Genetic and functional heterogeneity within the tumor-initiating cell compartment of human colon cancer

• Applicant: Dr. Claudia Ball
• Subject Area: General and Visceral Surgery
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101804013

• Final Report Year: 2019

Final Report Abstract

During the KFO 227 funding period, we have established and extensively characterized biobanks of patient-derived in vivo and in vitro cancer models and investigated clonal dynamics within the tumorinitiating cell (TIC) compartment in colorectal cancers. By analyzing the contribution of individual genetically marked colorectal TIC to tumor initiation, progression and metastasis formation we demonstrated that distinct types of colorectal TIC with different self-renewal capacity drive long-term progression and metastasis formation in serial xenotransplantation assays. Importantly, we were able to show that a fraction of quiescent TIC exists within established tumors in vivo and is enriched by chemotherapy. These cells can drive disease progression following chemotherapeutic treatment. Moreover, we have conclusively shown that TIC can home to the bone marrow. These bone marrow localized TIC can proliferate actively and are located in direct vicinity of endothelial cells, which may reflect a direct interaction. Such a bone marrow TIC niche interaction may provide a promising target for pharmacologically eradicating disseminated TIC in vivo. Our systematic analysis of genetic subclone contribution in serial xenografts and spheroids has demonstrated that, in CRC, multiple subclones drive long-term tumor formation. Individual subclones can grow out during serial in vitro and in vivo passaging, and within the same patient, the dominating subclones in the xenografts and spheroids can differ. Strikingly, functional differences and genetic-clone diversity are two independent layers of heterogeneity within individual CRC tumors that need to be addressed therapeutically to overcome treatment resistance. Our overall findings gained within the KFO227 provided important novel insights into the biology and clonal dynamics of distinct types of tumor initiating cells in human colorectal cancer. The pronounced phenotypic and genetic heterogeneity of CRC TIC has substantial implications for the development and design of future studies targeting tumorigenic CRC cells.

Publications

• Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Research 73(2), 865-74 (2013)
  Bach P, Abel T, Hoffmann C, Gal Z, Braun G, Voelker I, Ball CR, Johnston IC, Lauer UM, Herold- Mende C, Muhlebach MD, Glimm H and Buchholz CJ
  
• Transforming growth factor beta receptor 2 (TGFBR2) changes sialylation in the microsatellite unstable (MSI) Colorectal cancer cell line HCT116. PLoS One 8(2), e57074 (2013)
  Lee J, Ballikaya S, Schonig K, Ball CR, Glimm H, Kopitz J and Gebert J
  
• Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nature Communications 4, 2610 (2013)
  Voloshanenko O, Erdmann G, Dubash TD, Augustin I, Metzig M, Moffa G, Hundsrucker C, Kerr G, Sandmann T, Anchang B, Demir K, Boehm C, Leible S, Ball CR, Glimm H, Spang R and Boutros M
  
• Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells. Cancer Letters 371(2), 326-33 (2016)
  Dubash TD, Hoffmann CM, Oppel F, Giessler KM, Bergmann S, Dieter SM, Hüllein J, Zenz T, Herbst F, Scholl C, Weichert W, Werft W, Benner A, Schmidt M, Schneider M, Glimm H and Ball CR
  
• Colorectal cancer initiating cells caught in the act. EMBO Molecular Medicine 9(7), 856-858 (2017)
  Dieter SM, Glimm H and Ball CR
  
• Genetic subclone architecture of the tumor-initiating cell compartment in colorectal cancer. Journal of Experimental Medicine 214(7), 2073-2088 (2017)
  Giessler KM, Kleinheinz K, Hübschmann DI, Balasubramanian GP, Dubash TD, Dieter SM, Siegl C, Herbst F, Weber S, Hoffmann CM, Fronza R, Buchhalter I, Paramasivam N, Eils R, Schmidt M, von Kalle C, Schneider M, Ulrich A, Scholl C, Fröhling S, Weitz J, Weichert W, Brors B, Schlesner M, Ball CR and Glimm H
  
• Pan-cancer analysis implicates IRS4 and IGF2 in enhancer hijacking. Nature Genetics 49(1), 65-74 (2017)
  Weischenfeldt J, Dubash TD, Drainas AP, Mardin BR, Chen Y, Stütz AM, Waszak SM, Bosco G, Halvorsen AR, Raeder B, Efthymiopoulos T, Brenner H, Brustugun OT, Dieter SM, Northcott P, Petersen I, Pfister S, Schneider M, Solberg SK, Thunissen E, Weichert W, Zichner T, Thomas R, Peifer M, Helland A, Ball CR, Jechlinger M, Sotillo R, Glimm H and Korbel JO
  
• Patient-derived Xenografts of Gastrointestinal Cancers Are Susceptible to Rapid and Delayed B-Lymphoproliferation. International Journal of Cancer 140(6), 1356-1363 (2017)
  Dieter SM, Giessler KM, Kriegsmann M, Dubash TD, Möhrmann L, Schulz E, Siegl C, Weber S, Strakerjahn H, Oberlack A, Heger U, Gao J, Hartinger EM, Oppel F, Hoffmann CM, Ha N, Brors B, Lasitschka F, Ulrich A, Strobel O, Schneider M, Weichert W, Ehrenberg KR, Glimm H and Ball CR
  
• Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors. Clinical Cancer Research 24(9):2128-2137 (2018)
  Speck T, Heidbuechel JP, Veinalde R, Jaeger D, von Kalle C, Ball CR, Ungerechts G and Engeland CE