Molecular Medicine Partnership Unit

The MMPU is a joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).

Systems Medicine of Cancer Drugs

Wolfgang Huber and Sascha Dietrich

Our research interest

We aim to understand intra- and inter-patient heterogeneity of response to anti-cancer drugs, a major clinical and scientific challenge. Our focus is to study the interaction of tumour cells with their microenvironment and consequences for drug response.

Background and overall goals

Response to anti-cancer agents is often restricted to subsets of patients and, even within patients, to subfractions of the tumour. In addition, signals provided by the tumour micro-environment modify pathway activities, including those targeted by drugs. Our knowledge of such complex interactions of different factors underlying drug response is incomplete. Our goal is to increase the understanding of drug response heterogeneity and to provide the scientific basis for biology-based individualised treatment of lymphoma and leukaemia.

We pursue a systems medicine approach that integrates systematic modelling of niche compartments and their crosstalk with tumour cells subsets with drug perturbation assays of primary cancer cells, multi-omic molecular profiling, cutting-edge statistical data analysis, mathematical modelling and a setup aiming towards clinical exploitation.

Approach and foci

Ex-vivo drug testing platform to map the biological complexity and inter- and intra-patient heterogeneity of blood tumours in the context of their interaction with the micro-environment.

Niche models. We isolate tumour cells from surgically extracted lymph-nodes and bone marrow aspirates and characterise their functional states and pathway activities using phospho-proteomics and phospho-specific antibodies. These results serve as a reference for in vitro models that aim to resemble the niche specific context.

Further dimensions of drug sensitivity and resistance: 3D space, timing, and dynamics of clonal composition.

Cancer cell phenotyping using an automated microscopy platform and computational image analysis of cellular morphology (mitochondria, nuclei, microtubules) for dynamic understanding of cell fate in time.

Statistical multivariate modelling to explain and predict the heterogeneity of drug response by integration of cancer cell phenotypes and multi-omics data types.

Clinical applications. This includes assessment of our ex vivo tumour models for clinical outcome prediction and preparation for prospective clinical studies.

Important publications

Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia.
Lu J, Cannizzaro E, Meier-Abt F, Scheinost S, Bruch PM, Giles HA, Lütge A, Hüllein J, Wagner L, Giacopelli B, Nadeu F, Delgado J, Campo E, Mangolini M, Ringshausen I, Böttcher M, Mougiakakos D, Jacobs A, Bodenmiller B, Dietrich S, Oakes CC, Zenz T, Huber W.
Nat Cancer. 2021 Aug;2(8):853-864. doi: 10.1038/s43018-021-00216-6. Epub 2021 Jul 1. PMID: 34423310

Mapping drug-microenvironment-genetic interplay in CLL reveals trisomy 12 as a modulator of microenvironmental signals
Peter-Martin Bruch, Holly A. R. Giles, Carolin Kolb, Sophie A. Herbst, Tina Becirovic, Tobias Roider, Junyan Lu, Sebastian Scheinost, Lena Wagner, Jennifer Huellein, Ivan Berest, Mark Kriegsmann, Katharina Kriegsmann, Christiane Zgorzelski, Peter Dreger, Judith B. Zaugg, Carsten Müller-Tidow, Thorsten Zenz, Wolfgang Huber, Sascha Dietrich
biorxiv https://doi.org/10.1101/2021.07.23.453514

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas.
Liebers N, Duell J, Fitzgerald D, Kerkhoff A, Noerenberg D, Kaebisch E, Acker F, Fuhrmann S, Leng C, Welslau M, Chemnitz J, Middeke JM, Weber T, Holtick U, Trappe R, Pfannes R, Liersch R, Spoer C, Fuxius S, Gebauer N, Caillé L, Geer T, Koenecke C, Keller U, Claus R, Mougiakakos D, Mayer S, Huettmann A, Pott C, Trummer A, Wulf G, Brunnberg U, Bullinger L, Hess G, Mueller-Tidow C, Glass B, Lenz G, Dreger P, Dietrich S.
Blood Adv. 2021 Jul 13;5(13):2707-2716. doi: 10.1182/bloodadvances.2020004155. PMID: 34196677

The Protein Landscape of Chronic Lymphocytic Leukemia (CLL).
Meier-Abt F, Lu J, Cannizzaro E, Pohly MF, Kummer S, Pfammatter S, Kunz L, Collins BC, Nadeu F, Lee KS, Xue P, Gwerder M, Roiss M, Hüllein J, Scheinost S, Dietrich S, Campo E, Huber W, Aebersold R, Zenz T.
Blood. 2021 Jun 29:blood.2020009741. doi: 10.1182/blood.2020009741. Online ahead of print. PMID: 34189564

Transformation and Preprocessing of Single-Cell RNA-Seq Data
Constantin Ahlmann-Eltze, Wolfgang Huber
Biorxiv June 25, 2021 https://doi.org/10.1101/2021.06.24.449781

glmGamPoi: fitting Gamma-Poisson generalized linear models on single cell count data.
Ahlmann-Eltze C, Huber W.
Bioinformatics. 2021 Apr 5;36(24):5701-5702. doi: 10.1093/bioinformatics/btaa1009. PMID: 33295604

The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.
Roider T, Wang X, Hüttl K, Müller-Tidow C, Klapper W, Rosenwald A, Stewart JP, de Castro DG, Dreger P, Hermine O, Kluin-Nelemans HC, Grabe N, Dreyling M, Pott C, Ott G, Hoster E, Dietrich S.
Int J Cancer. 2021 Jan 1;148(1):150-160. doi: 10.1002/ijc.33202. Epub 2020 Aug 15. PMID: 32638373

Miniaturized Drug Sensitivity and Resistance Test on Patient-Derived Cells Using Droplet-Microarray.
Popova AA, Dietrich S, Huber W, Reischl M, Peravali R, Levkin PA.
SLAS Technol. 2020 Aug 13:2472630320934432. doi: 10.1177/2472630320934432. Online ahead of print. PMID: 32791934

The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.
Roider T, Wang X, Hüttl K, Müller-Tidow C, Klapper W, Rosenwald A, Stewart JP, Gonzalez de Castro D, Dreger P, Hermine O, Kluin-Nelemans HC, Grabe N, Dreyling M, Pott C, Ott G, Hoster E, Dietrich S.
Int J Cancer. 2020 Jul 7. doi: 10.1002/ijc.33202. Online ahead of print. PMID: 32638373

Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels.
Roider T, Seufert J, Uvarovskii A, Frauhammer F, Bordas M, Abedpour N, Stolarczyk M, Mallm JP, Herbst SA, Bruch PM, Balke-Want H, Hundemer M, Rippe K, Goeppert B, Seiffert M, Brors B, Mechtersheimer G, Zenz T, Peifer M, Chapuy B, Schlesner M, Müller-Tidow C, Fröhling S, Huber W, Anders S, Dietrich S.
Nat Cell Biol. 2020 Jul;22(7):896-906. doi: 10.1038/s41556-020-0532-x. Epub 2020 Jun 15. PMID: 32541878

Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies.
Lukas M, Velten B, Sellner L, Tomska K, Hüellein J, Walther T, Wagner L, Muley C, Wu B, Oleś M, Dietrich S, Jethwa A, Bohnenberger H, Lu J, Huber W, Zenz T.
Leukemia. 2020 May 13. doi: 10.1038/s41375-020-0846-5. Online ahead of print. PMID: 32404973

BRAF inhibitor treatment in classic hairy cell leukemia: a long-term follow-up study of patients treated outside clinical trials.
Liebers N, Roider T, Bohn JP, Haberbosch I, Pircher A, Ferstl B, Ebnöther M, Wendtner CM, Dearden C, Follows GA, Ho AD, Müller-Tidow C, Dreger P, Troussard X, Zenz T, Dietrich S.
Leukemia 2020 May;34(5):1454-1457. doi: 10.1038/s41375-019-0646-y. Epub 2019 Nov 18. PMID: 31740808

Quantification of Differential Transcription Factor Activity and Multiomics-Based Classification into Activators and Repressors: diffTF. Berest I, Arnold C, Reyes-Palomares A, Palla G, Rasmussen KD, Giles H, Bruch PM, Huber W, Dietrich S, Helin K, Zaugg JB.
Cell Rep. 2019 Dec 3;29(10):3147-3159.e12. doi: 10.1016/j.celrep.2019.10.106. PMID: 31801079

Multi-Omics Factor Analysis-a framework for unsupervised integration of multi-omics data sets.
Argelaguet R, Velten B, Arnol D, Dietrich S, Zenz T, Marioni JC, Buettner F, Huber W, Stegle O.
Mol Syst Biol. 2018 Jun 20;14(6):e8124. doi: 10.15252/msb.20178124. PMID:29925568

Drug-perturbation-based stratification of blood cancer.
Dietrich S, Oleś M, Lu J, Sellner L, Anders S, Velten B, Wu B, Hüllein J, da Silva Liberio M, Walther T, Wagner L, Rabe S, Ghidelli-Disse S, Bantscheff M, Oleś AK, Słabicki M, Mock A, Oakes CC, Wang S, Oppermann S, Lukas M, Kim V, Sill M, Benner A, Jauch A, Sutton LA, Young E, Rosenquist R, Liu X, Jethwa A, Lee KS, Lewis J, Putzker K, Lutz C, Rossi D, Mokhir A, Oellerich T, Zirlik K, Herling M, Nguyen-Khac F, Plass C, Andersson E, Mustjoki S, von Kalle C, Ho AD, Hensel M, Dürig J, Ringshausen I, Zapatka M, Huber W, Zenz T.
J Clin Invest. 2018 Jan 2;128(1):427-445. doi: 10.1172/JCI93801. Epub 2017 Dec 11.PMID:29227286

Data-driven hypothesis weighting increases detection power in genome-scale multiple testing.
Ignatiadis N, Klaus B, Zaugg JB, Huber W.
Nat Methods. 2016 Jul;13(7):577-80. doi: 10.1038/nmeth.3885.

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.
Dietrich S, Pircher A, Endris V, Peyrade F, Wendtner CM, Follows GA, Hüllein J, Jethwa A, Ellert E, Walther T, Liu X, Dyer MJ, Elter T, Brummer T, Zeiser R, Hermann M, Herold M, Weichert W, Dearden C, Haferlach T, Seiffert M, Hallek M, von Kalle C, Ho AD, Gaehler A, Andrulis M, Steurer M, Zenz T.
Blood. 2016 Jun 9;127(23):2847-55. doi: 10.1182/blood-2015-11-680074.
PMID: 26941398

A chemical-genetic interaction map of small molecules using high-throughput imaging in cancer cells.
Breinig M, Klein FA, Huber W, Boutros M.
Mol Syst Biol. 2015 Dec 23;11(12):846. doi: 10.15252/msb.20156400.
PMID: 26700849

Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells.
Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Küchler R, Huber W, Kyewski B, Steinmetz LM. Nat Immunol. 2015 Sep;16(9):933-41. doi: 10.1038/ni.3246.
PMID: 26237553

Recurrent CDKN1B (p27) mutations in hairy cell leukemia.
Dietrich S, Hüllein J, Lee SC, Hutter B, Gonzalez D, Jayne S, Dyer MJ, Oleś M, Else M, Liu X, Słabicki M, Wu B, Troussard X, Dürig J, Andrulis M, Dearden C, von Kalle C, Granzow M, Jauch A, Fröhling S, Huber W, Meggendorfer M, Haferlach T, Ho AD, Richter D, Brors B, Glimm H, Matutes E, Abdel Wahab O, Zenz T.
Blood. 2015 Aug 20;126(8):1005-8. doi: 10.1182/blood-2015-04-643361.
PMID: 26065650

Improved binding site assignment by high-resolution mapping of RNA-protein interactions using iCLIP.
Hauer C, Curk T, Anders S, Schwarzl T, Alleaume AM, Sieber J, Hollerer I, Bhuvanagiri M, Huber W, Hentze MW, Kulozik AE.
Nat Commun. 2015 Aug 11;6:7921. doi: 10.1038/ncomms8921.
PMID: 26260686

A map of directional genetic interactions in a metazoan cell.
Fischer B, Sandmann T, Horn T, Billmann M, Chaudhary V, Huber W, Boutros M.
Elife. 2015 Mar 6;4. doi: 10.7554/eLife.05464.

Orchestrating high-throughput genomic analysis with Bioconductor.
Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS, Bravo HC, Davis S, Gatto L, Girke T, Gottardo R, Hahne F, Hansen KD, Irizarry RA, Lawrence M, Love MI, MacDonald J, Obenchain V, Oleś AK, Pagès H, Reyes A, Shannon P, Smyth GK, Tenenbaum D, Waldron L, Morgan M.
Nat Methods. 2015 Feb;12(2):115-21. doi: 10.1038/nmeth.3252. Review.
PMID: 25633503

Continued response off treatment after BRAF inhibition in refractory hairy cell leukemia.
Dietrich S, Hüllein J, Hundemer M, Lehners N, Jethwa A, Capper D, Acker T, Garvalov BK, Andrulis M, Blume C, Schulte C, Mandel T, Meissner J, Fröhling S, von Kalle C, Glimm H, Ho AD, Zenz T.
J Clin Oncol. 2013 Jul 1;31(19):e300-3. doi: 10.1200/JCO.2012.45.9495. No abstract available.

Mapping genetic interactions in human cancer cells with RNAi and multiparametric phenotyping.
Laufer C, Fischer B, Billmann M, Huber W, Boutros M.
Nat Methods. 2013 May;10(5):427-31. doi: 10.1038/nmeth.2436.

BRAF inhibition in refractory hairy-cell leukemia.
Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T.
N Engl J Med. 2012 May 24;366(21):2038-40. doi: 10.1056/NEJMc1202124.

Sascha Dietrich and Wolfgang Huber