Overall goal is to pursue a research program that utilizes functional genomics approaches and state-of-the-art tools for the understanding and unraveling of cellular and molecular underpinnings of carcinogenesis and develops effective strategies for the discovery of cancer vulnerabilities, and hence potential future cancer drug targets.  In this context, we are interested in the following research themes: (i) understanding why and how non-small cell lung cancer (NSCLC) cells become resistant to targeted therapies, (ii) mapping out cancer cell essential genes and dependencies across cancer types using functional genomics screens, (iii) understanding and mining of the molecular mechanisms of cancer cell senescence and identifying novel druggable cellular targets in senescence-resistance.

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In order to do so, our lab is adopting the most comprehensive tools and relevant models for the examination of biological pathways and disease pathobiology.

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1. Cancer cell plasticity driven by Transforming Growth Factor Beta (TGF-β)-induced Epithelial-Mesenchymal Transition (EMT) reprogramming is a fundamental cell fate determination event in acquired drug resistance to EGFR-Tyrosine Kinase Inhibitors (EGFR-TKi) in NSCLC. Notably, our preliminary studies pointed out that EGFR-TKi resistant cells have a unique EMT-associated secretome which modulates complex and dynamic signaling networks and can be recapitulated by TGF-β treatment. In particular, we showed that autocrine loops between TNF- and TGF-β pathways play a key role in driving the resistance. Within the scope of this research theme, we are harnessing next generation genomic tools and various cellular models to define the molecular aspects of resistance to novel EGFR-TKi, in particular we are focusing on the identification and characterization of signaling factors by which the complex and multifaceted EMT program facilitates cellular communication and governs cell fate decisions in acquired resistance. We hope that our studies will further expand our understanding on the complex network of intracellular effectors and TGF-β pathway dynamics that correspond to drug resistance phenotypes in NSCLC.

2. Future drug targets are expected to emerge from high-throughput functional genomics screening technologies supported by genome engineering approaches and bioinformatics tools that identify the mechanisms regulating biological processes. Functional studies aimed at defining cancer drug targets are driven by the premise that genetic and/or non-genetic alterations modify the dependencies of cancer cells, making them highly vulnerable to the loss of driving alterations and to addictions that the cancer cell state achieves. Therefore, systematic interrogation of the functional basis of cancer by determining genes essential for growth and related phenotypes in different cancer cells is central to this research theme. Recent advancements in functional genomics screening platforms allow us to designate gene essentiality and dependency and characterize cancer vulnerabilities. Our lab is utilizing CRISPR-Cas9 technology to uncover cancer cell essential genes and delineate vulnerabilities in in vitro cellular models of bladder cancer and malignant pleural mesothelioma. Here, we are performing pooled screens using genome-wide lentivirus-based screening libraries for sgRNA delivery and Cas9 expression.

3. Previously, we showed that TGF-β pathway could provoke senescence in various in vitro and in vivo cellular models of early stage hepatocellular carcinoma (HCC) via induction of reactive oxygen species by Nox4, suggesting the potential use of pro-senescence therapies as tumor suppressive mechanisms to limit tumor growth and spreading. More importantly, we showed that cells normally undergoing TGF-β-induced senescence were able to generate resistant clones while still preserving an intact signaling state. These new findings allowed us to shed light on the mechanisms of intrinsic/acquired senescence-resistance in late stage HCCs. Currently, we are working to further define and characterize the molecular aspects of this resistance phenomenon using functional genomics approaches such as whole-genome transcriptomic analysis, RNAi and CRISPR-Cas9. Taken together, we strongly believe that such studies will help us uncover novel genes and pathways regulating cellular signaling mechanisms driving senescence-resistance in HCC.

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RESEARCH HIGHLIGHTS

We undertake a wide range of research efforts focused on the following major areas of investigation: (1) identification and characterization of the mechanisms driving cancer; (2) druggable target identification and validation against such mechanisms. The close proximity to basic and translational research for interdisciplinary collaboration is invaluable in the selection and validation of novel cancer drug discovery targets. Our lab is at the center of characterization of cancer-specific vulnerabilities using high-throughput data combined with information on genomic abnormalities in order to increase research opportunities and support improved treatment of such diseases.