Honors & Awards
MCHRI Postdoctoral Support Award, Stanford Maternal and Child Health Research Institute (2022)
National Natural Science Foundation, No.82102809, National Natural Science Foundation of China (NSFC) (2022)
2021 SBUR Travel Award, Society for Basic Urologic Research (2021)
Justice, Diversity, Equity & Inclusion Seed Grants in Radiology, Stanford University (2021-2022)
The National Scholarship, Ministry of Education of the People's Republic of China (2010-2012)
“Excellent graduates of Hunan” Award, Department of Education of Hunan province, China (2012)
Top Prize in the All China Medical Student Clinical skill competition, Department of Higher Education of Ministry of education (2012)
“The best contestant” award in the All China Medical Student Clinical skill competition, Department of Higher Education of Ministry of education (2012)
Joint PhD Student Scholarship, China Scholarship Council (2014-2016)
Resident, Central South University, Surgery (2019)
Doctor of Philosophy, Peking University (2017)
Joint PhD student, University of Miami, Surgery (2016)
Bachelor of Medicine, Central South University (2013)
Metastasis Model to Test the Role of Notch Signaling in Prostate Cancer.
Methods in molecular biology (Clifton, N.J.)
2022; 2472: 221-233
Distant metastasis is the main cause of death in prostate cancer patients. Notch signaling plays an important role in driving prostate cancer aggressiveness and metastasis. In this chapter, we describe a protocol to measure prostate cancer metastatic colonization, incidences of metastasis, accurately quantify the burden of metastasis, and test the role of NOTCH1 receptor on prostate cancer metastatic colonization and homing to distant sites. The metastasis model presented here is established by intracardiac injection of control human prostate cancer cells and NOTCH1 downregulated cells. The cells are engineered to express both red fluorescent protein (RFP) and luciferase. In this model, whole body bioluminescence imaging, high-resolution, and quantitative fluorescence imaging are utilized for quantitative assessment of metastatic colonization and metastasis burden. Further, histopathology analyses of diverse metastatic organs are performed. This model is a powerful and versatile tool to investigate the mechanisms underlying the function of NOTCH receptors in metastatic colonization in prostate cancer.
View details for DOI 10.1007/978-1-0716-2201-8_18
View details for PubMedID 35674904
Molecular Mechanisms Underlying the Development of Neuroendocrine Prostate Cancer.
Seminars in cancer biology
Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-associated deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. While patients with advanced prostate cancer initially respond to ADT, the disease frequently progresses to a lethal metastatic form, defined as castration-resistant prostate cancer (CRPC). After multiple rounds of anti-androgen therapies, 20-25% of metastatic CRPCs develop a neuroendocrine (NE) phenotype. These tumors are classified as neuroendocrine prostate cancer (NEPC). De novo NEPC is rare and accounts for less than 2% of all prostate cancers at diagnosis. NEPC is commonly characterized by the expression of NE markers and the absence of androgen receptor (AR) expression. NEPC is usually associated with tumor aggressiveness, hormone therapy resistance, and poor clinical outcome. Here, we review the molecular mechanisms underlying the emergence of NEPC and provide insights into the future perspectives on potential therapeutic strategies for NEPC.
View details for DOI 10.1016/j.semcancer.2022.05.007
View details for PubMedID 35597438
Discovery of CASP8 as a potential biomarker for high-risk prostate cancer through a high-multiplex immunoassay.
2021; 11 (1): 7612
Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addition, mRNA levels of CASP8 were higher in patients with recurrent prostate cancer when compared to patients with non-recurrent prostate cancer and high expression of CASP8 was associated with worse disease-free survival and overall survival in renal cancer. Together, our results suggest that CASP8 may potentially serve as a biomarker for high-risk prostate cancer and possibly renal cancer.
View details for DOI 10.1038/s41598-021-87155-5
View details for PubMedID 33828176
LncRNA GNAS-AS1 facilitates ER+ breast cancer cells progression by promoting M2 macrophage polarization via regulating miR-433-3p/GATA3 axis.
2020; 40 (7)
ER+ breast cancer is the most common type of breast cancer, which seriously affects the physical and mental health of women. Recently, lncRNAs mediated tumor-associated macrophages (TAM) were identified to involve in tumorigenesis. Therefore, the present study aimed at demonstrating the regulatory network of GNAS-AS1 in TAM-mediated ER+ breast cancer progress.The expression levels of genes were evaluated using qRT-PCR. The proportions of polarized macrophages (M1, M2) were assessed by flow cytometry. Cell proliferation, migration and invasion were evaluated by CCK-8, wound healing and transwell assay, respectively. Double-luciferase reporter system was used to detect the interaction between molecules. Western blot was applied to test protein levels.The expression of GNAS-AS1 was obviously increased in ER+ breast cancer tissues and cell lines, as well as M2 macrophages. GNAS-AS1 facilitated the capabilities of proliferation, migration and invasion of ER+ breast cancer cells by accelerating M2 macrophage polarization via directly sponging miR-433-3p. GATA3, as a target of miR-433-3p, could positively regulate by GNAS-AS1. Furthermore, either miR-433-3p overexpression or GATA3 knockdown impaired the effects of GNAS-AS1 on M2 macrophage polarization and ER+ breast cancer cells progression.GNAS-AS1/miR-433-3p/GATA3 axis promoted proliferation, metastasis of ER+ breast cancer cells by accelerating M2 macrophage polarization. The mechanism may provide a new strategy and target for ER+ breast cancer treatment.
View details for DOI 10.1042/BSR20200626
View details for PubMedID 32538432
View details for PubMedCentralID PMC7327181
Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer.
British journal of cancer
Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.
View details for DOI 10.1038/s41416-020-01200-0
View details for PubMedID 33288843
Gata3 restrains B cell proliferation and cooperates with p18(INK4c) to repress B cell lymphomagenesis
2016; 7 (39): 64007–20
GATA3, a lineage specifier, controls lymphoid cell differentiation and its function in T cell commitment and development has been extensively studied. GATA3 promotes T cell specification by repressing B cell potential in pro T cells and decreased GATA3 expression is essential for early B cell commitment. Inherited genetic variation in GATA3 has been associated with lymphoma susceptibility. However, it remains elusive how the loss of function of GATA3 promotes B cell development and induces B cell lymphomas. In this study, we found that haploid loss of Gata3 by heterozygous germline deletion increased B cell populations in the bone marrow (BM) and spleen, and decreased CD4 T cell populations in the thymus, confirming that Gata3 promotes T and suppresses B cell development. We discovered that haploid loss of Gata3 reduced thymocyte proliferation with induction of p18Ink4c (p18), an inhibitor of CDK4 and CDK6, but enhanced B cell proliferation in the BM and spleen independent of p18. Loss of p18 partially restored Gata3 deficient thymocyte proliferation, but further stimulated Gata3 deficient B cell proliferation in the BM and spleen. Furthermore, we discovered that haploid loss of Gata3 in p18 deficient mice led to the development of B cell lymphomas that were capable of rapidly regenerating tumors when transplanted into immunocompromised mice. These results indicate that Gata3 deficiency promotes B cell differentiation and proliferation, and cooperates with p18 loss to induce B cell lymphomas. This study, for the first time, reveals that Gata3 is a tumor suppressor specifically in B cell lymphomagenesis.
View details for DOI 10.18632/oncotarget.11746
View details for Web of Science ID 000387167800094
View details for PubMedID 27588406
View details for PubMedCentralID PMC5325421
Current and emerging therapies for neuroendocrine prostate cancer.
Pharmacology & therapeutics
Neuroendocrine prostate cancer is a histological variant of prostate cancer that is characterized by aggressiveness, poor clinical outcomes, and expression of neuroendocrine markers. Neuroendocrine prostate cancer usually manifests in late-stage prostate cancer patients who have undergone multiple rounds of anti-androgen therapies but can, although rarely, occur in treatment naïve patients de novo. Current therapies to treat neuroendocrine prostate cancer are largely based on their success in treating patients with small cell lung cancer, a lung cancer that shares the neuroendocrine phenotype with neuroendocrine prostate cancer. However, unfortunately these therapies are not durable. In this review, we discuss therapies currently in use to treat neuroendocrine prostate cancer, including platinum-based therapies, taxanes and etoposide. Additionally, we utilize ongoing clinical trials information to identify potential emerging therapies for neuroendocrine prostate cancer. Lastly, we discuss additional potential future opportunities for targeting neuroendocrine prostate cancer.
View details for DOI 10.1016/j.pharmthera.2022.108255
View details for PubMedID 35905791
- Volbots: Volvox Microalgae-Based Robots for Multimode Precision Imaging and Therapy ADVANCED FUNCTIONAL MATERIALS 2022
Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFβR2 signaling pathway.
Cell death & disease
2022; 13 (3): 195
BRCA1 deficient breast cancers are aggressive and chemoresistant due, in part, to their enrichment of cancer stem cells that can be generated from carcinoma cells by an epithelial-mesenchymal transition (EMT). We previously discovered that BRCA1 deficiency activates EMT in mammary tumorigenesis. How BRCA1 controls EMT and how to effectively target BRCA1-deficient cancers remain elusive. We analyzed murine and human tumors and identified a role for Tgfβr2 in governing the molecular aspects of EMT that occur with Brca1 loss. We utilized CRISPR to delete Tgfβr2 and specific inhibitors to block Tgfβr2 activity and followed up with the molecular analysis of assays for tumor growth and metastasis. We discovered that heterozygous germline deletion, or epithelia-specific deletion of Brca1 in mice, activates Tgfβr2 signaling pathways in mammary tumors. BRCA1 depletion promotes TGFβ-mediated EMT activation in cancer cells. BRCA1 binds to the TGFβR2 locus to repress its transcription. Targeted deletion or pharmaceutical inhibition of Tgfβr2 in Brca1-deficient tumor cells reduces EMT and suppresses tumorigenesis and metastasis. BRCA1 and TGFβR2 expression levels are inversely related in human breast cancers. This study reveals for the first time that a targetable TGFβR signaling pathway is directly activated by BRCA1-deficiency in the induction of EMT in breast cancer progression.
View details for DOI 10.1038/s41419-022-04646-7
View details for PubMedID 35236825
SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer.
Cell reports. Medicine
2022; 3 (2): 100502
Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells invitro, cell-line and patient-derived xenografts invivo, and exvivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth invitro and invivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens.
View details for DOI 10.1016/j.xcrm.2021.100502
View details for PubMedID 35243415
Protein signatures to distinguish aggressive from indolent prostate cancer.
Distinguishing men with aggressive from indolent prostate cancer is critical to decisions in the management of clinically localized prostate cancer. Molecular signatures of aggressive disease could help men overcome this major clinical challenge by reducing unnecessary treatment and allowing more appropriate treatment of aggressive disease.We performed a mass spectrometry-based proteomic analysis of normal and malignant prostate tissues from 22 men who underwent surgery for prostate cancer. Prostate cancer samples included Grade Groups (3-5), with 8 patients experiencing recurrence and 14 without evidence of recurrence with a mean of 6.8 years of follow-up. To better understand the biological pathways underlying prostate cancer aggressiveness, we performed a systems biology analysis and gene enrichment analysis. Proteins that distinguished recurrent from nonrecurrent cancer were chosen for validation by immunohistochemical analysis on tissue microarrays containing samples from a larger cohort of patients with recurrent and nonrecurrent prostate cancer.In all, 24,037 unique peptides (false discovery rate < 1%) corresponding to 3,313 distinct proteins were identified with absolute abundance ranges spanning seven orders of magnitude. Of these proteins, 115 showed significantly (p < 0.01) different levels in tissues from recurrent versus nonrecurrent cancers. Analysis of all differentially expressed proteins in recurrent and nonrecurrent cases identified several protein networks, most prominently one in which approximately 24% of the proteins in the network were regulated by the YY1 transcription factor (adjusted p < 0.001). Strong immunohistochemical staining levels of three differentially expressed proteins, POSTN, CALR, and CTSD, on a tissue microarray validated their association with shorter patient survival.The protein signatures identified could improve understanding of the molecular drivers of aggressive prostate cancer and be used as candidate prognostic biomarkers.
View details for DOI 10.1002/pros.24307
View details for PubMedID 35098564
Loss of function of GATA3 induces basal-like mammary tumors.
2022; 12 (2): 720-733
Purpose: GATA3 is a transcription factor essential for mammary luminal epithelial cell differentiation. Expression of GATA3 is absent or significantly reduced in basal-like breast cancers. Gata3 loss-of-function impairs cell proliferation, making it difficult to investigate the role of GATA3 deficiency in vivo. We previously demonstrated that CDK inhibitor p18INK4c (p18) is a downstream target of GATA3 and restrains mammary epithelial cell proliferation and tumorigenesis. Whether and how loss-of-function of GATA3 results in basal-like breast cancers remains elusive. Methods: We generated mutant mouse strains with heterozygous germline deletion of Gata3 in p18 deficient backgrounds and developed a Gata3 depleted mammary tumor model system to determine the role of Gata3 loss in controlling cell proliferation and aberrant differentiation in mammary tumor development and progression. Results: Haploid loss of Gata3 reduced mammary epithelial cell proliferation with induction of p18, impaired luminal differentiation, and promoted basal differentiation in mammary glands. p18 deficiency induced luminal type mammary tumors and rescued the proliferative defect caused by haploid loss of Gata3. Haploid loss of Gata3 accelerated p18 deficient mammary tumor development and changed the properties of these tumors, resulting in their malignant and luminal-to-basal transformation. Expression of Gata3 negatively correlated with basal differentiation markers in MMTV-PyMT mammary tumor cells. Depletion of Gata3 in luminal tumor cells also reduced cell proliferation with induction of p18 and promoted basal differentiation. We confirmed that expression of GATA3 and basal markers are inversely correlated in human basal-like breast cancers. Conclusions: This study provides the first genetic evidence demonstrating that loss-of-function of GATA3 directly induces basal-like breast cancer. Our finding suggests that basal-like breast cancer may also originate from luminal type cancer.
View details for DOI 10.7150/thno.65796
View details for PubMedID 34976209
View details for PubMedCentralID PMC8692904
Identifying a novel glycolytic inhibitor for treatment of aggressive prostate cancer.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000680263506119
Trop2 regulates prostate cancer growth and metastasis through distinct molecular mechanisms.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000680263502050
A novel oncogene mediated metabolic gene signature predicts breast cancer outcome.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000680263505341
Circular RNA circHIPK3 promotes breast cancer progression via sponging MiR-326
2021; 20 (13): 1320-1333
Background: This study investigated the potential molecular mechanism of circular RNA HIPK3 (circHIPK3) in breast cancer (BCa). Methods: BCa cells were transfected with miR-326 mimic, miR-326 inhibitor, circHIPK3, sicircHIPK3. The expressions of circHIPK3 and miR-326 in BCa tissues and BCa cell lines were determined by RT-qPCR. Cell viability, colony formation, migration, invasion, and apoptosis of the cells were detected by CCK-8 and colony formation, wound-healing, transwell and flow cytometric assays, respectively. The relationship between circHIPK3 and miR-326 was analyzed and confirmed by circInteractome, dual-luciferase reporter, RT-qPCR, Pearson's correlation assays. Western blot and RT-qPCR were performed to determine the expressions of apoptosis-related molecules (Bcl-2, Bax, and cleaved Caspase-3) and EMT-related molecules (E-cadherin, N-cadherin, and Vimentin) in the BCa cells and tumor tissues. The tumor growth in mice was examined in a xenograft tumor model in which Ki-67 expression was determined by immunohistochemistry (IHC). Results: In BCa, the expression of circHIPK3 was up-regulated and that of miR-326 was down-regulated. CircHIPK3 knockdown inhibited the cell proliferation, invasion, and migration. MiR-326 was the direct target of circHIPK3, and was inversely correlated with circHIPK3 expression. CircHIPK3 overexpression promoted proliferation, migration, invasion, apoptosis resistance, and tumor growth and up-regulated Ki-67 expression, at the same time, the expressions of Bcl-2, N-cadherin, Vimentin were up-regulated, and those of Bax, cleaved Caspase-3 and E-cadherin were inhibited. These above expressions were partially reversed by miR-326 overexpression. Conclusion: CircHIPK3 sponges miR-326 to promote BCa growth and metastasis. The current findings provide a novel therapeutic target for treating BCa.
View details for DOI 10.1080/15384101.2021.1939476
View details for Web of Science ID 000664574100001
View details for PubMedID 34152928
View details for PubMedCentralID PMC8331001
The role of Trop2 in prostate cancer: an oncogene, biomarker, and therapeutic target.
American journal of clinical and experimental urology
2021; 9 (1): 73-87
Prostate cancer remains the second leading cause of cancer-associated deaths amongst American men. Trop2, a cell surface glycoprotein, correlates with poor clinical outcome and is highly expressed in metastatic, treatment-resistant prostate cancer. High levels of Trop2 are prognostic for biochemical recurrence. Trop2 regulates tumor growth and metastatic ability of prostate cancer. Moreover, overexpression of Trop2 drives the transdifferentiation to neuroendocrine phenotype in prostate cancer. In addition, Trop2 is overexpressed across epithelial cancers and has emerged as a promising therapeutic target in various solid epithelial cancers. The FDA (Food and Drug Administration) recently approved the use of a Trop2-targeting ADC (antibody-drug conjugate), Sacituzumab Govitecan (IMMU-132), for metastatic, triple-negative breast cancer with at least two prior therapies. Here, we review the role of Trop2 in prostate tumorigenesis and its potential as a promising biomarker and therapeutic target for prostate cancer.
View details for PubMedID 33816696
View details for PubMedCentralID PMC8012837
PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors.
Breast cancer research : BCR
2021; 23 (1): 10
Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed.Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers.Heterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfrβ signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrβ in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrβ and its downstream target Pkcα suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells.Our work offers the first genetic and biochemical evidence that PDGFRβ-PKCα signaling is repressed by BRCA1, which establishes PDGFRβ-PKCα signaling as a therapeutic target for BRCA1-deficient breast cancers.
View details for DOI 10.1186/s13058-021-01387-x
View details for PubMedID 33478572
View details for PubMedCentralID PMC7819225
Engineering Polysaccharide-Based Hydrogel Photonic Constructs: From Multiscale Detection to the Biofabrication of Living Optical Fibers.
Advanced materials (Deerfield Beach, Fla.)
Solid-state optics has been the pillar of modern digital age. Integrating soft hydrogel materials with micro/nanooptics could expand the horizons of photonics for bioengineering. Here, wet-spun multilayer hydrogel fibers are engineered through ionic-crosslinked natural polysaccharides that serve as multifunctional platforms. The resulting flexible hydrogel structure and reversible crosslinking provide tunable design properties such as adjustable refractive index and fusion splicing. Modulation of the optical readout via physical stimuli, including shape, compression, and multiple optical inputs/outputs is demonstrated. The unique permeability of the hydrogels is also combined with plasmonic nanoparticles for molecular detection of SARS-CoV-2 in fiber-coupled biomedical swabs. A tricoaxial 3D printing nozzle is then employed for the continuous fabrication of living optical fibers. Light interaction with living cells enables the quantification and digitalization of complex biological phenomena such as 3D cancer progression and drug susceptibility. These fibers pave the way for advances in biomaterial-based photonics and biosensing platforms.
View details for DOI 10.1002/adma.202105361
View details for PubMedID 34617338
MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer.
2021; 11 (1): 13305
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.
View details for DOI 10.1038/s41598-021-92552-x
View details for PubMedID 34172788
Quantifying the invasion and migration ability of cancer cells with a 3D Matrigel drop invasion assay.
Biology methods & protocols
2021; 6 (1): bpab014
Metastasis is the main cause of cancer-associated morbidity which will account for ∼ 600,000 deaths in the USA in 2021. Defining new mechanisms that drive cancer metastasis is vital for developing new therapeutic strategies and improving clinical outcomes for cancer patients. Herein, we describe a recently established 3D Matrigel drop invasion assay to measure cancer cell invasion and migration capability in vitro. This assay is a versatile and simple tool to test the ability of cells to invade and migrate, test the functional role of genes of interest in cell invasion and migration, analyze the localization of the target proteins at the cell invasion edge in situ, and screen drug effects on cancer cell invasion and migration.
View details for DOI 10.1093/biomethods/bpab014
View details for PubMedID 34377838
View details for PubMedCentralID PMC8346651
Oncogene-mediated metabolic gene signature predicts breast cancer outcome.
NPJ breast cancer
2021; 7 (1): 141
Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.
View details for DOI 10.1038/s41523-021-00341-6
View details for PubMedID 34711841
Plectin is a regulator of prostate cancer growth and metastasis.
Prostate cancer is responsible for over 30,000 US deaths annually, attributed largely to incurable metastatic disease. Here, we demonstrate that high levels of plectin are associated with localized and metastatic human prostate cancer when compared to benign prostate tissues. Knock-down of plectin inhibits prostate cancer cell growth and colony formation in vitro, and growth of prostate cancer xenografts in vivo. Plectin knock-down further impairs aggressive and invasive cellular behavior assessed by migration, invasion, and wound healing in vitro. Consistently, plectin knock-down cells have impaired metastatic colonization to distant sites including liver, lung, kidney, bone, and genitourinary system. Plectin knock-down inhibited number of metastases per organ, as well as decreased overall metastatic burden. To gain insights into the role of plectin in prostate cancer growth and metastasis, we performed proteomic analysis of prostate cancer plectin knock-down xenograft tissues. Gene set enrichment analysis shows an increase in levels of proteins involved with extracellular matrix and laminin interactions, and a decrease in levels of proteins regulating amino acid metabolism, cytoskeletal proteins, and cellular response to stress. Collectively these findings demonstrate that plectin is an important regulator of prostate cancer cell growth and metastasis.
View details for DOI 10.1038/s41388-020-01557-9
View details for PubMedID 33219316
Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.
Proceedings of the National Academy of Sciences of the United States of America
Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.
View details for DOI 10.1073/pnas.1905384117
View details for PubMedID 31932422
A specific immune tolerance toward offspring cells is to exist after the mother lymphocyte infusion
2017; 222 (4): 658–63
To examine immune tolerance between maternal lymphocytes and offspring tissue after a donor lymphocyte infusion.Mouse models were established by mating female BALB/c mice with male C57BL mice. Splenic lymphocytes from donors of different genetic backgrounds were labeled with carboxyfluorescein succinimidyl ester (CFSE), and 1×107 of the labeled cells were intravenously injected into a recipient. At 6h, 24h, 72h and 120h after the infusion, mononuclear cells in recipient spleen, liver, thymus, lymph nodes, and peripheral blood were collected. CFSE+, CFSE-, CD3+, CD8+, CD4+, CD19+, NK1.1+, CD25+, and CD127+ lymphocytes in those samples were analyzed by flow cytometry. The distribution of donor T cells, B cells, NK cells, helper T cells, cytotoxic T cells, and recipient regulatory T cells in the tissues were then analyzed.Maternal lymphocytes were more likely to survive in offspring. At 120h after infusion, the percentages of maternal cells in the offspring were 0.52±0.11% in lymph nodes, 0.97±0.04% in peripheral blood, and 0.97±0.11% in the spleen. Few donor cells, if any, were detected in these tissues at 120h after aunt to child, father to child, and unrelated allogeneic infusions were performed. The subtype proportion of donor lymphocytes changed significantly in the recipient tissues. Recipient Treg cells increased in the mother to child group, but not in the aunt to child, father to child, and unrelated allogeneic groups, suggesting a decreased cellular immune response to allogeneic cells in the mother to child group. At 120h after the infusion, no donor cells were detected in the recipient livers and thymuses of all groups, implying that donor cells were barely able to colonize in the liver and thymus.Specific immune tolerance to maternal lymphocytes exists in offspring. An infusion of maternal donor lymphocytes may produce a relatively persistent effect of adoptive immunotherapy with reduced side-effects.
View details for DOI 10.1016/j.imbio.2016.12.003
View details for Web of Science ID 000396960500008
View details for PubMedID 28065449
p16 loss rescues functional decline of Brca1-deficient mammary stem cells
2017; 16 (8): 759–64
Recent evidence indicates that the accumulation of endogenous DNA damage can induce senescence and limit the function of adult stem cells. It remains elusive whether deficiency in DNA damage repair is associated with the functional alteration of mammary stem cells. In this article, we reported that senescence was induced in mammary epithelial cells during aging along with increased expression of p16Ink4a (p16), an inhibitor of CDK4 and CKD6. Loss of p16 abrogated the age-induced senescence in mammary epithelial cells and significantly increased mammary stem cell function. We showed that loss of Brca1, a tumor suppressor that functions in DNA damage repair, in the mammary epithelium induced senescence with induction of p16 and a decline of stem cell function, which was rescued by p16 loss. These data not only answer the question as to whether deficiency in DNA damage repair is associated with the functional decline of mammary stem cells, but also identify the role of p16 in suppressing Brca1-deficient mammary stem cell function.
View details for DOI 10.1080/15384101.2017.1295185
View details for Web of Science ID 000399738300011
View details for PubMedID 28278054
View details for PubMedCentralID PMC5405722
p16(INK4a) suppresses BRCA1-deficient mammary tumorigenesis
2016; 7 (51): 84496–507
Senescence prevents the proliferation of genomically damaged, but otherwise replication competent cells at risk of neoplastic transformation. p16INK4A (p16), an inhibitor of CDK4 and CDK6, plays a critical role in controlling cellular senescence in multiple organs. Functional inactivation of p16 by gene mutation and promoter methylation is frequently detected in human breast cancers. However, deleting p16 in mice or targeting DNA methylation within the murine p16 promoter does not result in mammary tumorigenesis. How loss of p16 contributes to mammary tumorigenesis in vivo is not fully understood.In this article, we reported that disruption of Brca1 in the mammary epithelium resulted in premature senescence that was rescued by p16 loss. We found that p16 loss transformed Brca1-deficient mammary epithelial cells and induced mammary tumors, though p16 loss alone was not sufficient to induce mammary tumorigenesis. We demonstrated that loss of both p16 and Brca1 led to metastatic, basal-like, mammary tumors with the induction of EMT and an enrichment of tumor initiating cells. We discovered that promoter methylation silenced p16 expression in most of the tumors developed in mice heterozygous for p16 and lacking Brca1. These data not only identified the function of p16 in suppressing BRCA1-deficient mammary tumorigenesis, but also revealed a collaborative effect of genetic mutation of p16 and epigenetic silencing of its transcription in promoting tumorigenesis. To the best of our knowledge, this is the first genetic evidence directly showing that p16 which is frequently deleted and inactivated in human breast cancers, collaborates with Brca1 controlling mammary tumorigenesis.
View details for DOI 10.18632/oncotarget.13015
View details for Web of Science ID 000391353200057
View details for PubMedID 27811360
View details for PubMedCentralID PMC5356676
Immunophenotypic analysis of abnormal plasma cell clones in bone marrow of primary systemic light chain amyloidosis patients
CHINESE MEDICAL JOURNAL
2014; 127 (15): 2765–70
Primary systemic light chain amyloidosis (AL) is a rare plasma cell disease, our purpose was to analyze the immunophenotypic characteristics of the plasma cells in bone marrow in AL patients, and explore whether the detection of abnormal plasma cell clones in bone marrow by flow cytometry (FCM) could be used as an important indicator of AL diagnosis.Fresh bone marrow samples were collected from 51 AL, 21 multiple myeloma (MM), and 5 Waldenström's macroglobulinemia (WM) patients. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD38, CD138, CD117, CD56, and CD19.In AL, light chain restriction could be identified in 31 cases (60.9%), in which the λ light chain restriction was found in 24 cases (77.4%). In MM, κ light chain restriction was found in 13 cases (61.9%), and λ light chain restriction in eight cases. CD45 on abnormal plasma cells was negative to weakly positive in both AL and MM, but was positive to strongly positive in WM. In the bone marrow plasma cells of the 51 AL, 78.4% were CD56+, 68.6% were CD117+, and 88.2% were CD19-. While in the 21 MM cases, 66.7% were CD56+, 38.1% were CD117+, and 90.4% were CD19-. The plasmacytoid lymphocytes in the five WM patients were CD19+ and CD56-, CD117-.Detection of abnormal plasma cell clones in bone marrow by FCM is valuable for the diagnosis of AL.
View details for DOI 10.3760/cma.j.issn.0366-6999.20141053
View details for Web of Science ID 000340691000008
View details for PubMedID 25146610
[Identification of splenic marginal zone lymphoma from B lymphoproliferative disorders by flow cytometry].
Zhongguo shi yan xue ye xue za zhi
2014; 22 (2): 349-56
The splenic marginal zone lymphoma (SMZL) is a relatively rare chronic B lymphoproliferative disease, which primarily manifest increase of peripheral blood lymphocyte count and/or scale, and splenomegaly, while the peripheral superficial lymph nodes are often not swollen. Therefore, the splenectomy are usually needed to confirm the diagnosis, but the majority of patients could not accept such management, resulting in early difficult diagnosis. This study was purposed to explore the more prior way for diagnosis based flow cytometry (FCM). Six patients with suspected diagnosis of SMZL were used as research objects, 10 healthy bone marrow donors and 10 cases of chronic lymphocytic leukemia (CLL), 3 cases of hairy cell leukemia (HCL), 3 cases of lymphatic plasma cell lymphoma/Waldenströ's macroglobulinemia (LPL/WM) were selected as control. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD5, CD10, CD19, CD20, CD22, CD23, CD25, CD103, CD11c, CD123, κ,λ, Cyclin D1, and combined with bone marrow cell morphology. The results indicated that 6 cases of suspected SMZL showed a large increase of lymphocytes and splenomegaly. Because absence of peripheral lymphadenopathy, 6 patients did not suffer from lymph node biopsy, only 1 patient underwent diagnostic splenectomy. The immunophenotypes of bone marrow in patients and controls were analyzed by FCM, as a result, except for the healthy donors, varying degrees of abnormal mature B cell clones were found in bone marrow of all patients, and the further differentiation from other B-cell tumors was performed through CD5, CD10 expression and combination with other B-cell phenotype. All 6 cases of SMZL patients expressed CD19(+) and CD20(+), but CD10 expression was negative, 4 patients expressed CD5(-), 2 patients expressed CD5(+). The expressions of CD23, CD38, ZAP-70, CD11c, CD103, CD123, Cyclin D1 were negative. The morphological examination of bone marrow cells showed velutinous abnormal lymphocytes. Combined with clinical characteristics, 6 patients were diagnosed as SMZL, 1 patient suffered from splenectomy because of concurrent hypersplenism, and this postoperative pathologic examination confirmed the patient with SMZL. Ten cases of CLL mainly expressed CD5, CD23; 3 cases of HCL had more typical morphology of "hair like" in addition to CD11c, CD103 and CD123 positive; 3 cases of LPL/WM had significantly increased light chain restriction expression, IgM, plasmacytoid lymphocytes. It is concluded that the FCM immunophenotype analysis can be used as a powerful tools for clinical diagnosis of SMZL.
View details for DOI 10.7534/j.issn.1009-2137.2014.02.016
View details for PubMedID 24763004
- The Significance Of Abnormal Plasma Cell Clone In Bone Marrow Of Primary Systemic Light Chain Amyloidosis Patients AMER SOC HEMATOLOGY. 2013
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