title: Heterogeneous tumor subpopulations cooperate to drive invasion.
abstract: Clonal selection and transcriptional reprogramming (e.g., epithelial-mesenchymal transition or phenotype switching) are the predominant theories thought to underlie tumor progression. However, a "division of labor" leading to cooperation among tumor-cell subpopulations could be an additional catalyst of progression. Using a zebrafish-melanoma xenograft model, we found that in a heterogeneous setting, inherently invasive cells, which possess protease activity and deposit extracellular matrix (ECM), co-invade with subpopulations of poorly invasive cells, a phenomenon we term "cooperative invasion". Whereas the poorly invasive cells benefit from heterogeneity, the invasive cells switch from protease-independent to an MT1-MMP-dependent mode of invasion. We did not observe changes in expression of the melanoma phenotype determinant MITF during cooperative invasion, thus ruling out the necessity for phenotype switching for invasion. Altogether, our data suggest that cooperation can drive melanoma progression without the need for clonal selection or phenotype switching and can account for the preservation of heterogeneity seen throughout tumor progression.
authors: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors: Anna
authors: A
authors: Chapman
authors: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors: Laura
authors: L
authors: Fernandez del Ama
authors: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors: Jennifer
authors: J
authors: Ferguson
authors: Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland.
authors: Jivko
authors: J
authors: Kamarashev
authors: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK. Electronic address: claudia.wellbrock@manchester.ac.uk.
authors: Claudia
authors: C
authors: Wellbrock
authors: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK. Electronic address: adam.hurlstone@manchester.ac.uk.
authors: Adam
authors: A
authors: Hurlstone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D065150:Cellular Reprogramming; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000145:classification / Q000502:physiology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010641:Phenotype; D015027:Zebrafish
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D053511:Matrix Metalloproteinase 14