Spatial-temporal metabolic dynamics in lung tumorigenesis

Dr. Siavash Mansouri/ Prof. Dr. Rajkumar Savai

Dr. Siavash Mansouri is a scientist at ILH, Justus Liebig university Giessen, Germany, where he co-leads the research group “spatial-temporal metabolic dynamic in lung tumorigenesis’’ with Prof. Dr. Rajkumar Savai as a Professor at the Institute for lung health (ILH), Justus Liebig university Giessen, Germany. Prof. Dr. Savai is jointly appointed at the Department of Lung Development and Remodelling at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany.

Siavash Mansouri was born in Iran. He graduated from veterinary medical faculty and completed his professional doctoral thesis (D.V.M.) with a special focus on cancer cell metabolism at Shahid Chamran University, Ahvaz, Iran. Following this, he moved to Germany to pursue further academic and research endeavors. Dr. Mansouri completed his Ph.D. at the Department of Lung Development and Remodeling at the Max Planck Institute for Heart and Lung Research in Bad Nauheim. He was also part of the Graduate Program in Molecular Biology and Medicine of the Lung (MBML) at the Justus Liebig University (JLU) under the supervision of Prof. Dr. Savai. Dr. Mansouri has started his postdoctoral training in group of ‘’lung microenvironmental niche in cancerogenesis” at ILH. His research focused on cancer cell metabolism and immune-metabolism in lung cancer by focusing on the spatial metabolome profiling of the lung tumor microenvironment (TME). Dr. Mansouri has received several awards for his scientific accomplishments, highlighting his contributions to the field of lung cancer metabolism.

Prof. Dr. Rajkumar Savai was born in Warangal, Telangana, India. After receiving his Masters (MSc) in Biochemistry from Kakatiya University, Warangal, India he moved to Germany and finished his PhD and Postdoctoral training at the Pneumology/Oncology Department at the Justus Liebig University Giessen (JLU). In 2010, he moved to the Max Planck Institute for Heart and Lung Research in Bad Nauheim. Prof. Dr. Savai serves as Scientific Coordinator at the Germany the German Center for Lung Research (DZL), Executive Committee and Planning Committee Member at the Thoracic Oncology, American Thoracic Society (ATS), Task force member of Lung cancer– Translational Research, national Network Genomic Medicine (nNGM) Lung Cancer and Co-speaker of the LOEWE program on ICANx. Prof. Dr. Savai is also Project leader and Member of the German Lung Center (DZL), Cardio-Pulmonary Institute (CPI) and Frankfurt Cancer Institute (FCI). In 2018, he served as Visiting professor at Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center. Portland, USA. Prof. Dr. Savai received several national and international awards for his scientific accomplishments. Prof. Dr. Savai published 137 research articles (Date: 15^th Sep 2024) in well-renowned scientific journals such as Science, Nature Medicine, Science Translational Medicine, Nature Genetics, Science Advances, Nature Chemical Biology, Nature Communications, Journal of Experimental Medicine, Journal of Clinical Investigation, Cancer Research, American Journal of Respiratory and Critical Care Medicine, EMBO J, EMBO Molecular Medicine. etc. (https://ilh-giessen.de/en/professorships/microenvironmental-niche-in-cancer/)

The Mansouri/Savai lab aims to elucidate the spatial-temporal metabolic architecture of lung tumors, focusing on both cancer cells and components of the TME. Our research seeks to understand how organism and cellular metabolism influence lung tumor initiation, progression, and metastasis. Our long-term goal is to translate the spatial metabolic characteristics of lung tumors into clinical applications, beginning with diagnosis. By incorporating spatial tumor metabolic characteristics into standard tumor classification together with whole human metabolic status, we aim to enhance diagnostic precision and improve the overall understanding of tumor biology. Ultimately, this will lead to more precise and effective treatments for lung cancer.

Despite significant advancements in lung cancer diagnosis and therapy, lung cancer remains one of the leading causes of cancer-related deaths worldwide, posing a substantial public health challenge. This underscores the need for a revolutionary understanding of lung tumor biology. Tumors are constrained by finite size and age parameters, with decisions regarding growth cessation and division closely linked to spatial availability of nutrients and oxygen within both the macro- and microenvironment. In tumors, this spatial decision-making is particularly important. For instance, pro-tumor macrophages are typically located in close proximity to lung cancer cells, promoting tumor growth, while anti-tumor macrophages are often kept at a distance. However, the spatial metabolic profile between pro-tumor macrophages and cancer cells are not yet defined. Moreover, as cancer cells evolve, the metabolic status of TME and cancer cell face the spatial-temporally changes, either halting or supporting tumor development. This dynamic process is achieved by constantly monitoring the spatial characteristic in surroundings, allowing cancer cells and TME components to not only appropriately time and adopt their growth, function and division processes but also metabolically crosstalk together within lung also between other organs.

This spatial metabolic awareness enables cancer cells to adapt to their TME and vice versa, facilitating survival and progression of a tumor. Understanding these spatial metabolic dynamics within the lung TME and other organs is crucial for developing effective treatments, emphasizing the need to metabolically target not only the cancer cells and TME components but also the spatial and temporal changes within the entire tumor ecosystem. By addressing the metabolic complexity and heterogeneity that contribute to tumor resilience and progression, more comprehensive and effective therapeutic strategies can be developed, ultimately improving patient outcomes. At ILH, Mansouri/Savai’s lab leverage the power of spatial metabolism by applying the cutting-edge spatial biology techniques to delve deeper into the intricacies of lung tumorigenesis in vitro, ex vivo by using precision cut lung slices and in vivo including various lung tumor models. We will integrate spatial metabolome profile with spatial transcriptomic and multiplex immunophenotyping to define the genomic and cell-specific spatial metabolome characteristic in lung TME and other organs during lung tumor progression. Based on preliminary data of spatial-temporal profiling of human lung tumor microenvironment, the following objectives (projects) are designed (Figure 1):

• Investigate lung tumor metabolic heterogeneity by focusing on identification and characterization of TME cellular components and cancer cells based on spatial metabolic profiles.
• Identify spatial metabolic biomarkers that can predict clinical outcomes by leveraging information about cellular organization and intercellular relationships.
• Understand metabolic organotropism and the seed and soil hypothesis of metastasis by the spatial metabolic profiling of the organs which targeted by lung cancer cells.
• Develop subcellular spatial resolution imaging to reveal receptor-ligand (metabolites) and mitochondria localization at cellular interfaces as important parts of tumor immunity.
• Integrate layers of spatial data to establish the spatial gene-metabolite-cell identity network and clinical relevance of subclonal alterations.

Contact

Siavash Mansouri

Spatial-temporal metabolic dynamics in lung tumorigenesis

Institute for Lung Health (ILH); Justus Liebig University

Aulweg 130

D-35392, Giessen, Germany

Max Planck Institute for Heart and Lung Research

Parkstr. 1

D-61231 Bad Nauheim, Germany

Tel: +49 (0) 6032 705 -203

Email: siavash.mansouri@mpi-bn.mpg.de

Rajkumar Savai

Professor and Chair for Lung Microenvironmental Niche in Cancerogenesis

Institute for Lung Health (ILH); Justus Liebig University

Aulweg 130

D-35392, Giessen, Germany

Max Planck Institute for Heart and Lung Research

Parkstr. 1

D-61231 Bad Nauheim, Germany

Oncology Research Unit Head

Medical Clinic IV, University Hospital of Giessen and Marburg

Scientific Coordinator – Lung Cancer Disease Area

German Center for Lung Research (DZL)

Co Speaker– LOEWE-Schwerpunkt iCANx

Cancer – Lung (Disease) Crosstalk: Tumor and Organ Microenvironment

Tel: +49 (0) 6032 705 420 (direct); Tel: +49 (0) 641 99 36451 (assistant)

Fax: +49 (0) 6032 705 471

Email: rajkumar.savai@mpi-bn.mpg.de

Email: savai.rajkumar@innere.med.uni-giessen.de

Ten most important publications

1. Mansouri S, Hemmerling I, Hesami G, Cremer S, Kirschbaum K, Klatt S, Behjati F, Schulz M, Li X, Scheller M, Müller-Tidow C, Arndt P, Günther S, Padmasekar M, Looso M, Rieger M, Kuhnert S, Vogelmeier C, Bals R, Fleming I, Zeiher A, Seeger W, Leuschner F, Savai R, Dimmeler S, Pullamsetti SS. Metabolic alterations drive inflammatory phenotypes in CHIP-associated heart failure. bioRxiv 2024 July 605744; doi: https://doi.org/10.1101/2024.07.30.605744
2. Karger A, Mansouri S, Leisegang MS, Weigert A, Günther S, Kuenne C, Wittig I, Zukunft S, Klatt S, Aliraj B, Klotz LV, Winter H, Mahavadi P, Fleming I, Ruppert C, Witte B, Alkoudmani I, Gattenlöhner S, Grimminger F, Seeger W, Pullamsetti SS, Savai R. ADPGK-AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth. EMBO J. 2023 Sep 18;42(18):e111620. IF: 11,4
3. Mansouri S, Heylmann D, Stiewe T, Kracht M, Savai R. Cancer genome and tumor microenvironment: Reciprocal crosstalk shapes lung cancer plasticity. Elife. 2022 Sep 8;11:e79895. IF: 6,4
4. Kuhnert S, Mansouri S, Rieger MA, Savai R, Avci E, Díaz-Piña G, Padmasekar M, Looso M, Hadzic S, Acker T, Klatt S, Wilhelm J, Fleming I, Sommer N, Weissmann N, Vogelmeier C, Bals R, Zeiher A, Dimmeler S, Seeger W, Pullamsetti SS. Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD. Cells. 2022 Jul 5;11(13):2121. IF: 5,1
5. Zheng X, Mansouri S, Krager A, Grimminger F, Seeger W, Pullamsetti SS, Wheelock CE, Savai R. Metabolism in tumour-associated macrophages: a quid pro quo with the tumour microenvironment. Eur Respir Rev. 2020 Oct 1;29(157):200134. IF: 9
6. Zheng X, Weigert W, Reu S, Guenther S, Mansouri S, Bassaly B, Gattenlöhner S, Grimminger F, Pullamsetti SS, Seeger W, Winter H, Savai R. Spatial Density and Distribution of Tumor-Associated Macrophages Predict Survival in Non-Small-Cell Lung Carcinoma. Cancer Res. 2020 Oct 15;80(20):4414-4425. IF: 12,5. Selected as highlight of the issue and cover page.
7. Salazar Y, Zheng X, Brunn D, Raifer H, Vogel D, Winter H, Guenther S, Weigert A, Schmall A, Tufman A, Fink L, Brüne B, Grimminger F, Seeger W, Pullamsetti SS, Huber M, Savai R. Microenvironmental Th9– and Th17– lymphocytes induce metastatic spreading in lung cancer. J Clin Invest. 2020 Jun 2:124037. IF: 13,3. Selected as highlight of the issue and cover page
8. -Pullamsetti SS, Kojonazarov B, Storn S, Gall H, Salazar Y, Wolf J, Weigert A, El-Nikhely N, Ghofrani HA, Krombach GA, Fink L, Gattenlöhner S, Rapp UR, Schermuly RT, Grimminger F, Seeger W, Savai R. Lung cancer–associated pulmonary hypertension: role of microenvironmental inflammation based on tumor cell-immune cell crosstalk. Sci Transl Med. 2017; 15;9(416). IF: 16,9. Selected as cover page
9. Savai R, Al-Tamari HM, Sedding D, Kojonazarov B, Muecke C, Teske R, Capecchi MR, Weissmann N, Grimminger G, Seeger W, Schermuly RT, Pullamsetti SS. Pro-proliferative and inflammatory signaling converge on the FoxO1 transcription factor in pulmonary hypertension. Nat Med. 2014;20:1289-300. IF: 58,7
10. Talaiezadeh A, Shahriari A, Tabandeh MR, Fathizadeh P, Mansouri S. (corresponding author) Kinetic characterization of lactate dehydrogenase in normal and malignant human breast tissues. Cancer Cell Int. 2015 Feb 15;15:19. IF:5.3

Doctoral Students

Nadezhda Nikulina, Marieke Boecker

Technical Assistant
Tim Schach