- Pediatric Liver Tumors
- Cancer Genetics & Genomics
- Pediatric Hematology-Oncology
Instructor, Pediatrics - Hematology & Oncology
Honors & Awards
Forbeck Scholar Award, William Guy Forbeck Research Foundation (2022)
Damon Runyon-Jake Wetchler Award for Pediatric Innovation, Jake Wetchler Foundation/DRCRF (2021)
Damon Runyon-Sohn Pediatric Cancer Fellowship Award, Damon Runyon Cancer Research Foundation (2019-2023)
Ernest and Amelia Gallo Endowed Postdoctoral Fellowship, Stanford Maternal & Child Health Research Institute (2017-2019)
Days of Molecular Medicine Global Foundation Fellows Award, DMM Global Foundation (2012)
Individual Predoctoral Kirschstein-NRSA F30 Fellowship, NIH/NIA (2009-2012)
William Randolph Hearst Fellow, The Rockefeller University (2008)
Phi Beta Kappa, MIT (2004)
Whitehead Prize (outstanding promise for research career), MIT Dept of Biology (2004)
Merck Index Award (outstanding scholarship), MIT Dept of Chemistry (2004)
Burchard Scholar, MIT School of Humanities, Arts, & Social Sciences (2002-2003)
Boards, Advisory Committees, Professional Organizations
Member, Children's Oncology Group (2016 - Present)
Member, American Society of Pediatric Hematology/Oncology (2016 - Present)
Member, American Society of Clinical Oncology (2019 - Present)
Fellowship: Stanford University Pediatric Hematology Oncology Fellowship (2019) CA
Board Certification: American Board of Pediatrics, Pediatrics (2017)
Residency: UCSF Pediatric Residency (2016) CA
Medical Education: Weill Cornell Medical College (2013) NY
Ph.D., The Rockefeller University (2012)
S.B., Massachusetts Institute of Technology, Chemistry, Biology, Literature (minor) (2004)
Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver.
Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of systemic FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.
View details for DOI 10.7554/eLife.82311
View details for PubMedID 36719070
View details for PubMedCentralID PMC9889086
Current Approaches in Hepatoblastoma-New Biological Insights to Inform Therapy.
Current oncology reports
As the most common pediatric primary liver cancer with rising incidence, hepatoblastoma remains challenging to treat. Here, we review the current understanding of the biology of hepatoblastoma and discuss how recent advances may lead to new treatment modalities.Standard chemotherapy regimens including cisplatin, in addition to surgery, have led to high cure rates among patients with low stage hepatoblastoma; however, metastatic and relapsed disease continue to have poor outcomes. Recent genomics and functional studies in cell lines and mouse models have established a central role for the Wnt/β-catenin pathway in tumorigenesis. Targeted agents and immunotherapy approaches are emerging as potential treatment avenues. With recent gains in knowledge of the genomic and transcriptomic landscape of hepatoblastoma, new therapeutic mechanisms can now be explored to improve outcomes for metastatic and relapsed hepatoblastoma and to reduce the toxicity of current treatments.
View details for DOI 10.1007/s11912-022-01230-2
View details for PubMedID 35438389
Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
2022; 119 (30): e2203849119
View details for DOI 10.1073/pnas.2203849119
3D Culture of Primary Patient-Derived Hepatoblastoma Tumoroids
Methods in Molecular Biology
View details for DOI 10.1007/978-1-0716-2557-6_19
PATIENT-DERIVED HEPATOBLASTOMA TUMOR ORGANOIDS MAINTAINED PATIENT SPECIFIC FEATURES FROM FRESHLY ISOLATED PARENT CELLS AND CAN BE USED TO GENERATE A PATIENT SPECIFIC DRUG SENSITIVITY PROFILE
WILEY. 2021: 144A-145A
View details for Web of Science ID 000707188000218
PATIENT-DERIVED HEPATOBLASTOMA TUMOROIDS DEPEND ON BOTH RTK SIGNALING AND WNT ACTIVATION
WILEY. 2021: S69
View details for Web of Science ID 000642514400137
- Inflammatory Cytokine TNF alpha Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture CELL 2018; 175 (6): 1607-+
Telomeric 3 ' Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CST
2012; 150 (1): 39-52
A 3' overhang is critical for the protection and maintenance of mammalian telomeres, but its synthesis must be regulated to avoid excessive resection of the 5' end, which could cause telomere shortening. How this balance is achieved in mammals has not been resolved. Here, we determine the mechanism for 3' overhang synthesis in mouse cells by evaluating changes in telomeric overhangs throughout the cell cycle and at leading- and lagging-end telomeres. Apollo, a nuclease bound to the shelterin subunit TRF2, initiates formation of the 3' overhang at leading-, but not lagging-end telomeres. Hyperresection by Apollo is blocked at both ends by the shelterin protein POT1b. Exo1 extensively resects both telomere ends, generating transient long 3' overhangs in S/G2. CST/AAF, a DNA polα.primase accessory factor, binds POT1b and shortens the extended overhangs produced by Exo1, likely through fill-in synthesis. 3' overhang formation is thus a multistep, shelterin-controlled process, ensuring functional telomeric overhangs at chromosome ends.
View details for DOI 10.1016/j.cell.2012.05.026
View details for Web of Science ID 000306115000005
View details for PubMedID 22748632
View details for PubMedCentralID PMC3392515
Apollo Contributes to G Overhang Maintenance and Protects Leading-End Telomeres
2010; 39 (4): 606-617
Mammalian telomeres contain a single-stranded 3' overhang that is thought to mediate telomere protection. Here we identify the TRF2-interacting factor Apollo as a nuclease that contributes to the generation/maintenance of this overhang. The function of mouse Apollo was determined using Cre-mediated gene deletion, complementation with Apollo mutants, and the TRF2-F120A mutant that cannot bind Apollo. Cells lacking Apollo activated the ATM kinase at their telomeres in S phase and showed leading-end telomere fusions. These telomere dysfunction phenotypes were accompanied by a reduction in the telomeric overhang signal. The telomeric functions of Apollo required its TRF2-interaction and nuclease motifs. Thus, TRF2 recruits the Apollo nuclease to process telomere ends synthesized by leading-strand DNA synthesis, thereby creating a terminal structure that avoids ATM activation and resists end-joining. These data establish that the telomeric overhang is required for the protection of telomeres from the DNA damage response.
View details for DOI 10.1016/j.molcel.2010.06.031
View details for Web of Science ID 000281421100013
View details for PubMedID 20619712
View details for PubMedCentralID PMC2929323
Human Telomerase caught in the Act
2009; 138 (3): 432-434
Based on prior work, it was expected that telomerase would preferentially elongate the shortest telomeres in a cell, extending the telomeric G-rich strand through a process that is coupled to the synthesis of the complementary strand. Contrary to this view, Zhao et al. (2009) now show that telomerase in human cancer cells extends most telomeres during every S phase and that complementary strand synthesis does not immediately follow telomerase action.
View details for DOI 10.1016/j.cell.2009.07.018
View details for Web of Science ID 000268771900009
View details for PubMedID 19665967
No overt nucleosome eviction at deprotected telomeres
MOLECULAR AND CELLULAR BIOLOGY
2008; 28 (18): 5724-5735
Dysfunctional telomeres elicit the canonical DNA damage response, which includes the activation of the ATM or ATR kinase signaling pathways and end processing by nonhomologous end joining (NHEJ) or homologous recombination (HR). The cellular response to DNA double-strand breaks has been proposed to involve chromatin remodeling and nucleosome eviction, but whether dysfunctional telomeres undergo chromatin reorganization is not known. Here, we report on the nucleosomal organization of telomeres that have become deprotected through the deletion of the shelterin components TRF2 or POT1. We found no evidence of changes in the nucleosomal organization of the telomeric chromatin or nucleosome eviction near the telomere terminus. An unaltered chromatin structure was observed at telomeres lacking TRF2, which activate the ATM kinase and are a substrate for NHEJ. Similarly, telomeres lacking POT1a and POT1b, which activate the ATR kinase, showed no overt nucleosome eviction. Finally, telomeres lacking TRF2 and Ku70, which are processed by HR, appeared to maintain their original nucleosomal organization. We conclude that ATM signaling, ATR signaling, NHEJ, and HR at deprotected telomeres can take place in the absence of overt nucleosome eviction.
View details for DOI 10.1128/MCB.01764-07
View details for Web of Science ID 000258951000014
View details for PubMedID 18625717
View details for PubMedCentralID PMC2546919
Assessment of antiangiogenic effect using 99mTc-EC-endostatin.
Cancer biotherapy & radiopharmaceuticals
2002; 17 (2): 233-45
Tumor vascular density may provide a prognostic indicator of metastatic potential or survival. The purpose of this study was to develop 99mTc-ethylenedicysteine-endostatin (99mTc-EC-endostatin) for the evaluation of anti-angiogenesis therapy.99mTc-EC-endostatin was prepared by conjugating ethylenedicysteine (EC) to endostatin, followed by adding pertechnetate and tin chloride. Radiochemical purity was > 95%. In vitro cell viability, affinity and TUNEL assays were performed. Tissue distribution and planar imaging of radiolabeled endostatin were determined in tumor-bearing rats. To assess anti-angiogenic treatment response, rats were treated with endostatin, paclitaxel and saline, followed by imaging with 99mTc-EC-endostatin. Tumor response to endostatin therapy in tumor-bearing animal models was assessed by correlating tumor uptake dose with microvessel density, VEGF, bFGF and IL-8 expression during endostatin therapy.In vitro cell viability and TUNEL assays indicated no marked difference between EC-endostatin and endostatin. Cellular uptake assay suggests that endostatin binds to endostatin receptor. Biodistribution of 99mTc-EC-endostatin in tumor-bearing rats showed increased tumor-to-tissue count density ratios as a function of time. Tumor uptake (%ID/g) of 99mTc-EC-endostatin was 0.2-0.5. Planar images confirmed that the tumors could be visualized clearly with 99mTc-EC-endostatin. The optimal time for imaging using radiolabeled endostatin was 2 hrs. 99mTc-EC-endostatin could assess treatment response. There was a correlation between tumor uptake and cellular targets expression.The results indicate that it is feasible to use 99mTc-EC-endostatin to assess efficiency of anti-angiogenesis therapy.
View details for DOI 10.1089/108497802753773856
View details for PubMedID 12030117
In vivo and in vitro measurement of apoptosis in breast cancer cells using 99mTc-EC-annexin V.
Cancer biotherapy & radiopharmaceuticals
2001; 16 (1): 73-83
The purpose of this study was to develop an imaging technique to measure and monitor tumor cells undergoing programmed death caused by radiation and chemotherapy using 99mTc-EC-annexin V. Annexin V has been used to measure programmed cell death both in vitro and in vivo. Assessment of apoptosis would be useful to evaluate the efficacy and mechanisms of therapy and disease progression or regression.Ethylenedicysteine (EC) was conjugated to annexin V using sulfo-N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl as coupling agents. The yield of EC-annexin V was 100%. In vitro cellular uptake, pre- and post-radiation (10-30 Gy) and paclitaxel treatment, was quantified using 99mTc-EC-annexin V. Tissue distribution and planar imaging of 99mTc-EC-annexin V were determined in breast tumor-bearing rats at 0.5, 2, and 4 hrs. To demonstrate in vivo cell apoptosis that occurred during chemotherapy, a group of rats was treated with paclitaxel and planar imaging studies were conducted at 0.5-4 hrs. Computer outlined region of interest (ROI) was used to quantify tumor uptake on day 3 and day 5 post-treatment.In vitro cellular uptake showed that there was significantly increased uptake of 99mTc-EC-annexin V after irradiation (10-30 Gy) and paclitaxel treatment. In vivo biodistribution of 99mTc-EC-annexin in breast tumor-bearing rats showed increased tumor-to-blood, tumor-to-lung and tumor-to-muscle count density ratios as a function of time. Conversely, tumor-to-blood count density ratios showed a time-dependent decrease with 99mTc-EC in the same time period. Planar images confirmed that the tumors could be visualized clearly with 99mTc-EC-annexin. There was a significant difference of ROI ratios between pre- and post-paclitaxel treatment groups at 2 and 4 hrs post injection.The results indicate that apoptosis can be quantified using 99mTc-EC-annexin and that it is feasible to use 99mTc-EC-annexin to image tumor apoptosis.
View details for DOI 10.1089/108497801750096087
View details for PubMedID 11279800