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Helmholtz Munich | AAP
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Bioengineering Center Research Unit Analytical Pathology

The Research Unit Analytical Pathology (AAP) carries out scientific development, as a complement to research units with a clinical and fundamental orientation of translational research on diseases that occur in tissue.

The Research Unit Analytical Pathology (AAP) carries out scientific development, as a complement to research units with a clinical and fundamental orientation of translational research on diseases that occur in tissue.

Institute: About our Research (Option B)

The Research Unit Analytical Pathology (AAP) carries out scientific development, as a complement to research units with a clinical and fundamental orientation of translational research on diseases that occur in tissue. AAP is involved in the translation of (for example) in-vitro models or animal models to application in humans. AAP thus links basic research with diagnostic application, subsequently translating the findings of experimental and molecular pathology into procedures for the classification of diseases and predictive diagnostics dealing with tissue.

Institute: Research Groups | Option A

Helmholtz Munich | AAP

Diabetes and Obesity

In the field of diabetes research we focus on the morphological and molecular background of the disease in the endocrine pancreas, insulin resistance in peripheral organs and complications which are caused by type 2 diabetes to generate a deeper understanding of the disease which can be used as a new basis for interventional strategies. High-resolution mass spectrometry imaging (MALDI imaging) is used for investigating unsolved questions in diabetes research. The technology makes it possible to examine the distribution of metabolic products (cell metabolites) and many other molecular classes directly in tissue sections without the need of tissue homogenization and thus enables the generation of very high quality and complex data. Data are further processed in highly sophisticated statistical approaches to extract biologically important information. The unique combination of thus generated data with further in depth tissue analytics as electron microscopy or in vitro analytics we use to generate a deeper understanding of the background of diseases. In the field of diabetes research we focus on the morphological and molecular background of the disease in the endocrine pancreas, insulin resistance in peripheral organs and complications which are caused by type 2 diabetes to generate a deeper understanding of the disease which can be used as a new basis for interventional strategies. High-resolution mass spectrometry imaging (MALDI imaging) is used for investigating unsolved questions in diabetes research. The technology makes it possible to examine the distribution of metabolic products (cell metabolites) and many other molecular classes directly in tissue sections without the need of tissue homogenization and thus enables the generation of very high quality and complex data. Data are further processed in highly sophisticated statistical approaches to extract biologically important information. The unique combination of thus generated data with further in depth tissue analytics as electron microscopy or in vitro analytics we use to generate a deeper understanding of the background of diseases.

Helmholtz Munich

Endocrine Pathology

In situ metabolite MALDI imaging offers enormous clinical potential by enabling the imaging of a largely previously intractable class of biomolecules. Combined with known metabolic pathways, this approach provides a means to image the activities of the pathways in tissues. The endocrine system is a collection of glands that secrete hormones directly into the circulatory system. The MALDI imaging based endocrinology project fills the heuristic gap to visualize the distributions of hormones, metabolites and drugs within tissues. Recently, tissue metabolomic studies have been initiated on adrenal tissues, which have revealed a refined functional structure beyond classical histological anatomy in human adrenal glands (Sun et al. Endocrinology, 2018 PubMed). Future developments will extend the so far existing clinicopathologic application areas by imaging the activities of pathways in tissues, imaging of hormones (steroids, catecholamines), drugs and their metabolites in the cortex and medulla of the adrenal glands and other endocrine organs of tissue from patients and animal models. The aims of these projects are to advance the understanding of the mechanism of endocrine diseases and to improve diagnosis, prognostic and therapeutic decision making.

Helmholtz Munich | AAP

Cancer metabolism and inter-/intratumoral metabolic heterogeneity

Understanding tumor heterogeneity presents one of the most important tasks in cancer research towards improving both diagnosis and treatment of patients. Heterogeneity of tumors contributes to treatment failure and disease recurrence, whereas the interaction between tumor cells and the associated stroma poses novel therapeutic opportunities. Intratumoral heterogeneity refers to the fact that cells within a tumor mass can be highly diverse due to an evolving process in cancer development driven by the stepwise accumulation of molecular changes and clonal selection, while intertumoral heterogeneity describes molecular alterations in several (metastatic) tumors present within or between patients. In malignant cells alteration in molecular features and clonal selection constantly takes place and provides either a selective advantage in function such as proliferation and survival, proceed neutral without any effects, or has negative cell damaging effects. Thereby, the fitness of a neoplastic cell is affected by the interactions with itself and other cells in its microenvironment competing with one another for the available resources. Tumor heterogeneity has mainly been described at a genetic, chromosomal, or transcriptional level. The approaches used to analyze tumor heterogeneity are mostly targeted either focusing on the distribution of a single molecule in tissues such as proteins by using immunohistochemistry, or provide detailed molecular insight in tumor subpopulations by the targeted selection of tumor subpopulations. However, selection of representative tumor areas leads only to an average picture which describes the most dominant clone and therefore underestimates the extent and pattern of clonal heterogeneity. MALDI MSI has demonstrated its suitability to study tumor heterogeneity in its native microenvironment.

Institute: Scientists at AAP

Prof. Dr. med. Axel Karl Walch

Head

Ulrike Buchholz

MTLA

Claudia-Mareike Pflüger

MTLA
Portrait Andreas Voss

Dipl.-Ing. Andreas Voss

Engineer

Dr. Na Sun

Postdoc

Sükriye Koccayir

Service Assistant

Jun Wang

PhD Student

Qian Wang

PhD student

Recent Publications

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2023 Scientific Article in Neural regeneration research

Mayer, J.M.*# ; Krug, C.*# ; Saller, M.M.* ; Feuchtinger, A. ; Giunta, R.E.* ; Volkmer, E.* ; Holzbach, T.*

Hypoxic pre-conditioned adipose-derived stem/progenitor cells embedded in fibrin conduits promote peripheral nerve regeneration in a sciatic nerve graft model.

Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells (ADSPCs) in peripheral nerve recovery. Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs. This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned (2% oxygen for 72 hours) autologous ADSPCs (n = 9). This treatment mode was compared with three others: fibrin conduit seeded with ADSPCs cultivated under normoxic conditions (n = 9); non-cell-carrying conduit (n = 9); and nerve autograft only (n = 9). A 16-week follow-up included functional testing (sciatic functional index and static sciatic index) as well as postmortem muscle mass analyses and morphometric nerve evaluations (histology, g-ratio, axon density, and diameter). At 8 weeks, the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups, indicating faster functional regeneration. Furthermore, histologic evaluation showed significantly increased axon outgrowth/branching, axon density, remyelination, and a reduced relative connective tissue area. Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts. Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice.

2022 Scientific Article in JCI insight

Buck, A.# ; Prade, V.M.# ; Kunzke, T. ; Erben, R.G.*&deg ; Walch, A.K.&deg

Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice.

Patients with the renal phosphate-wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI-based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency-induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization.

2022 Scientific Article in Scientific Reports

Klein-Rodewald, T. ; Micklich, K. ; Sanz-Moreno, A. ; Tost, M. ; Calzada-Wack, J. ; Adler, T. ; Klaften, M. ; Sabrautzki, S. ; Aigner, B.* ; Kraiger, M.J. ; Gailus-Durner, V. ; Fuchs, H. ; German Mouse Clinic Consortium (Aguilar-Pimentel, J.A. ; Becker, L. ; Garrett, L. ; Hölter, S.M. ; Prehn, C. ; Rácz, I. ; Rozman, J. ; Puk, O. ; Schrewe, A. ; Adamski, J. ; Esposito, I. ; Wurst, W. ; Stöger, C.) ; Gründer, A.* ; Pahl, H.* ; ... ; Hrabě de Angelis, M. ; Rathkolb, B.

New C3H KitN824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance.

Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.

2022 Scientific Article in Nature Communications

Koch, J.* ; Schober, S.J.* ; Hindupur, S.V.* ; Klein, F.G.* ; ... ; Aichler, M. ; Nawroth, R.*&deg ; Holm, P.S.*&deg

Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus.

CDK4/6 inhibitors (CDK4/6i) and oncolytic viruses are promising therapeutic agents for the treatment of various cancers. As single agents, CDK4/6 inhibitors that are approved for the treatment of breast cancer in combination with endocrine therapy cause G1 cell cycle arrest, whereas adenoviruses induce progression into S-phase in infected cells as an integral part of the their life cycle. Both CDK4/6 inhibitors and adenovirus replication target the Retinoblastoma protein albeit for different purposes. Here we show that in combination CDK4/6 inhibitors potentiate the anti-tumor effect of the oncolytic adenovirus XVir-N-31 in bladder cancer and murine Ewing sarcoma xenograft models. This increase in oncolytic potency correlates with an increase in virus-producing cancer cells, enhanced viral genome replication, particle formation and consequently cancer cell killing. The molecular mechanism that regulates this response is fundamentally based on the reduction of Retinoblastoma protein expression levels by CDK4/6 inhibitors.

2022 Scientific Article in Frontiers in Immunology

Kuhn, L.# ; Valentin, S.# ; Stojanovic, K.# ; Strobl, D.C. ; Babushku, T. ; Wang, Y. ; Rambold, U. ; Scheffler, L. ; Grath, S.* ; John-Robbert, D.* ; Blum, H.* ; Feuchtinger, A. ; Blutke, A. ; ... ; Strobl, L.J. ; Zimber-Strobl, U.

RelB contributes to the survival, migration and lymphomagenesis of B cells with constitutively active CD40 signaling.

Activation of CD40-signaling contributes to the initiation, progression and drug resistance of B cell lymphomas. We contributed to this knowledge by showing that constitutive CD40-signaling in B cells induces B cell hyperplasia and finally B cell lymphoma development in transgenic mice. CD40 activates, among others, the non-canonical NF-ĸB signaling, which is constitutively activated in several human B cell lymphomas and is therefore presumed to contribute to lymphopathogenesis. This prompted us to study the regulatory role of the non-canonical NF-ĸB transcription factor RelB in lymphomagenesis. To this end, we crossed mice expressing a constitutively active CD40 receptor in B cells with conditional RelB-KO mice. Ablation of RelB attenuated pre-malignant B cell expansion, and resulted in an impaired survival and activation of long-term CD40-stimulated B cells. Furthermore, we found that hyperactivation of non-canonical NF-кB signaling enhances the retention of B cells in the follicles of secondary lymphoid organs. RNA-Seq-analysis revealed that several genes involved in B-cell migration, survival, proliferation and cytokine signaling govern the transcriptional differences modulated by the ablation of RelB in long-term CD40-stimulated B cells. Inactivation of RelB did not abrogate lymphoma development. However, lymphomas occurred with a lower incidence and had a longer latency period. In summary, our data suggest that RelB, although it is not strictly required for malignant transformation, accelerates the lymphomagenesis of long-term CD40-stimulated B cells by regulating genes involved in migration, survival and cytokine signaling.

Previous Funding

DFG - SFB 824 "Imaging for the Selection, Monitoring and Individualization of Cancer Therapy", 3. Förderperiode (Projekt C04: "Molecular and metabolic imaging and targeting of tumor heterogeneity in pancreatic cancer")

ERA-NET TRANSCAN-2 Verbundprojekt „ARREST, Approching recurrence and resistance nechamisms in esophagogastric adenocarcinomas from the prospective MEMORI trial“

BMBF SYS-Stomach 2.Förderperiode, Verbundprojekt Sys-Stomach / Teilprojekt 5 „In-situ Proteom und Metabolomanalyse des Magenkarzinoms“

Deutsche Krebshilfe “High throughput in situ metabolomics in adrenal tumors”

BMBF SYS-Stomach 1.Förderperiode, Verbundprojekt Sys-Stomach / Teilprojekt 5 „In-situ Proteom und Metabolomanalyse des Magenkarzinoms“

DFG - SFB 824 "Imaging for the Selection, Monitoring and Individualization of Cancer Therapy" (Zentralprojekt Z02: "Zentralbereich für Histopathologie, Immunhistochemie und analytische Pathologie"), 2. Förderperiode

DFG „Improving the Clinical Application Areas of Imaging Mass Spectrometry for Selection, Monitoring and Individualization of Cancer Therapies"

BMBF „MALDI-AMK - 3D MALDI Imaging zur Analyse proteomischer Marker und klinischer Wirkstoffverteilung"

DFG „Exploring the potential of MALDI imaging mass specrometry for personalized biomarker analysis in triple-negative breast cancer patients"

BMBF „Multimodal Proteome Imaging: an Entry to Biomedical Tissue Systems Biology“

DFG - SFB 824 „Imaging for the Selection, Monitoring and Individualization of Cancer Therapy” (Zentralprojekt Z02: „Zentralbereich für Histopathologie, Immunhistochemie und analytische Mikroskopie“)

DFG - SFB 824 „Imaging for the Selection, Monitoring and Individualization of Cancer Therapy” (Teilprojekt B01: „Proteombasierte Analyse und molekulare Bildgebung des Tumormetabolismus zur Identifizierung neuer Targets für Prognosebeurteilung und ...

BMBF „Verbund EndoMed: Frühdiagnose von intraepithelialen Neoplasien und Karzinomen des Magens mittels molekularer Floureszenzendoskopie“ (Teilprojekt 4: „Identifizierung von neuen molekularen Zielstrukturen für die in vivo Bildgebung von ...

Deutsche Krebshilfe „Vergleichende lokale und systematische Proteomanalyse für die Identifizierung von Biomarkern für das Magenkarzinom“

Contact

Prof. Dr. med. Axel Karl Walch

Head

37 / 002, Building 37, Room 2