Wenhui Zhou

All Publications

• Estrogen Receptor-targeted PET Imaging for Breast Cancer. Radiology Zhou, W., Franc, B. L., DeMartini, W. B., Rosen, E. L. 2024; 312 (2): e240315

  Abstract

  Two complementary patient cases are presented to highlight the importance of estrogen receptor (ER)-targeting imaging in treatment planning and selection for endocrine therapy in breast cancer patients. This article will discuss the radiopharmaceuticals and biology, imaging interpretation, and current clinical applications of ER-targeting imaging using fluorine 18 fluoroestradiol PET.

  View details for DOI 10.1148/radiol.240315

  View details for PubMedID 39136565

• Outcomes Analysis of 90Y Radioembolization for Tumors Other Than Metastatic Colorectal Cancer from the RESiN (Radiation-Emitting SIR-spheres in Non-resectable liver tumors) Registry. Journal of vascular and interventional radiology : JVIR Zhou, W., Du, L., Brown, D. B., Shah, R. P., Sze, D. Y. 2024

  Abstract

  To characterize the response and survival outcomes of yttrium-90 transarterial radioembolization (90Y-TARE) for unresectable, liver-dominant metastases from primary neoplasms other than colorectal carcinoma.This study included 1474 patients enrolled in the RESiN registry who received resin 90Y-TARE as part of their oncologic management for unresectable primary or secondary liver tumors (NCT02685631). 33% (481/1474) were treated for liver metastases of non-colorectal origin (m-nonCRC), compared to 34% (497/1474) treated for colorectal liver metastases (mCRC) and 34% (496/1474) treated for hepatocellular carcinoma (HCC). Treatment response and cancer survival probabilities were computed and compared for each primary cancer type. The Kaplan-Meier method and log-rank test were used to compare survival outcomes.Radiological responses were observed in 12 unique cancer types, mostly heavily pre-treated malignancies refractory to multiple lines of systemic therapies. The overall use of resin 90Y-TARE in m-nonCRC resulted in better treatment outcomes in terms of duration of response, progression free survival, time to progression and overall survival (P = 0.04, P = 0.02, P = 0.01, P = 0.04). Analyses of cancer cell types revealed that metastatic neuroendocrine tumor, sarcoma, and ovarian, renal, prostate, and breast cancers were associated with superior treatment outcomes, whereas worse treatment outcomes were observed in metastatic lung, gastric, pancreatic and esophageal cancers.Real-world data demonstrate the use of resin 90Y-TARE in m-nonCRC refractory to standard chemotherapy. For some cell types, this expanded use achieved superior treatment outcomes relative to the reference standard of mCRC, suggesting the need for inquiry into broadened indications for 90Y-TARE.

  View details for DOI 10.1016/j.jvir.2024.07.006

  View details for PubMedID 39009301

• Examination of genomic profile of true single circulating tumor cells (sCTC) from hepatocellular carcinoma and its effect on mutational features Bharde, A., Shafi, G., Dongare, M., Jadhav, V., Khutale, G., Andhari, S., Prajapati, S., Jadhav, B., Mobeen, F., Hariramani, K., Basavalingegowda, M., Deshpande, R., Zhou, W., Uttarwar, M., Patel, K., Kishore, S., Singhal, M., Gupta, V., Thirumalairaj, R., Khandare, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557403796

• Study of single live circulating tumor cells capture and their genomic profile and enriched mutations of PIK3CA and HRR pathway in patients with breast cancer Khandare, J., Bharde, A., Kishore, S., Andhari, S., Khutale, G., Jadhav, B., Prajapati, S., Zhou, W., Mobeen, F., Hariramani, K., Basavalingegowda, M., Jadhav, V., Uttarwar, M., Joshi, A., Ghadyalpatil, N., Velkuru, S., Thirumalairaj, R., Shafi, G. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557403265

• Frequent Amplification and Overexpression of PSMA in Basallike Breast Cancer from Analysis of The Cancer Genome Atlas. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Zhou, W., Halder, S., Herwald, S., Ghijsen, M., Shafi, G., Uttarwar, M., Rosen, E., Franc, B., Kishore, S. 2024

  Abstract

  Prostate-specific membrane antigen (PSMA) is frequently overexpressed in nonprostate malignancies. This preclinical study investigated the molecular basis of the application of PMSA-targeting radiopharmaceuticals in breast cancer subtypes. Methods: The somatic copy number status and the transcriptomic and protein expressions of FOLH1 (gene name of PSMA) were analyzed across breast cancer subtypes in 998 patients from The Cancer Genome Atlas dataset. Results: FOLH1 was frequently amplified in basallike breast cancer (BLBC) (32%) compared with luminal and human epidermal growth factor receptor 2-positive subtypes (16% and 17%, respectively; P < 0.01). FOLH1 expression was higher in BLBC (P < 0.001) and was negatively correlated with estrogen-receptor and progesterone-receptor expressions. Consistently, the PSMA protein level was higher in BLBC (P < 0.05). Interestingly, FOLH1 expression was associated with relapse-free and distant metastasis-free survival in patients with BLBC. Conclusion: The BLBC subtype exhibited frequent amplification and overexpression of PSMA, supporting the exploration of PSMA-targeting radiopharmaceuticals in this aggressive breast cancer subtype.

  View details for DOI 10.2967/jnumed.123.266659

  View details for PubMedID 38664014

• Combined genicular artery embolization and genicular nerve block to treat chronic pain following total knee arthroplasty. CVIR endovascular Zhou, W., Bultman, E., Mandl, L. A., Giori, N. J., Kishore, S. A. 2024; 7 (1): 4

  Abstract

  Chronic knee pain after total knee arthroplasty (TKA) is a common complication that is difficult to treat. This report aims to highlight the benefit of combining embolotherapy and neurolysis intervention for symptomatic relief of post-TKA pain in a patient with long-standing pain refractory to conservative management.A 77-year-old man who had previously undergone left knee arthroplasty has been grappling with worsening knee effusion and debilitating pain, resulting in limited mobility and progressive musculature deconditioning over a 20-year period. Diagnostic arteriography showed marked diffuse periarticular hyperemia around the medial and lateral joint spaces of the left knee, along with capsular distention. The patient initially underwent microsphere embolization to selectively target multiple branches of the genicular arteries, achieving a 50% reduction in pain at the one-month follow-up. Subsequently, the patient underwent image-guided genicular nerve neurolysis, targeting multiple branches of the genicular nerves, which led to further pain reduction (80% compared to the initial presentation or 60% compared to post-embolization) at the one-month follow-up. This improvement facilitated weight-bearing and enabled participation in physical therapy, with sustained pain relief over the 10-month follow-up period.The combination of genicular artery embolization and genicular nerve block may be a technically safe and effective option for alleviating chronic pain after total knee arthroplasty.

  View details for DOI 10.1186/s42155-023-00409-3

  View details for PubMedID 38170403

  View details for PubMedCentralID PMC10764703

• Quantitative Breast Parenchymal Enhancement to Predict Breast Cancer Recurrence. Radiology Zhou, W., Rahbar, H. 2024; 310 (1): e240021

  View details for DOI 10.1148/radiol.240021

  View details for PubMedID 38259209

• A Case-Based Primer on FDG PET/CT for Imaging Cardiovascular Infections: Protocol, Interpretation, and Pitfalls. Zhou, W., Moradi, F., Davidzon, G., Song, H., Grady, E., Nguyen, J., Franc, B., Aparici, C., Iagaru, A., Shah, J. SOC NUCLEAR MEDICINE INC. 2023

  View details for Web of Science ID 001109210201036

• Frequency and Outcomes of Ipsilateral Axillary Lymphadenopathy After COVID-19 Vaccination. JAMA network open Zhou, W., DeMartini, W. B., Ikeda, D. M. 2022; 5 (6): e2216172

  View details for DOI 10.1001/jamanetworkopen.2022.16172

  View details for PubMedID 35675077

• Gastric Outlet Obstruction Following Radioembolization: Extrahepatic complication from proximity to a superficial hepatic tumor treated with an ablative dose. Journal of vascular and interventional radiology : JVIR Zhou, W., Sze, D. Y. 2021

  View details for DOI 10.1016/j.jvir.2021.09.001

  View details for PubMedID 34534651

• Computed Tomography-Guided Microwave Ablation of Cystic Renal Cell Carcinoma: Assessment of Technique and Complications. Journal of vascular and interventional radiology : JVIR Zhou, W., Herwald, S. E., Arellano, R. S. 2021; 32 (4): 544–47

  Abstract

  This report evaluates the techniques and complications of microwave ablation of cystic renal cell carcinoma. Five patients with cystic renal cell carcinoma were treated with microwave ablation between October 2015 and June 2020. Medical records were reviewed to evaluate technique and complications. Technical success and primary technique efficacy both were 100%. There were no complications. Mean follow-up time was 18 months (range, 6-36 months). No local recurrence was identified during the follow-up period. Renal function remained stable at 1 month and the last follow-up. Percutaneous microwave ablation is promising for the nonsurgical management of cystic renal cell carcinoma.

  View details for DOI 10.1016/j.jvir.2020.12.021

  View details for PubMedID 33795074

• Inflammatory Pseudotumor Mimics Local Recurrence following a Microwave Ablation of Renal Cell Carcinoma. Journal of vascular and interventional radiology : JVIR Zhou, W., Herwald, S. E., Arellano, R. S. 2021

  View details for DOI 10.1016/j.jvir.2020.12.025

  View details for PubMedID 33526344

• 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 Pgc1α 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-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-κB 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-κB. 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