Overview

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

TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors
Cell Reports
Prudova, Anna and Gocheva, Vasilena and Keller, Ulrich Auf Dem and Eckhard, Ulrich and Olson, Oakley C. and Akkari, Leila and Butler, Georgina S. and Fortelny, Nikolaus and Lange, Philipp F. and Mark, Jennifer C. and Joyce, Johanna A. and Overall, Christopher M.
DOI: 10.1016/j.celrep.2016.06.086
2016

Active 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, Ulrich and Huesgen, Pitter F. and Schilling, Oliver and Bellac, Caroline L. and Butler, Georgina S. and Cox, Jennifer H. and Dufour, Antoine and Goebeler, Verena and Kappelhoff, Reinhild and Keller, Ulrich Auf Dem and Klein, Theo and Lange, Philipp F. and Marino, Giada and Morrison, Charlotte J. and Prudova, Anna and Rodriguez, David and Starr, Amanda E. and Wang, Yili and Overall, Christopher M.
DOI: 10.1016/j.matbio.2015.09.003
2016

Active 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.
2015

Proteome 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, Nikolaus and Yang, Sharon and Pavlidis, Paul and Lange, Philipp F. and Overall, Christopher M.
DOI: 10.1093/nar/gku1012
2015

LysargiNase mirrors trypsin for protein C-terminal and methylation-site identification
Nature Methods
Pitter F Huesgen, Philipp F Lange, Lindsay D Rogers, Nestor Solis, Ulrich Eckhard, Oded Kleifeld, Theodoros Goulas, F Xavier Gomis-Rüth, Christopher M Overall
DOI: 10.1038/nmeth.3177
11/2014

Ensembles of protein termini and specific proteolytic signatures as candidate biomarkers of disease.
Huesgen PF, Lange PF, Overall CM
DOI: 10.1002/prca.201300104
PubMed: 24497460
02/2014

Macrophage Matrix Metalloproteinase-12 Dampens Inflammation and Neutrophil Influx in Arthritis
Cell Reports
Bellac, Caroline L. and Dufour, Antoine and Krisinger, Michael J. and Loonchanta, Anantasak and Starr, Amanda E. and Keller, Ulrich Auf Dem and Lange, Philipp F. and Goebeler, Verena and Kappelhoff, Reinhild and Butler, Georgina S. and Burtnick, Leslie D. and Conway, Edward M. and Roberts, Clive R. and Overall, Christopher M.
DOI: 10.1016/j.celrep.2014.09.006
2014

Annotating N Termini for the Human Proteome Project: N Termini and N alpha-Acetylation Status Differentiate Stable Cleaved Protein Species from Degradation Remnants in the Human Erythrocyte Proteome
Journal of Proteome Research
Lange, Philipp F. and Huesgen, Pitter F. and Nguyen, Karen and Overall, Christopher M.
DOI: 10.1021/pr401191w
2014

Characterization of LysargiNase for use in phosphoproteomics experiments, partII
2014

Network Analyses Reveal Pervasive Functional Regulation Between Proteases in the Human Protease Web
Plos Biology
Fortelny, Nikolaus and Cox, Jennifer H. and Kappelhoff, Reinhild and Starr, Amanda E. and Lange, Philipp F. and Pavlidis, Paul and Overall, Christopher M.
DOI: 10.1371/journal.pbio.1001869
2014

LysargiNase and tryptic digest of MDA-MB 231 cell lysates
2014

Protein TAILS: when termini tell tales of proteolysis and function.
Lange PF, Overall CM
DOI: 10.1016/j.cbpa.2012.11.025
PubMed: 23298954
02/2013

Proteomic amino-termini profiling reveals targeting information for protein import into complex plastids.
Huesgen PF, Alami M, Lange PF, Foster LJ, Schröder WP, Overall CM, Green BR
DOI: 10.1371/journal.pone.0074483
PubMed: 24066144
2013

TopFIND 2.0-linking protein termini with proteolytic processing and modifications altering protein functionNucleic Acids Research
Lange, Philipp F. and Huesgen, Pitter F. and Overall, Christopher M.
DOI: 10.1093/nar/gkr1025
2012

Towards kit-like (18)F-labeling of marimastat, a noncovalent inhibitor drug for in vivo PET imaging cancer associated matrix metalloproteases
Medchemcomm
Li, Ying and Ting, Richard and Harwig, Curtis W. and Keller, Ulrich Auf Dem and Bellac, Caroline L. and Lange, Philipp F. and Inkster, James A. H. and Schaffer, Paul and Adam, Michael J. and Ruth, Thomas J. and Overall, Christopher M. and Perrin, David M.
DOI: 10.1039/c1md00117e
2011

TopFIND, a knowledgebase linking protein termini with function
Nature Methods
Lange, P.F. and Overall, C.M.
DOI: 10.1038/nmeth.1669
2011

Novel 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
2010

ClC-7 requires Ostm1 as a ß-subunit to support bone resorption and lysosomal function
Nature
Lange, P.F. and Wartosch, L. and Jentsch, T.J. and Fuhrmann, J.C.
DOI: 10.1038/nature04535
2006

Research

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.

Honours & Awards

Feodor Lynen Research Fellowship for Postdoctoral Research (Alexander von Humboldt Foundation) (2009-2011)

Nomination for the Canada Research Chair Tier II in 'Translational and Applied Genomics of Pediatric Malignancy'

Joint Michael Smith Foundation for Health Research & Breast Cancer Society of Canada Research Award (2011-2012)

Research Group Members

Brenda Tse, Research Coordinator
Lorenz Nierves
Samuel Weng
Janice Tsui
Enes Kemal Ergin, Graduate Student
Amanda Lorentzian
Erin Kim
Anuli Uzozie, Postdoctoral Fellow