LAB PROJECTS

TNBC-specific epigenetic landscape for uncovering novel cancer driver genes

Key genomic alterations associated with different subtypes of breast cancer have been comprehensively studied. However, deregulation of epigenome in different breast cancer subtypes remains poorly characterized. Using multiomic profiling coupled with Crispr/Cas9 gene editing, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes, and identified oncogenes that are specifically regulated by TNBC-specific super-enhancers. We aim at leveraging the epigenetic landscape to identify novel TNBC players, and determine how they drive tumorigenesis, for developing prognostic and therapeutic modalities.

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Patient-derived breast tumor organoids: genomic and functional studies for the characterization of different subtypes of breast cancer

Our laboratory aims at generating organoids from freshly resected breast tumors. High-throughput sequencing and comprehesive genomic analysis will be performed on these patient-derived organoids to identify novel genes and pathways perturbed by genetic alterations in TNBC. We will also use these tumor organoids to study patient-specific differences in pathway dependency, and screen compounds to identify personalized therapy strategies.

Dissecting mechanisms of TNBC brain metastasis colonization

Brain metastasis is commonly observed in TNBC patients, and is often fatal. Furthermore, increased frequency of brain metastasis is found in young and premenopausal patients of TNBC. The brain microenvironment contains unique sets of cell types that imposes selective pressure on tumor cells. Recent studies, however, have demonstrated that tumor cells can interact with astrocytes, microglia and neurons to promote their metastatic outgrowth. We have set up in vivo brain metastasis model and 3D co-culture systems which allow us to examine functions of TNBC genes in brain microenvironment. By performing Crispr screening, we anticipate to uncover novel genes that could be targeted to halt brain metastasis.

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Akt isoform-specific function in breast cancer growth and therapy resistance

The three isoforms of Akt (Akt1-3) were originally thought to function redundantly in pathophysiology. Our work uncovered distinct functions of Akt isoforms in tumorigenesis. We have identified an actin-bundling protein palladin as an Akt1-specific substrate, and further provided a molecular mechanism that accounts for the functional distinction between Akt isoforms in breast cancer metastasis. In addition, by modulating gene function in a temporally controlled manner in 3D culture, we have uncovered a distinct dependency of PTEN-deficient cancer cell survival on Akt2. Furthermore, our studies revealed a key function of Akt3 in regulating TNBC growth and therapeutic resistance. These findings underscored the importance of precisely dissecting the molecular mechanisms of Akt isoforms in order to identify potential synthetic lethal interactions. We have developed a genome-wide, mass spectrometry-based proteomic strategy to identify novel Akt isoform-specific targets. Live cell imaging is also utilized to examine the intracellular dynamics in a real-time manner. The goal is to identify novel biomarkers and therapeutic targets, as well as design new mechanism-based inhibitors and combination strategies to circumvent resistance.