs measuring 1.2-3.9 cm were treated with computed tomography-guided RF ablation (n = 244, 82%), cryoablation (n = 26, 9%), and MW ablation (n = 27, 9%). There were no significant differences in patient demographics among the 3 groups (P = .09). Technical success rates were similar among the 3 treatments (P = .33). Primary efficacy at 1 month postablation was more likely to be achieved with RF ablation and MW ablation than with cryoablation. At 2 years' follow-up, there was no local recurrence, metastatic progression, or RCC-related death observed in the 3 groups. There was no significant change in estimated glomerular filtration rate among the 3 ablation groups compared with baseline at 2-year follow-up (P = .71).RF ablation, cryoablation, and MW ablation are equivalent at 2 years for treatment of T1a RCC for therapeutic outcome, stability of renal function, and low adverse event rate.

    View details for DOI 10.1016/j.jvir.2018.12.013

    View details for Web of Science ID 000475412000009

    View details for PubMedID 30956075

  • Risk Assessment of Chronic Kidney Disease following Microwave Ablation for Stage T1 Renal Cell Carcinoma JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Zhou, W., Herwald, S. E., Uppot, R. N., Arellano, R. S. 2018; 29 (12): 1685?91

    Abstract

    To assess safety and renal-function outcomes after microwave (MW) ablation of localized stage T1 renal cell carcinoma (RCC).A retrospective review was conducted of 38 patients (28 men; mean age, 69 y; range, 51-88 y) who underwent computed tomography (CT)-guided MW ablation for stage T1N0M0 RCC. Baseline and follow-up renal function surrogates including creatinine level and estimated glomerular filtration rate (eGFR) were statistically compared. Peri- and postoperative complication rates, technical success, and treatment response were also assessed.A total of 44 biopsy-proven stage T1N0M0 RCCs measuring 1.2-6.9 cm (mean, 2.5 cm) were treated, and renal function was measured 1 mo after treatment. Mean eGFRs were 60 mL/min/1.73 m2 at baseline and 59 mL/min/1.73 m2 at 1 month after ablation. At 1-year and last follow-ups, the means of difference were 3.3% (95% confidence interval, -4.4 to 4.3; P = .99) and 3.3% (95% confidence interval, -4.3 to 4.8; P = .91), respectively. The 2-years freedom from eGFR decrease to < 60 mL/min/1.73 m2 was 2% (P = .91). Among the 5 patients (13%) with preexisting stage 4 chronic kidney disease (CKD; eGFR < 30 mL/min/1.73 m2) before ablation, there was no significant postablative onset of decline or CKD upstaging (P = .001). There were no major complications, and 5 patients (13%) had small asymptomatic perinephric hematomas (Society of Interventional Radiology minor complication, class A/B) that were managed conservatively.At 2-year follow-up, CT-guided percutaneous MW ablation is safe and well-tolerated and achieves nephron preservation similar to existing ablative modalities.

    View details for DOI 10.1016/j.jvir.2018.06.021

    View details for Web of Science ID 000453341200009

    View details for PubMedID 30297311

  • Image-Guided Thermal Ablation for Non-resectable Recurrence of Renal Cell Cancer Following Nephrectomy: Clinical Experience with Eleven Patients CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY Zhou, W., Herwald, S. E., Uppot, R. N., Arellano, R. S. 2018; 41 (11): 1743?50

    Abstract

    To assess the feasibility, safety and clinical outcomes of image-guided percutaneous thermal ablation as salvage therapy for local recurrence of renal cell carcinoma (RCC) in patients initially treated surgically with curative intent.A retrospective review of 11 consecutive patients (M/F?=?8:3, mean age?=?76 years) who underwent computed tomography (CT)-guided thermal ablation for locally recurrent RCC after partial (72%, 8/11) or radical nephrectomy (28%, 3/11) with a mean time to recurrence of 48 months (range 2-156). Assessment of technical success, complication (peri- and post-procedural), oncological outcome and survival analysis were performed. Patient baseline and follow-up renal function surrogates including creatinine level (Cr) and estimated glomerular filtration rate (eGFR) were statistically compared.Eleven biopsy-proven recurrent RCC measuring 1.4-3.9 cm (mean?=?2.8 cm) were treated with CT-guided thermal ablation. Technical success was achieved in 100% (11/11) of the cases. There were no major complications except for one (9%) asymptomatic hemorrhage (Clavien-Dindo grade I complication). Complete response, local progression-free and overall survival rate were 91, 91 and 82% during the mean follow-up time of 2.5 years (range 0.1-7.1). Renal function was overall stable without significant change at 1 month and last follow-up (p?=?0.21; GFR, p?=?0.10; creatinine).Image-guided percutaneous thermal ablation is a feasible, safe and effective for local recurrence after nephrectomy, representing a non-surgical alternative for unresectable disease.

    View details for DOI 10.1007/s00270-018-1976-2

    View details for Web of Science ID 000451930300013

    View details for PubMedID 29721615

  • Thermal Ablation of T1c Renal Cell Carcinoma: A Comparative Assessment of Technical Performance, Procedural Outcome, and Safety of Microwave Ablation, Radiofrequency Ablation, and Cryoablation JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Zhou, W., Arellano, R. S. 2018; 29 (7): 943?51

    Abstract

    To evaluate perioperative outcomes of thermal ablation with microwave (MW), radiofrequency (RF), and cryoablation for stage T1c renal cell carcinoma (RCC).A retrospective analysis of 384 patients (mean age, 71 y; range, 22-88 y) was performed between October 2006 and October 2016. Mean radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, and location relative to polar lines; preoperative aspects and dimensions used for anatomic classification; and centrality index scores were 6.3, 7.9, and 2.7, respectively. Assessment of pre- and postablation serum blood urea nitrogen, creatinine, and estimated glomerular filtration rate was performed to assess functional outcomes. Linear regression analyses were performed to compare sedation medication dosages among the three treatment cohorts. Univariable and multivariable logistic regression analyses were performed to compare rates of residual disease and complications among treatment modalities.A total of 437 clinical stage T1N0M0 biopsy-proven RCCs measuring 1.2-6.9 cm were treated with computed tomography (CT)-guided MW ablation (n = 44; 10%), RF ablation (n = 347; 79%), or cryoablation (n = 46; 11%). There were no significant differences in patient demographic or tumor characteristics among cohorts. Complication rates and immediate renal function changes were similar among the three ablation modalities (P = .46 and P = .08, respectively). MW ablation was associated with significantly decreased ablation time (P < .05), procedural time (P < .05), and dosage of sedative medication (P < .05) compared with RF ablation and cryoablation.CT-guided percutaneous MW ablation is comparable to RF ablation or cryoablation for the treatment of stage T1N0M0 RCC with regard to treatment response and is associated with shorter treatment times and less sedation than RF ablation or cryoablation. In addition, the safety profile of CT-guided MW ablation is noninferior to those of RF ablation or cryoablation.

    View details for DOI 10.1016/j.jvir.2017.12.020

    View details for Web of Science ID 000438179300006

    View details for PubMedID 29628298

  • CDK6 inhibits white to beige fat transition by suppressing RUNX1 NATURE COMMUNICATIONS Hou, X., Zhang, Y., Li, W., Hu, A. J., Luo, C., Zhou, W., Hu, J. K., Daniele, S. G., Wang, J., Sheng, J., Fan, Y., Greenberg, A. S., Farmer, S. R., Hu, M. G. 2018; 9: 1023

    Abstract

    Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6 -/- mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1? by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.

    View details for DOI 10.1038/s41467-018-03451-1

    View details for Web of Science ID 000427027200011

    View details for PubMedID 29523786

    View details for PubMedCentralID PMC5845007

  • Percutaneous Image-Guided Thermal Ablation for Multifocal Renal Cell Carcinoma: 10-Year Experience at a Single Center AMERICAN JOURNAL OF ROENTGENOLOGY Zhou, W., Uppot, R. N., Feldman, A. S., Arellano, R. S. 2017; 209 (4): 733?39

    Abstract

    The objective of our study was to assess the technical success, safety, and oncologic and renal function outcomes of CT-guided percutaneous thermal ablation for synchronous multiple renal masses in a single session.A retrospective analysis of 23 patients (16 men and 7 women; median age, 70 years) with biopsy-proven multifocal renal cell carcinoma (RCC) masses treated with radiofrequency ablation (RFA), cryoablation, or microwave ablation (MWA) was performed. Preablation, postablation, and follow-up serum blood urea nitrogen, creatinine, and estimated glomerular filtration rate (GFR) levels were recorded to evaluate the stability of renal function. Technical success, complications, treatment response, oncologic outcome, and overall survival were assessed.Biopsy-proven RCCs were treated in 23 patients. Median tumor size was 2.3 cm (range, 1.0-4.0 cm). The mean RENAL (radius, exophytic vs endophytic properties, nearness of tumor to the collecting system or sinus, anterior vs posterior, location relative to polar lines) nephrometry score was 6.3 (range, 4.0-10.0); mean PADUA (preoperative aspects and dimensions used for anatomical) score, 7.8 (range, 6.0-11.0); and mean centrality index (C-index), 3.1 (range, 0.7-6.8). The mean ablation time was 23 minutes (range, 3-24 minutes). Technical success was achieved for 100% of tumors. Of the 49 complications, nine (18%) were classified as Clavien-Dindo grade I complications. Complete response was achieved in 41 of the 49 (84%) tumors. Local progression-free, RCC-specific disease-free, and overall survival rates during the imaging follow-up time (mean, 3.1 years; range, 0.1-9.6 years) were 96% (22/23), 100% (23/23), and 91% (21/23), respectively.CT-guided percutaneous thermal ablation is a safe, effective, and durable treatment intervention for multifocal renal masses.

    View details for DOI 10.2214/AJR.17.18290

    View details for Web of Science ID 000411440600014

    View details for PubMedID 28678572

  • Epigenetic Reprogramming of Lineage-Committed Human Mammary Epithelial Cells Requires DNMT3A and Loss of DOT1L STEM CELL REPORTS Breindel, J. L., Skibinski, A., Sedic, M., Wronski-Campos, A., Zhou, W., Keller, P. J., Mills, J., Bradner, J., Onder, T., Kuperwasser, C. 2017; 9 (3): 943?55

    Abstract

    Organogenesis and tissue development occur through sequential stepwise processes leading to increased lineage restriction and loss of pluripotency. An exception to this appears in the adult human breast, where rare variant epithelial cells exhibit pluripotency and multilineage differentiation potential when removed from the signals of their native microenvironment. This phenomenon provides a unique opportunity to study mechanisms that lead to cellular reprogramming and lineage plasticity in real time. Here, we show that primary human mammary epithelial cells (HMECs) lose expression of differentiated mammary epithelial markers in a manner dependent on paracrine factors and epigenetic regulation. Furthermore, we demonstrate that HMEC reprogramming is dependent on gene silencing by the DNA methyltransferase DNMT3A and loss of histone transcriptional marks following downregulation of the methyltransferase DOT1L. These results demonstrate that lineage commitment in adult tissues is context dependent and highlight the plasticity of somatic cells when removed from their native tissue microenvironment.

    View details for DOI 10.1016/j.stemcr.2017.06.019

    View details for Web of Science ID 000410279200018

    View details for PubMedID 28781076

    View details for PubMedCentralID PMC5599181

  • Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers CANCER DISCOVERY Olsen, S., Wronski, A., Castano, Z., Dake, B., Malone, C., De Raedt, T., Enos, M., DeRose, Y. S., Zhou, W., Guerra, S., Loda, M., Welm, A., Partridge, A. H., McAllister, S. S., Kuperwasser, C., Cichowski, K. 2017; 7 (2): 202?17

    Abstract

    Luminal breast cancers are typically estrogen receptor-positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-?B, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-?B activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-?B. Cancer Discov; 7(2); 202-17. ©2016 AACR.See related commentary by Sears and Gray, p. 131This article is highlighted in the In This Issue feature, p. 115.

    View details for DOI 10.1158/2159-8290.CD-16-0520

    View details for Web of Science ID 000396018000026

    View details for PubMedID 27974415

    View details for PubMedCentralID PMC6461361

  • Hydrodissection-Assisted Percutaneous Drainage of Deep Pelvic Abscess JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Zhou, W., Arellano, R. S. 2017; 28 (2): 308?10

    View details for DOI 10.1016/j.jvir.2016.10.011

    View details for Web of Science ID 000393543200025

    View details for PubMedID 28110764

  • The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer CELL REPORTS Zhou, W., Ni, T. K., Wronski, A., Glass, B., Skibinski, A., Beck, A., Kuperwasser, C. 2016; 17 (5): 1302?17

    Abstract

    Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here, we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.

    View details for DOI 10.1016/j.celrep.2016.10.006

    View details for Web of Science ID 000386527100010

    View details for PubMedID 27783945

    View details for PubMedCentralID PMC5108094

  • The Histone Deacetylase Sirt2 Regulates Slug in Basal-like Breast Cancer Zhou, W., Kuperwasser, C. FEDERATION AMER SOC EXP BIOL. 2016

    View details for Web of Science ID 000406444703313

  • Ultra-sensitive protein detection via Single Molecule Arrays towards early stage cancer monitoring SCIENTIFIC REPORTS Schubert, S. M., Arendt, L. M., Zhou, W., Baig, S., Walter, S. R., Buchsbaum, R. J., Kuperwasser, C., Walt, D. R. 2015; 5: 11034

    Abstract

    The early diagnosis of cancers and continued monitoring of tumor growth would be greatly facilitated by the development of a blood-based, non-invasive, screening technique for early cancer detection. Current technologies for cancer screening and detection typically rely on imaging techniques or blood tests that are not accurate or sensitive enough to definitively diagnose cancer at its earliest stages or predict biologic outcomes. By utilizing Single Molecule Arrays (SiMoA), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA) technique, we were able to measure increasing levels of prostate specific antigen (PSA) within murine serum over time, which we attribute to tumor development. The measured concentrations of PSA were well below the detectable limits of both a leading clinical diagnostic PSA ELISA assay as well as a commercial ultra-sensitive PSA assay. Our work benchmarks the role of SiMoA as a vital tool in monitoring previously non-detectable protein biomarkers in serum for early cancer detection and offers significant potential as a non-invasive platform for the monitoring of early stage cancer.

    View details for DOI 10.1038/srep11034

    View details for Web of Science ID 000356068500001

    View details for PubMedID 26052106

    View details for PubMedCentralID PMC4458912

  • Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17 NATURE COMMUNICATIONS Maretzky, T., Evers, A., Zhou, W., Swendeman, S. L., Wong, P., Rafii, S., Reiss, K., Blobel, C. P. 2011; 2: 229

    Abstract

    The fibroblast growth factor receptor 2-IIIb (FGFR2b) and the vascular endothelial growth factor receptor 2 (VEGFR2) are tyrosine kinases that can promote cell migration and proliferation and have important roles in embryonic development and cancer. Here we show that FGF7/FGFR2b-dependent activation of epidermal growth factor receptor (EGFR)/ERK1/2 signalling and cell migration in epithelial cells require stimulation of the membrane-anchored metalloproteinase ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). Moreover, VEGF-A/VEGFR2-induced migration of human umbilical vein endothelial cells also depends on EGFR/ERK1/2 signalling and shedding of the ADAM17 substrate HB-EGF. The pathway used by the FGF7/FGFR2b signalling axis to stimulate shedding of substrates of ADAM17, including ligands of the EGFR, involves Src, p38 mitogen-activated protein-kinase and PI3K, but does not require the cytoplasmic domain of ADAM17. Based on these findings, ADAM17 emerges as a central component in a triple membrane-spanning pathway between FGFR2b or VEGFR2 and EGFR/ERK1/2 that is required for cell migration in keratinocytes and presumably also in endothelial cells.

    View details for DOI 10.1038/ncomms1232

    View details for Web of Science ID 000289982600019

    View details for PubMedID 21407195

    View details for PubMedCentralID PMC3074487

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