Kolch Group

Current research interests focus on understanding molecular mechanisms of malignant transformation, network mediated drug resistance in cancer, and the construction of Digital Twins for personalized cancer diagnosis and therapy.

Key Research Highlights

• Discovered that Raf-1 kinase is essential for cell proliferation and malignant transformation.First use of dominant negative mutants in mammalian cells to reveal physiological and pathological functions of Raf-1. Kolch et al.Nature349: 426 1991.
• Discovered RKIP as the first physiological inhibitor protein of the Raf-MEK-MAPK/ERK pathway.RKIP was subsequently validated as main metastasis suppressor in cancer. Yeung … Kolch, W.Nature401, 173, 1999.
• Discovered MST2/Hippo as novel Raf-1 regulated pathway.This study identified the kinase independent regulation of MST2 as a new target for the Raf-1 kinase. O'Neill, E …Kolch, W.Science306, 2267, 2004.
• Discovered that dynamic interactome changes in kinase substrates are linked to cell fate decisions.Von Kriegsheim, A …Kolch, W.Nature Cell Biology11: 1458, 2009.
• Discovered intrinsic mechanisms of drug resistance mediated by network topologies.This study was one of the first to reveal that drug resistance can be network mediated and can result from dynamic network motifs. Sturm, O … Kolch, W.Science Signaling3 (153), ra90, 2010.
• Discovered that mutant KRAS can induce apoptosis via MST2 mediated activation of p53.Activation of the MST2 pathway by mutant KRAS induces apoptosis in colorectal cancer via promoting accumulation of the tumor suppressor protein p53. Matallanas, D …Kolch, W.Molecular Cell44, 893, 2011.
• Discovered protein interaction-based switches that coordinate signaling pathways.This work showed that protein interaction dynamics can generate switch-like pathway crosstalk and inspired the concept that protein interactions work as information processing devices. Romano, D…Kolch, W.Nature Cell Biology16: 673, 2014.
• Co-developed methods to extract computational mechanistic models from AI/ML inferred network reconstructions. Halasz, M, Kholodenko, B, Kolch, W., Santra, T.Science Signaling9(455): ra114, 2016.
• Developed a multi-omics data integration method that can analyze multiscale signal processing by biological networks. Santra et al…Kolch, W. Cell Reports26: 3100-3115.e3107, 2019.
• Discovered that oncogenic RAS mutations induce the extensive rewiring of protein-protein interaction networks that re-programs signal processing and enables malignant transformation.Kennedy, S … Kolch, W.Nature Communications11:499, 2020.

Recent Publications

(opens in a new window)Genomic and Transcriptomic Analysis of a Patient with Early-Onset Colorectal Cancer and Therapy-Induced Focal Nodular Hyperplasia: A Case Report.
O'Reilly M, Krstic A, Iglesias-Martinez LF, Ryan ÉJ, Moran B, Winter D, Sheahan K, McDermott R,Kolch W.J Pers Med. 2024 Jun 15;14(6):639. doi: 10.3390/jpm14060639.

(opens in a new window)A Systems Biology Approach to Understand the Racial Disparities in Colorectal Cancer.
Nwaokorie A,Kolch W, Fey D.Cancer Res Commun. 2024 Jan 12;4(1):103-117. doi: 10.1158/2767-9764.CRC-22-0464.

(opens in a new window)Transcriptional profiling of early differentiation of primary human mesenchymal stem cells into chondrocytes.
Schwarzl T, Keogh A, Shaw G, Krstic A, Clayton E, Higgins DG,Kolch W, Barry F.Sci Data. 2023 Nov 3;10(1):758. doi: 10.1038/s41597-023-02686-y.

(opens in a new window)Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib.
Nolan A, Raso C,Kolch W, Kriegsheim AV, Wynne K, Matallanas D.Cancers (Basel). 2023 Aug 17;15(16):4141. doi: 10.3390/cancers15164141.

(opens in a new window)Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells.
Liu Z, Krstic A, Neve A, Casalou C, Rauch N, Wynne K, Cassidy H, McCann A, Kavanagh E, McCann B, Blanco A, Rauch J,Kolch W.Int J Mol Sci. 2023 Jul 23;24(14):11821. doi: 10.3390/ijms241411821.

(opens in a new window)Reversing pathological cell states: the road less travelled can extend the therapeutic horizon.
Kholodenko BN,Kolch W, Rukhlenko OS.Trends Cell Biol. 2023 Nov;33(11):913-923. doi: 10.1016/j.tcb.2023.04.004

(opens in a new window)Small Gene Networks Delineate Immune Cell States and Characterize Immunotherapy Response in Melanoma.
Egan D, Kreileder M, Nabhan M, Iglesias-Martinez LF, Dovedi SJ, Valge-Archer V, Grover A, Wilkinson RW, Slidel T, Bendtsen C, Barrett IP, Brennan DJ,Kolch W, Zhernovkov V.Cancer Immunol Res. 2023 Aug 3;11(8):1125-1136. doi: 10.1158/2326-6066.CIR-22-0563.

(opens in a new window)Interactome dynamics of RAF1-BRAF kinase monomers and dimers.
Iglesias-Martinez LF, Rauch N, Wynne K, McCann B,Kolch W, Rauch J.Sci Data. 2023 Apr 12;10(1):203. doi: 10.1038/s41597-023-02115-0.

(opens in a new window)Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.
Hastings JF, Latham SL, Kamili A, Wheatley MS, Han JZR, Wong-Erasmus M, Phimmachanh M, Nobis M, Pantarelli C, Cadell AL, O'Donnell YEI, Leong KH, Lynn S, Geng FS, Cui L, Yan S, Achinger-Kawecka J, Stirzaker C, Norris MD, Haber M, Trahair TN, Speleman F, De Preter K, Cowley MJ, Bogdanovic O, Timpson P, Cox TR,Kolch W, Fletcher JI, Fey D, Croucher DR.Sci Adv. 2023 Mar 3;9(9):eabp8314. doi: 10.1126/sciadv.abp8314

(opens in a new window)B-cell and complement signature in severe hidradenitis suppurativa that does not respond to adalimumab
Hambly R, Gatault S, Smith C, Iglesias-Martinez L, Kearns S, Rea H, Marasigan V, Lynam-Loane K, Kirthi S, Hughes R, Fletcher J,Kolch W, Kirby B. British Journal of Dermatology. 2023 Jan; 188(1), 52-63; doi: 10.1093/bjd/ljac007

(opens in a new window)Oncotherapeutic Strategies in Early Onset Colorectal Cancer
O'Reilly M, Linehan A, Krstic A,Kolch W, Sheahan K, Winter D, Mc Dermott R. Cancers (Basel). 2023 Jan 16; 15(2), 552; doi: 10.3390/cancers15020552

(opens in a new window)Dynamic regulation of RAS and RAS signaling
Kolch W, Berta D, Rosta E. Biochemical Journal. 2023 Jan 6; 480 (1): 1-23; doi: 10.1042/BCJ20220234

(opens in a new window)Targeting KRAS in Pancreatic Cancer
Cowzer D, Zameer M, Conroy M,Kolch W, Duffy A. Journal of Personalized Medicine. 2022 Nov 8; 12(11), 1870; doi: 10.3390/jpm12111870

(opens in a new window)CRABP2 - A novel biomarker for high-risk endometrial cancer
Egan D, Moran B, Wilkinson M, Pinyol M, Guerra E, Gatius S, Matias-Guiu X,Kolch W, le Roux C, Brennan D. Gynecologic Oncology. 2022 Nov; 167(2), 314-322; doi: 10.1016/j.ygyno.2022.09.020

(opens in a new window)Control of cell state transitions
Rukhlenko O, Halasz M, Rauch N, Zhernovkov V, Prince T, Wynne K, Maher S, Kashdan E, MacLeod K, Carragher N,Kolch W, Kholodenko B. Nature. 2022 Sept 14; 609, 975-985 (2022); doi: 10.1038/s41586-022-05194-y