Multiplexed Deconvolution of metastasis in vivo

• Applicant: Professorin Dr. Barbara Grüner
• Subject Area: Gastroenterology ; Hematology, Oncology ; Cell Biology
• Term: from 2017 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 341532333

• Final Report Year: 2024

Final Report Abstract

Metastasis and its consequences to the patient are the primary cause of cancer deaths. Yet, how a tumor cell switches from a non-metastatic to a metastatic cell state is complex and still poorly understood at the molecular and cellular levels. Cancer cells need to leave their primary site, travel through the bloodstream to secondary sites, exit the bloodstream, seed, and start proliferating. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, as its incidence nearly equals its mortality, indicated by a 5-year survival rate of only 13 %. Metastasis of PDAC prior to detection as well as its high intrinsic resistance to all therapeutic approaches tested so far render it one of the most-difficult-to-treat cancers. Therefore, it is of pivotal importance to improve our knowledge of every aspect of this fatal disease, particularly the metastatic transition. New therapeutic approaches and agents are urgently needed and under intense investigation. Within this Emmy Noether project, we achieved several goals: We identified statins as crucial regulators of epithelial-to mesenchymal transition on pancreatic cancer, with distinct effects on cancer initiation, progression and metastasis. We found that the chromatin-remodeling factor Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC but has limited if any direct functional impact on PDAC progression and therapy resistance. We have performed multiple experiments that allowed us to lay the ground work for successful participation in the CRC 1430. And we have made profound progress in understanding the role of lipid metabolism in pancreatic cancer metastasis, work that is ongoing and of central focus for my scientific research group with focus on cell plasticity and metastasis. Taken together, by combining quantitative methods and powerful in vivo tools, we are uncovering general principles that govern tumor progression and metastatic spread. The results of this Emmy Noether project made it possible to gain new insights into metastasis and to form the basis for a successful research group on cell plasticity and metastasis.

Publications

• Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance. Scientific Reports, 8(1).
  Chiou, Shin-Heng; Dorsch, Madeleine; Kusch, Eva; Naranjo, Santiago; Kozak, Margaret M.; Koong, Albert C.; Winslow, Monte M. & Grüner, Barbara M.
  
• Cancer cells stock up in lymph vessels to survive. Nature, 585(7823), 36-37.
  Grüner, Barbara M. & Fendt, Sarah-Maria
  
• Altered Mitochondria Functionality Defines a Metastatic Cell State in Lung Cancer and Creates an Exploitable Vulnerability. Cancer Research, 81(3), 567-579.
  Chuang, Chen-Hua; Dorsch, Madeleine; Dujardin, Philip; Silas, Sukrit; Ueffing, Kristina; Hölken, Johanna M.; Yang, Dian; Winslow, Monte M. & Grüner, Barbara M.
  
• Barcoding Technology for Multiplexed Analysis of Metastatic Ability In Vivo. Methods in Molecular Biology, 239-251.
  Dujardin, Philip & Grüner, Barbara M.
  
• Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis. Cell Reports, 37(8), 110056.
  Dorsch, Madeleine; Kowalczyk, Manuela; Planque, Mélanie; Heilmann, Geronimo; Urban, Sebastian; Dujardin, Philip; Forster, Jan; Ueffing, Kristina; Nothdurft, Silke; Oeck, Sebastian; Paul, Annika; Liffers, Sven T.; Kaschani, Farnusch; Kaiser, Markus; Schramm, Alexander; Siveke, Jens T.; Winslow, Monte M.; Fendt, Sarah-Maria; Nalbant, Perihan & Grüner, Barbara M.
  
• Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC. Cancers, 13(16), 4187.
  Dujardin, Philip; Baginska, Anna K.; Urban, Sebastian & Grüner, Barbara M.
  
• A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma. Clinical Cancer Research, 29(2), 488-500.
  Kebir, Sied; Ullrich, Vivien; Berger, Pia; Dobersalske, Celia; Langer, Sarah; Rauschenbach, Laurèl; Trageser, Daniel; Till, Andreas; Lorbeer, Franziska K.; Wieland, Anja; Wilhelm-Buchstab, Timo; Ahmad, Ashar; Fröhlich, Holger; Cima, Igor; Prasad, Shruthi; Matschke, Johann; Jendrossek, Verena; Remke, Marc; Grüner, Barbara M. ... & Scheffler, Björn
  
• Decrypting drug actions and protein modifications by dose- and time-resolved proteomics. Science, 380(6640), 93-101.
  Zecha, Jana; Bayer, Florian P.; Wiechmann, Svenja; Woortman, Julia; Berner, Nicola; Müller, Julian; Schneider, Annika; Kramer, Karl; Abril-Gil, Mar; Hopf, Thomas; Reichart, Leonie; Chen, Lin; Hansen, Fynn M.; Lechner, Severin; Samaras, Patroklos; Eckert, Stephan; Lautenbacher, Ludwig; Reinecke, Maria; Hamood, Firas ... & Kuster, Bernhard
  
• KDM5B predicts temozolomide-resistant subclones in glioblastoma. iScience, 27(1), 108596.
  Ullrich, Vivien; Ertmer, Sarah; Baginska, Anna; Dorsch, Madeleine; Gull, Hanah H.; Cima, Igor; Berger, Pia; Dobersalske, Celia; Langer, Sarah; Meyer, Loona; Dujardin, Philip; Kebir, Sied; Glas, Martin; Blau, Tobias; Keyvani, Kathy; Rauschenbach, Laurèl; Sure, Ulrich; Roesch, Alexander; Grüner, Barbara M. & Scheffler, Björn