- Overview
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My research team strives to develop new diagnostic and therapeutic approaches to detect and treat children suffering from cancer earlier, better and with reduced impact on their life.
The fundamental question is how cancer cells are different from healthy, normal cells? If we understand this we will be able to better detect and kill cancer while leaving the rest of the body untouched.
Our research focuses on proteins, the structural and functional building blocks of a cell. To do this we combine genomics and proteomics, a technology that enables us to monitor all of the proteins in our body and detect how they are changed in childhood cancer. We then use computational approaches to further analyze and integrate our findings and to make them accessible to clinicians and fellow scientists around the world.
- Publications
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Statistical Testing for Protein Equivalence Identifies Core Functional Modules Conserved across 360 Cancer Cell Lines and Presents a General Approach to Investigating Biological Systems
Journal of Proteome Research
Enes K. Ergin and Junia J.K. Myung and Philipp F. Lange
DOI: 10.1021/acs.jproteome.4c00131
06/2024Analysis of protein levels and solubility in distinct brain regions reveals several elements of the protein homeostasis network that are impacted by aging
Cristen Molzahn and Erich Kuechler and Lorenz Nierves and Gary Cole and Jing Wang and Neil Cashman and Aly Karsan and Philipp F. Lange and Jörg Gsponer and Thibault Mayor
DOI: 10.1101/2024.02.28.582597
02/2024ASAP-Automated Sonication-Free Acid-Assisted Proteomes-from Cells and FFPE Tissues
Analytical Chemistry
Georgina D. Barnabas and Verena Goebeler and Janice Tsui and Jonathan W. Bush and Philipp F. Lange
DOI: 10.1021/acs.analchem.2c04264
02/2023Mechanisms of Pathogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant R278C+/- During Development
bioRxiv
DOI: 10.1101/2023.06.06.542948
2023RNA Polymerase II transcription independent of TBP
eLife
DOI: 10.7554/elife.83810
2023Molecular and metabolomic characterization of hiPSC-derived cardiac fibroblasts transitioning to myofibroblasts
bioRxiv
DOI: 10.1101/2023.10.08.561455
2023Shift of the insoluble content of the proteome in the aging mouse brain
Proceedings of the National Academy of Sciences of the United States of America
DOI: 10.1073/pnas.2310057120
2023Positional proteomics: is the technology ready to study clinical cohorts?
Expert Review of Proteomics
DOI: 10.1080/14789450.2023.2272046
2023Adaptation of the Th-MYCN Mouse Model of Neuroblastoma for Evaluation of Disseminated Disease
International Journal of Molecular Sciences
DOI: 10.3390/ijms241512071
2023Title: Inducing an oxidized redox-balance improves anti-tumor CD8+ T cell function
bioRxiv
DOI: 10.1101/2023.03.27.533229
2023Targetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia
Nature Communications
DOI: 10.1038/s41467-023-42701-9
2023SQuAPP—simple quantitative analysis of proteins and PTMs
Bioinformatics
Enes K Ergin and Anuli C Uzozie and Siyuan Chen and Ye Su and Philipp F Lange
DOI: 10.1093/bioinformatics/btac628
10/2022Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation
Nature Communications
Zhengcheng He and Ryan Ghorayeb and Susanna Tan and Ke Chen and Amanda C. Lorentzian and Jack Bottyan and Syed Mohammed Musheer Aalam and Miguel Angel Pujana and Philipp F. Lange and Nagarajan Kannan and Connie J. Eaves and Christopher A. Maxwell
DOI: 10.1038/s41467-022-29885-2
04/2022Multi-omic profiling of the leukemic microenvironment shows bone marrow interstitial fluid is distinct from peripheral blood plasma
Lorenz Nierves and Jian Guo and Siyuan Chen and Janice Tsui and Anuli Uzozie and Jonathan W. Bush and Tao Huan and Philipp F. Lange
DOI: 10.1101/2022.03.30.486272
04/2022Persistence of targetable lesions, predicted therapy sensitivity and proteomes through disease evolution in pediatric acute lymphoblastic leukemia
Amanda C. Lorentzian and Jenna Rever and Enes K. Ergin and Meiyun Guo and Neha M. Akella and Nina Rolf and C. James Lim and Gregor S.D. Reid and Christopher A. Maxwell and Philipp F. Lange
DOI: 10.1101/2022.03.04.22271927
03/2022Sensitive Identification of Known and Unknown Protease Activities by Unsupervised Linear Motif Deconvolution
Analytical Chemistry
Anuli C. Uzozie and Theodore G. Smith and Siyuan Chen and Philipp F. Lange
DOI: 10.1021/acs.analchem.1c04937
02/2022A cross-standardized flow cytometry platform to assess phenotypic stability in precursor B-cell acute lymphoblastic leukemia (B-ALL) xenografts
Cytometry Part A
Nina Rolf and Lorraine Y. T. Liu and Angela Tsang and Philipp F. Lange and Chinten James Lim and Christopher A. Maxwell and Suzanne M. Vercauteren and Gregor S. D. Reid
DOI: 10.1002/cyto.a.24473
01/2022HUNTER: Sensitive Automated Characterization of Proteolytic Systems by N Termini Enrichment from Microscale Specimen
Methods in Molecular Biology
DOI: 10.1007/978-1-0716-2124-0_8
2022Shift of the insoluble content of the proteome in aging mouse brain
bioRxiv
Molzahn, C. and Kuechler, E. and Zemlyankina, I. and Nieves, L. and Ali, T. and Cole, G. and Wang, J. and Albu, R.F. and Zhu, M. and Cashman, N. and Gilch, S. and Karsan, A. and Lange, P.F. and Gsponer, J. and Mayor, T.
DOI: 10.1101/2022.12.13.520290
2022Modification of BRCA1-associated breast cancer risk by HMMR overexpression
Nature Communications
Mateo, F. and He, Z. and Mei, L. and de Garibay, G.R. and Herranz, C. and García, N. and Lorentzian, A. and Baiges, A. and Blommaert, E. and Gómez, A. and Mirallas, O. and Garrido-Utrilla, A. and Palomero, L. and Espín, R. and Extremera, A.I. and Soler-Monsó, M.T. and Petit, A. and Li, R. and Brunet, J. and Chen, K. and Tan, S. and Eaves, C.J. and McCloskey, C. and Hakem, R. and Khokha, R. and Lange, P.F. and Lázaro, C. and Maxwell, C.A. and Pujana, M.A.
DOI: 10.1038/s41467-022-29335-z
2022Isolation of Detergent Insoluble Proteins from Mouse Brain Tissue for Quantitative Analysis Using Data Independent Acquisition (DIA)
Methods in Molecular Biology
DOI: 10.1007/978-1-0716-2124-0_3
2022Detectability of Biotin Tags by LC-MS/MS
Journal of Proteome Research
Nierves, L. and Lange, P.F.
DOI: 10.1021/acs.jproteome.0c01049
2021Robust unsupervised deconvolution of linear motifs characterizes 68 protein modifications at proteome scale
Scientific Reports
Smith, T.G. and Uzozie, A.C. and Chen, S. and Lange, P.F.
DOI: 10.1038/s41598-021-01971-3
2021PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways
Journal of Experimental and Clinical Cancer Research
Uzozie, A.C. and Ergin, E.K. and Rolf, N. and Tsui, J. and Lorentzian, A. and Weng, S.S.H. and Nierves, L. and Smith, T.G. and Lim, C.J. and Maxwell, C.A. and Reid, G.S.D. and Lange, P.F.
DOI: 10.1186/s13046-021-01835-8
2021Fold-Change Compression: An Unexplored but Correctable Quantitative Bias Caused by Nonlinear Electrospray Ionization Responses in Untargeted Metabolomics
Analytical Chemistry
Yu, H. and Xing, S. and Nierves, L. and Lange, P.F. and Huan, T.
DOI: 10.1021/acs.analchem.0c00246
2020Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy
Frontiers in Cell and Developmental Biology
Richmond, P.A. and van der Kloet, F. and Vaz, F.M. and Lin, D. and Uzozie, A. and Graham, E. and Kobor, M. and Mostafavi, S. and Moerland, P.D. and Lange, P.F. and van Kampen, A.H.C. and Wasserman, W.W. and Engelen, M. and Kemp, S. and van Karnebeek, C.D.M.
DOI: 10.3389/fcell.2020.00520
2020Tumor Variant Identification That Accounts for the Unique Molecular Landscape of Pediatric Malignancies
JNCI Cancer Spectrum
Amanda Lorentzian and Jaclyn A Biegel and D Gigi Ostrow and Nina Rolf and Chi-Chao Liu and S Rod Rassekh and Rebecca J Deyell and Timothy Triche and Kirk R Schultz and Jacob Rozmus and Gregor S D Reid and C James Lim and Philipp F Lange and Christopher A Maxwell
DOI: 10.1093/jncics/pky079
01/2019Origins and clinical relevance of proteoforms in pediatric malignancies
Expert Review of Proteomics
Lorentzian, A. and Uzozie, A. and Lange, P.F.
DOI: 10.1080/14789450.2019.1575206
2019Sensitive determination of proteolytic proteoforms in limited microscale proteome samples
Molecular and Cellular Proteomics
Weng, S.S.H. and Demir, F. and Ergin, E.K. and Dirnberger, S. and Uzozie, A. and Tuscher, D. and Nierves, L. and Tsui, J. and Huesgen, P.F. and Lange, P.F.
DOI: 10.1074/mcp.TIR119.001560
2019HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development
eLife
Connell, M. and Chen, H. and Jiang, J. and Kuan, C.-W. and Fotovati, A. and Chu, T.L.H. and He, Z. and Lengyell, T.C. and Li, H. and Kroll, T. and Li, A.M. and Goldowitz, D. and Frappart, L. and Ploubidou, A. and Patel, M.S. and Pilarski, L.M. and Simpson, E.M. and Lange, P.F. and Allan, D.W. and Maxwell, C.A.
DOI: 10.7554/eLife.28672
2017TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors
Cell Reports
Prudova, A. and Gocheva, V. and auf dem Keller, U. and Eckhard, U. and Olson, O.C. and Akkari, L. and Butler, G.S. and Fortelny, N. and Lange, P.F. and Mark, J.C. and Joyce, J.A. and Overall, C.M.
DOI: 10.1016/j.celrep.2016.06.086
2016Active site specificity profiling of the matrix metalloproteinase family: Proteomic identification of 4300 cleavage sites by nine MMPs explored with structural and synthetic peptide cleavage analyses
Matrix Biology
Eckhard, U. and Huesgen, P.F. and Schilling, O. and Bellac, C.L. and Butler, G.S. and Cox, J.H. and Dufour, A. and Goebeler, V. and Kappelhoff, R. and auf dem Keller, U. and Klein, T. and Lange, P.F. and Marino, G. and Morrison, C.J. and Prudova, A. and Rodriguez, D. and Starr, A.E. and Wang, Y. and Overall, C.M.
DOI: 10.1016/j.matbio.2015.09.003
2016Active site specificity profiling datasets of matrix metalloproteinases (MMPs) 1, 2, 3, 7, 8, 9, 12, 13 and 14
Data in Brief
Eckhard, U. and Huesgen, P.F. and Schilling, O. and Bellac, C.L. and Butler, G.S. and Cox, J.H. and Dufour, A. and Goebeler, V. and Kappelhoff, R. and auf dem Keller, U. and Klein, T. and Lange, P.F. and Marino, G. and Morrison, C.J. and Prudova, A. and Rodriguez, D. and Starr, A.E. and Wang, Y. and Overall, C.M.
DOI: 10.1016/j.dib.2016.02.036
2016Proteome TopFIND 3.0 with TopFINDer and PathFINDer: Database and analysis tools for the association of protein termini to pre- and post-translational events
Nucleic Acids Research
Fortelny, N. and Yang, S. and Pavlidis, P. and Lange, P.F. and Overall, C.M.
DOI: 10.1093/nar/gku1012
2015COSMC knockdown mediated aberrant O-glycosylation promotes oncogenic properties in pancreatic cancer
Molecular Cancer
Hofmann, B.T. and Schlüter, L. and Lange, P. and Mercanoglu, B. and Ewald, F. and Fölster, A. and Picksak, A.-S. and Harder, S. and El Gammal, A.T. and Grupp, K. and Güngör, C. and Drenckhan, A. and Schlüter, H. and Wagener, C. and Izbicki, J.R. and Jücker, M. and Bockhorn, M. and Wolters-Eisfeld, G.
DOI: 10.1186/s12943-015-0386-1
2015Active Site Specificity Profiling of the Matrix Metalloproteinase Family: Proteomic Identification of 4,300 Cleavage Sites by MMPs 1, 2, 3, 7, 8, 9, 12, 13, and 14.
2015LysargiNase and tryptic digest of MDA-MB 231 cell lysates
2014Network Analyses Reveal Pervasive Functional Regulation Between Proteases in the Human Protease Web
PLoS Biology
Fortelny, N. and Cox, J.H. and Kappelhoff, R. and Starr, A.E. and Lange, P.F. and Pavlidis, P. and Overall, C.M.
DOI: 10.1371/journal.pbio.1001869
2014Ensembles of protein termini and specific proteolytic signatures as candidate biomarkers of disease
Proteomics - Clinical Applications
Huesgen, P.F. and Lange, P.F. and Overall, C.M.
DOI: 10.1002/prca.201300104
2014Annotating N termini for the human proteome project: N termini and Na-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome
Journal of Proteome Research
Lange, P.F. and Huesgen, P.F. and Nguyen, K. and Overall, C.M.
DOI: 10.1021/pr401191w
2014Characterization of LysargiNase for use in phosphoproteomics experiments, partII
2014LysargiNase mirrors trypsin for protein C-terminal and methylation-site identification
Nature Methods
Huesgen, P.F. and Lange, P.F. and Rogers, L.D. and Solis, N. and Eckhard, U. and Kleifeld, O. and Goulas, T. and Gomis-Rüth, F.X. and Overall, C.M.
DOI: 10.1038/nmeth.3177
2014Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis
Cell Reports
Bellac, C.L. and Dufour, A. and Krisinger, M.J. and Loonchanta, A. and Starr, A.E. and auf dem Keller, U. and Lange, P.F. and Goebeler, V. and Kappelhoff, R. and Butler, G.S. and Burtnick, L.D. and Conway, E.M. and Roberts, C.R. and Overall, C.M.
DOI: 10.1016/j.celrep.2014.09.006
2014Proteomic Amino-Termini Profiling Reveals Targeting Information for Protein Import into Complex Plastids
PLoS ONE
Huesgen, P.F. and Alami, M. and Lange, P.F. and Foster, L.J. and Schröder, W.P. and Overall, C.M. and Green, B.R.
DOI: 10.1371/journal.pone.0074483
2013Protein TAILS: When termini tell tales of proteolysis and function
Current Opinion in Chemical Biology
Lange, P.F. and Overall, C.M.
DOI: 10.1016/j.cbpa.2012.11.025
2013TopFIND 2.0 - Linking protein termini with proteolytic processing and modifications altering protein function
Nucleic Acids Research
Lange, P.F. and Huesgen, P.F. and Overall, C.M.
DOI: 10.1093/nar/gkr1025
2012Towards kit-like 18F-labeling of marimastat, a noncovalent inhibitor drug for in vivo PET imaging cancer associated matrix metalloproteases
MedChemComm
Li, Y. and Ting, R. and Harwig, C.W. and Auf Dem Keller, U. and Bellac, C.L. and Lange, P.F. and Inkster, J.A.H. and Schaffer, P. and Adam, M.J. and Ruth, T.J. and Overall, C.M. and Perrin, D.M.
DOI: 10.1039/c1md00117e
2011TopFIND, a knowledgebase linking protein termini with function
Nature Methods
Lange, P.F. and Overall, C.M.
DOI: 10.1038/nmeth.1669
2011Novel matrix metalloproteinase inhibitor [18F]marimastat- aryltrifluoroborate as a probe for in vivo positron emission tomography imaging in cancer
Cancer Research
Auf Dem Keller, U. and Bellac, C.L. and Li, Y. and Lou, Y. and Lange, P.F. and Ting, R. and Harwig, C. and Kappelhoff, R. and Dedhar, S. and Adam, M.J. and Ruth, T.J. and Bénard, F. and Perrin, D.M. and Overall, C.M.
DOI: 10.1158/0008-5472.CAN-10-1584
2010ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function
GBM Annual Spring meeting Mosbach 2007
Jens C. Fuhrmann and Philipp F. Lange and Lena Wartosch and Thomas J. Jentsch
DOI: 10.1240/sav_gbm_2007_m_001701
03/2007ClC-7 requires Ostm1 as a ß-subunit to support bone resorption and lysosomal function
Nature
DOI: 10.1038/nature04535
2006 - Research
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Current Projects
The overall objective of my team's research is to monitor and detect aberrant protein presence and function in cancer and exploit this difference to diagnose and treat cancer and improve the wellbeing of cancer survivors.
We are particularly interested in how the post-translational modification of proteins affects cancer progression and secondary disease, which can hit childhood cancer survivors years after successful treatment. After translation proteins can be modified by, for example, proteolytic processing or phosphorylation. This creates a repertoire of "proteoforms", which are all the variant and modified protein products of a single gene. They often differ in their localization, function and interaction with other proteins.
Our research program follows four main axes that inform each other:
I: We use proteo-genomics to study differences in tissue specimen from children suffering from select cancers and healthy individuals, and translate these findings into a new diagnostic and treatment approach.
II: We integrate cell biology, biochemistry, genomics, proteomics and bioinformatics to study the role of post-translational modification in the regulation of select cell signaling networks. By investigating patient-derived cells and mouse models we strive to identify new ways of altering these signaling networks to improve drug efficacy and reduce side effects.
III: Computational biology plays an integral role in our research. Our main focus is the development of algorithms for multi-scale data integraction, protein function analysis, pattern recognition and de-convolution of network effects in complex systems. Building on these we develop new biological knowledgebases and applications to improve the functional analysis of genomics and proteomics data and to guide personalized treatment decisions.
IV: We continuously strive to improve existing- and develop new technologies for the mass spectrometric analysis of complex biological specimen enabling a more comprehensive, specific and sensitive investigation of smaller biopsies.
My research team is embedded in the Michael Cuccione Childhood Cancer Research Program and affiliated with the BC Cancer Research Centre and BC Children’s Hospital. This creates a stimulating environment in which we work closely with world-class experts in clinical oncology, cancer biology, genomics and computer sciences.Grants"Proteolytic protein termini as a new strategy for cancer cell-specific therapy," Innovation Grant, Canadian Cancer Society, 2016-2018
"Bioinformatics resources for genomewide assessment of protein function at the proteoform level," NSERC Discovery Grant, $28,000/ year, 2018-2023
Honours & AwardsMichael Smith Health Foundation Research Scholar Award (2016)
Canada Research Chair Tier 2 Award in Translational Proteomics of Childhood Malignancies (2015-2020)
Feodor Lynen Research Fellowship for Postdoctoral Research (Alexander von Humboldt Foundation) (2009-2011)
Joint Michael Smith Foundation for Health Research & Breast Cancer Society of Canada Research Award (2011-2012)
Research Group MembersGeorgina Barnabas, Postdoctoral Fellow
Agustina Conrrero, Research Assistant
Enes Kemal Ergin, Graduate Student
Kirsty Ferguson, Research Associate
Verena Goebeler, Research Assistant
Erik Gomez Cardona, Postdoctoral Fellow
Farah Jayousi, Research Technician
Junia Myung
Jehan Nazri, Research Technician
Bantval Sharvari Somayaji, Ms
Fabian Stockert, Visiting Research Student
Brenda Tse, Research Coordinator
Moones Yadegari, Masters Student
New study shows the potential of new treatment strategies for most common childhood cancer
Researchers made a key discovery about how childhood acute lymphoblastic leukemia (ALL) evolves and responds to targeted therapies suggesting that clinicians can start looking for precision treatments for a child’s cancer immediately after diagnosis, rather than waiting until the cancer has come back.
