Location: Cleveland Clinic Main Campus
As normal cells are transformed into cancer cells, they acquire a series of capabilities that allow them to multiply and spread uncontrollably. These capabilities include sustaining proliferative signaling and the ability to modify their cellular metabolism to support neoplastic growth (Hanahan D. and Weinberg R.A. 2011). The Chan lab is interested in (1) understanding how crosstalk between different cancer signaling pathways can promote or antagonize malignant transformation, and (2) studying how metabolic status, flexibility and plasticity evolve during disease progression, with an emphasis on hematological malignancies. Development of drug resistance and relapse remains a critical challenge in the treatment of patients with hematologic cancers. We aim to use the knowledge gained from our studies to identify disease-specific vulnerabilities to improve precision medicine.
Dr. Lai (Linda) Chan completed her PhD with Dr. Fuyuhiko Tamanoi at the University of California Los Angeles where she applied a chemical biology approach to study lipid posttranslational modifications of RAS family of small G-proteins in solid tumors. For her postdoctoral training, she joined Dr. Markus Müschen’s laboratory at Children’s Hospital Los Angeles and later at the University of California San Francisco to investigate mechanisms that drive disease progression and therapeutic responses in B-cell malignancies. She uncovered the unexpected involvement of frequent genetic inactivation in B-lymphoid transcription factors, e.g. IKZF1 and PAX5, in elevating glucose and energy supply to fuel leukemic transformation. This study resulted in several travel awards from the American Society of Hematology (ASH) and the American Association for Cancer Research and a publication in Nature (‘Metabolic gatekeeper function of B-lymphoid transcription factors,’ 2017).
As an Assistant Research Professor at the City of Hope NCI Comprehensive Cancer Center, she discovered that efficient transformation in B-cell acute lymphoblastic leukemia (B-AL) requires convergence on a central oncogenic driver and that genetic lesions non-aligned with the central pathway are counterproductive. Notably, she established a platform for single-cell phosphoprotein analysis and developed an innovative therapeutic concept based on pharmacological reactivation of the divergent pathway to subvert leukemic transformation. For this work, she received a travel award from ASH and authored a publication in Nature (‘Signalling input from divergent pathways subverts B-cell transformation,’ 2020). More recently, at Yale University, she investigated the molecular mechanisms underpinning pathogenesis of RAS-driven B-ALL. RAS-pathway genetic lesions are oncogenic drivers in ~40% of B-ALL cases and are associated with high-risk clinical features including relapse and chemoresistance. The goal of her study was to identify new therapeutic targets in this disease to ameliorate long-term clinical outcome. Currently, she is an Assistant Staff in the Department of Cancer Biology at the Lerner Research Institute, Cleveland Clinic.
Education and Research Experience
Honors and Awards
Dr. Chan’s research is focused on how oncogenic signaling pathways interact in hematological malignancies and how such interactions can influence malignant transformation and disease progression. Using multi-disciplinary approaches including cell and molecular biology, biochemistry, chemical biology, immunology, mouse genetics and CRISPR-based gene editing, we aim (1) to develop a target discovery platform based on disease-specific pathway interactions, and (2) to identify new combination therapies to prevent drug resistance which remains a central challenge in treatment of hematologic cancers.
The metabolic status of cancer cells can be influenced by both intrinsic (e.g. dysregulation of signal transduction and transcription factor activity) and extrinsic (e.g. nutrient availability, interactions with surrounding stromal cells, tumor locations) mechanisms. Thus, to effectively target cancer metabolism for therapeutic intervention, it is crucial to consider the tumor’s genotype, tumor microenvironment, and tissue-specific metabolite composition. The second arm of Dr. Chan’s research will be focused on investigating how metabolic status, flexibility and plasticity evolve during disease progression in hematologic cancers. Particularly, we are interested in understanding how cancer cell metabolism and the host microenvironment can control cancer development and metastasis (dissemination). We aim to identify disease-specific metabolic checkpoints for therapeutic intervention.
Pan L*, Hong C*, Chan LN*§, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras S, Wang S, Wajapeyee N & Müschen M§. PON2 subverts metabolic gatekeeper functions in B-cells to promote leukemogenesis. Proc Natl Acad Sci USA (2021) 118: e2016553118. (*contributed equally to this study. §corresponding author.)
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Diversity, Equity and Inclusion Statement:
Differences in gender, race, ethnicity, language and socioeconomic status have a major bearing on opportunities and security. Therefore, our lab is committed to creating an inviting environment where underrepresented minorities, women, and socioeconomically underprivileged students and postdoctoral fellows can have the tools and resources they need to achieve their educational and career goals.
Apart from ethnicity and gender, diversity encompasses differences in one’s academic background, scientific training, and general thought process. We understand that being in an inclusive environment can elevate our research, allow us to learn from others, facilitate problem solving and lead to innovation. For this reason, our goal is to provide an inclusive environment where everyone can freely voice their opinions.
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