Honors & Awards
Fellowship for Ph.D. research studies abroad, German academic exchange program (DAAD) (11/2011-10/2012)
Fellowship for Diploma thesis research, DAAD (08/2010-11/2010)
Diploma fellowship, PROSA LMU (06/2010-07/2010)
Core Exploratory Award, UC San Francisco (05/2012-04/2013)
Woman in Cancer Research Award, WICR (04/2015)
Current Research and Scholarly Interests
My research focuses on understanding the evolution of tumor cell populations, on how selective pressures, such as those imposed by chemo- and radiotherapies, favor the survival of one tumor cell population over another. Towards this goal I develop algorithms that measure intra-tumor heterogeneity from next-generation sequencing data or from more traditional diagnostic procedures, such as H&E stainings.
My long-term goal is to develop an adaptable therapeutic strategy that vastly increases the number of alternative therapy options and that rationalizes therapy choice.
EXPANDS: expanding ploidy and allele frequency on nested subpopulations
2014; 30 (1): 50-60
Several cancer types consist of multiple genetically and phenotypically distinct subpopulations. The underlying mechanism for this intra-tumoral heterogeneity can be explained by the clonal evolution model, whereby growth advantageous mutations cause the expansion of cancer cell subclones. The recurrent phenotype of many cancers may be a consequence of these coexisting subpopulations responding unequally to therapies. Methods to computationally infer tumor evolution and subpopulation diversity are emerging and they hold the promise to improve the understanding of genetic and molecular determinants of recurrence.To address cellular subpopulation dynamics within human tumors, we developed a bioinformatic method, EXPANDS. It estimates the proportion of cells harboring specific mutations in a tumor. By modeling cellular frequencies as probability distributions, EXPANDS predicts mutations that accumulate in a cell before its clonal expansion. We assessed the performance of EXPANDS on one whole genome sequenced breast cancer and performed SP analyses on 118 glioblastoma multiforme samples obtained from TCGA. Our results inform about the extent of subclonal diversity in primary glioblastoma, subpopulation dynamics during recurrence and provide a set of candidate genes mutated in the most well-adapted subpopulations. In summary, EXPANDS predicts tumor purity and subclonal composition from sequencing data.EXPANDS is available for download at http://code.google.com/p/expands (matlab version--used in this manuscript) and http://cran.r-project.org/web/packages/expands (R version).
View details for DOI 10.1093/bioinformatics/btt622
View details for Web of Science ID 000329059700008
View details for PubMedID 24177718
Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
2016; 22 (1): 105-113
Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.
View details for DOI 10.1038/nm.3984
View details for PubMedID 26618723
Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma
2014; 20 (12): 1394-1396
Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.
View details for DOI 10.1038/nm.3716
View details for Web of Science ID 000345817900013
View details for PubMedID 25401693
- BIOLOGICALLY-BASED THERAPEUTICS FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS 20th International Conference on Brain Tumor Research and Therapy OXFORD UNIV PRESS INC. 2014
- STEM- AND PROGENITOR-LIKE CELL CONTRIBUTION TO MALIGNANT ASTROCYTOMA HETEROGENEITY 20th International Conference on Brain Tumor Research and Therapy OXFORD UNIV PRESS INC. 2014
Asymmetry-Defective Oligodendrocyte Progenitors Are Glioma Precursors
2011; 20 (3): 328-340
Postnatal oligodendrocyte progenitor cells (OPC) self-renew, generate mature oligodendrocytes, and are a cellular origin of oligodendrogliomas. We show that the proteoglycan NG2 segregates asymmetrically during mitosis to generate OPC cells of distinct fate. NG2 is required for asymmetric segregation of EGFR to the NG2(+) progeny, which consequently activates EGFR and undergoes EGF-dependent proliferation and self-renewal. In contrast, the NG2(-) progeny differentiates. In a mouse model, decreased NG2 asymmetry coincides with premalignant, abnormal self-renewal rather than differentiation and with tumor-initiating potential. Asymmetric division of human NG2(+) cells is prevalent in non-neoplastic tissue but is decreased in oligodendrogliomas. Regulators of asymmetric cell division are misexpressed in low-grade oligodendrogliomas. Our results identify loss of asymmetric division associated with the neoplastic transformation of OPC.
View details for DOI 10.1016/j.ccr.2011.08.011
View details for Web of Science ID 000295205700009
View details for PubMedID 21907924