Research
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.
Biography
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 & Professional Highlights
Research Experience
- Research Scientist (Research Faculty) – Yale University, Yale Cancer Center
Center of Molecular and Cellular Oncology
New Haven, CT USA
2022 - Assistant Research Professor – City of Hope NCI Comprehensive Cancer Center
Department of Systems Biology
Duarte, CA USA
2020
Education and Training
- Postdoctoral Fellow – University of California, San Francisco
Department of Laboratory Medicine
San Francisco, CA USA
- University of California, Los Angeles
PhD in Molecular Biology
Los Angeles, CA USA
Awards
- DeLuca Center for Innovation in Hematology Research Pilot Award, 2021-2022
- Cleveland Clinic Foundation Caregiver Catalyst Grant, 2023-2024
- American Cancer Society IRG Award, 2023-2024
- WES Leukemia Research Foundation, 2024-2025
- VeloSano 10 Pediatric Pilot Award, 2024-2026
- Ohio Cancer Research Grant, 2024-2026
- Gabrielle's Angel Foundation for Cancer Research Medical Research Award, 2024-2027
Research
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.
Our Team
Selected Publications
- Watanabe M, Fiji HD, Guo L, Chan L, Kinderman SS, Slamon DJ, Kwon O, Tamanoi F. Inhibitors of protein geranylgeranyltransferase I and Rab geranylgeranyltransferase identified from a library of allenoate-derived compounds. J Biol. Chem. (2008) 283:9571-9579.
- Chan LN*, Hart C*, Guo L, Nyberg T, Davies BSJ, Fong LG, Young SG, Agnew BJ, Tamanoi F. A novel approach to tag and identify geranylgeranylated proteins. Electrophoresis (2009) 30:3598-3606. (*contributed equally to this study)
- Lu J, Chan L, Fiji HD, Dahl R, Kwon O, Tamanoi F. In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase I. Mol. Cancer Ther. (2009) 8:1218-26.
- Chan LN, Fiji HDG, Watanabe M, Kwon O, Tamanoi F. Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I. PLoS One (2011) 6:e26135.
- Zimonjic DB, Chan LN, Tripathi V, Lu J, Kwon O, Popescu NC, Lowy DR, Tamanoi F. In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells. BMC Cancer (2013) 13:198.
- Ramezani-Rad P, Geng H, Chen Z, Chan LN, Jumaa H, Melnick A, Paietta E, Carroll WL, Willman CL, Lefebvre V, Müschen M. SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood (2013) 121:148-155.
- Kharabi Masouleh B, Geng H, Hurtz C, Chan LN, Logan AC, Chang MS, Huang C, Swaminathan S, Sun H, Paietta E, Melnick AM, Koeffler P, Müschen M. Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA (2014) 111: E2219-2228.
- Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, Müschen M. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell (2015) 28:114-128.
- Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Mark Ansel K, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia. Cancer Cell (2015) 27:409-425.
- Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A, Cazzaniga G, Melnick A, Kornblau SM, Graeber TG, Wu H, Jumaa H, Müschen M. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat. Med. (2016) 22:379-387.
- Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus Z, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, Müschen M. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature (2017) 542:479-483.
- Chan LN§, Müschen M. B cell identity as a metabolic barrier against malignant transformation. Exp. Hematol. (2017) 53:1-6. (§corresponding author)
- Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang, QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Müschen M. B-cell-specific diversion of glucose carbon utilization reveals a unique vulnerability in B cell malignancies. Cell (2018) 173:470-484.
- Martín-Lorenzo A*, Auer F*, Chan LN*, García-Ramírez I, Gonzalez-Herrero I, Rodríguez-Hernández G, Bartenhagen C, Dugas M, Gombert M, Ginzel S, Blanco O, Orfao A, Alonso-López D, De Las Rivas J, Begoña García-Cenador M, Javier García Criado F, Müschen M, Sánchez-García I, Borkhardt A, Vicente-Dueñas C, Hauer J. Loss of Pax5 exploits Sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL. Cancer Res. (2018) 78:10. (*contributed equally to this study)
- Hurtz C*, Chan LN*, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Chen CW, Armstrong SA, Chen J, Ernst P, Melnick A, Milne T, Müschen M. Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia. Genes Dev. (2019) 33:1265-1279. (*contributed equally to this study)
- Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed AM, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Pölönen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM & Müschen M. Signalling input from divergent pathways subverts B cell transformation. Nature (2020) 583:845-851.
- Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature (2020) 588:491-497.
- 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.)
- Qing Y, Dong L, Gao L, Li C, Li Y, Han L, Prince E, Tan B, Deng X, Wetzel C, Shen C, Gao M, Chen Z, Li W, Zhang B, Braas D, Ten Hoeve J, Sanchez GJ, Chen H, Chan LN, Chen CW, Ann D, Jiang L, Müschen M, Marcucci G, Plas DR, Li Z, Su R, Chen J. R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis. Molecular Cell (2021) 81:922-939.e9.
- Sadras T, Chan LN, Xiao G, Müschen M. Metabolic gatekeepers of pathological B cell activation. Annu. Rev. Pathol. (2021) 16:323-349.
- Chan LN, Aghania E, Leveille E, Müschen M. Metabolic determinants of B-cell selection. Biochem. Soc. Trans. (2021) 39:1467-1478.
- Leveille E, Chan LN, Mirza AS, Kume K, Müschen M. SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cell Signal. (2022) 94:110331.
- Li M, Yang L, Chan AKN, Pokharel SP, Liu Q, Mattson N, Xu X, Chang WH, Miyashita K, Singh P, Zhang L, Li M, Wu J, Wang J, Chen B, Chan LN, Lee J, Zhang XH, Rosen ST, Müschen M, Qi J, Chen J, Hiom K, Bishop AJR, Chen CW. Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1-EEF1A1 Axis. Adv Sci (Weinh). (2023) 19:e2206584.
- Samiksha, Chan LN. Unlocking the therapeutic potential of targeting MALT1 in B-cell acute lymphoblastic leukemia. Haematologica (2023) doi: 10.3324/haematol.2023.284237.
- Chan AKN, Han L, Delaney CD, Wang X, Mukhaleva E, Li M, Yang L, Pokharel SP, Mattson N, Garcia M, Wang B, Xu X, Zhang L, Singh P, Elsayed Z, Chen R, Kuang B, Wang J, Yuan YC, Chen B, Chan LN, Rosen ST, Horne D, Müschen M, Chen J, Vaidehi N, Armstrong SA, Su R, Chen CW. Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery. Sci Adv. (2024) 10(8):eadk3127.
Careers
We are looking for creative and driven scientists to join us! We are accepting undergraduate students.
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.