[{"article_type":"original","department":[{"_id":"EdHa"},{"_id":"MiSi"},{"_id":"GradSch"},{"_id":"AnSa"},{"_id":"NanoFab"}],"date_created":"2026-09-20T22:01:48Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","month":"09","dataavailabilitystatement":" All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials and the associated data and code repositories. Source data underlying all figures and supplementary figures have been deposited in a Zenodo repository (DOi: 10.5281/zenodo.21718217) and will be made publicly available upon publication. custom simulation and analysis codes used in this study are available at https://codeocean.com/capsule/1237446/tree. no unique biological materials were generated in this study. Microfluidic mask designs generated for this work are available from the corresponding authors upon reasonable request.","DOAJ_listed":"1","_id":"22963","intvolume":"        12","file_date_updated":"2026-10-06T11:30:48Z","oa_version":"Published Version","publication":"Science Advances","oa":1,"file":[{"content_type":"application/pdf","date_created":"2026-10-06T11:30:48Z","access_level":"open_access","relation":"main_file","checksum":"79f419b659650a39b3dfa58c782690a8","file_size":11691064,"creator":"dernst","file_name":"2026_ScienceAdv_Dunajova.pdf","date_updated":"2026-10-06T11:30:48Z","file_id":"23062","success":1}],"date_updated":"2026-10-06T11:36:34Z","related_material":{"record":[{"relation":"earlier_version","status":"public","id":"21427"}]},"das_tickbox":"1","year":"2026","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"researchdata_availability":"yes","volume":12,"publication_status":"published","OA_place":"publisher","citation":{"mla":"Dunajova, Zuzana, et al. “Substrate Heterogeneity Promotes Cancer Cell Dissemination through Interface Roughening.” <i>Science Advances</i>, vol. 12, no. 37, eaed0587, AAAS, 2026, doi:<a href=\"https://doi.org/10.1126/sciadv.aed0587\">10.1126/sciadv.aed0587</a>.","ama":"Dunajova Z, Tasciyan S, Majek J, et al. Substrate heterogeneity promotes cancer cell dissemination through interface roughening. <i>Science Advances</i>. 2026;12(37). doi:<a href=\"https://doi.org/10.1126/sciadv.aed0587\">10.1126/sciadv.aed0587</a>","ista":"Dunajova Z, Tasciyan S, Majek J, Merrin J, Jenkins RP, Sahai E, Sixt MK, Hannezo EB. 2026. Substrate heterogeneity promotes cancer cell dissemination through interface roughening. Science Advances. 12(37), eaed0587.","ieee":"Z. Dunajova <i>et al.</i>, “Substrate heterogeneity promotes cancer cell dissemination through interface roughening,” <i>Science Advances</i>, vol. 12, no. 37. AAAS, 2026.","short":"Z. Dunajova, S. Tasciyan, J. Majek, J. Merrin, R.P. Jenkins, E. Sahai, M.K. Sixt, E.B. Hannezo, Science Advances 12 (2026).","apa":"Dunajova, Z., Tasciyan, S., Majek, J., Merrin, J., Jenkins, R. P., Sahai, E., … Hannezo, E. B. (2026). Substrate heterogeneity promotes cancer cell dissemination through interface roughening. <i>Science Advances</i>. AAAS. <a href=\"https://doi.org/10.1126/sciadv.aed0587\">https://doi.org/10.1126/sciadv.aed0587</a>","chicago":"Dunajova, Zuzana, Saren Tasciyan, Juraj Majek, Jack Merrin, Robert P. Jenkins, Erik Sahai, Michael K Sixt, and Edouard B Hannezo. “Substrate Heterogeneity Promotes Cancer Cell Dissemination through Interface Roughening.” <i>Science Advances</i>. AAAS, 2026. <a href=\"https://doi.org/10.1126/sciadv.aed0587\">https://doi.org/10.1126/sciadv.aed0587</a>."},"OA_type":"gold","doi":"10.1126/sciadv.aed0587","publisher":"AAAS","project":[{"name":"Motile active matter models of migrating cells and chiral filaments","grant_number":"26360","_id":"34d75525-11ca-11ed-8bc3-89b6307fee9d"},{"_id":"bd91e723-d553-11ed-ba76-fe7eeb2185fd","grant_number":"101071793","name":"Pushing from within: Control of cell shape, integrity and motility by cytoskeletal pushing forces"}],"status":"public","issue":"37","quality_controlled":"1","title":"Substrate heterogeneity promotes cancer cell dissemination through interface roughening","abstract":[{"text":"Although studies of tumor invasion have mainly emphasized the evolution of genetic and epigenetic heterogeneity, cellular behaviors also depend on the physical microenvironment. Yet, the tumor microenvironment is both complex and continuously remodeled, making it hard to rigorously test its causal influence on tumor dissemination. Here, we adopted a reductionist approach to studying tumor cell invasion in microengineered environments of tunable patterned geometries. We find that not only the presence of obstacles but more unexpectedly their spatial disorder causes a drastic shift from a collective to a single-cell mode of invasion—comparable in strength to loss of cell-cell adhesion. Combining live-imaging and perturbation experiments with minimal biophysical modeling, we demonstrate that cell dissemination results both from local geometrical constraints and a global integration of spatial disorder over time. We identify generic universality classes of invasion dynamics dependent on environmental geometry, enabling us to identify quantitative physical principles for tumor dissemination.","lang":"eng"}],"acknowledgement":"We thank all the members of the Hannezo and Sixt groups for fruitful discussions and t. Kato for advice on the experimental setup. We are also thankful for support from the Scientific Service Units (SSU) of IST Austria through resources provided by the imaging and Optics Facility (iOF) and the Lab Support Facility (lSF). We used chatGPt (GPt- 5,OpenAi, 2025) to make minor grammatical and stylistic revisions to the original manuscript, which was written by us. We carefully reviewed and verified all changes and are solely responsible for all scientific content, data, interpretation, and conclusions. Funding: Z.D. has received funding from the Doctoral Programme of the Austrian Academy of Sciences (OeAW):grant agreement 26360. this work was supported by the European Research council (grant ERC- SyG 101071793 to M.S.). E.S. and R.P.J. are supported by the Francis Crick Institute, which receives its core funding from cancer Research UK (cc2040), the UK Medical Research council(cc2040), and the Wellcome trust (cc2040) and the European Research council (ERC Advanced Grant cAn_ORGAniSe, grant agreement number 101019366).","fulldoi":"https://doi.org/10.1126/sciadv.aed0587","ddc":["570"],"has_accepted_license":"1","pmid":1,"external_id":{"pmid":["42715298"]},"date_published":"2026-09-09T00:00:00Z","language":[{"iso":"eng"}],"supplementarymaterial":"no","article_number":"eaed0587","corr_author":"1","author":[{"last_name":"Dunajova","first_name":"Zuzana","id":"4B39F286-F248-11E8-B48F-1D18A9856A87","full_name":"Dunajova, Zuzana"},{"last_name":"Tasciyan","orcid":"0000-0003-1671-393X","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren","full_name":"Tasciyan, Saren"},{"last_name":"Majek","full_name":"Majek, Juraj","first_name":"Juraj","id":"3e6d9473-f38e-11ec-8ae0-c4e05a8aa9e1"},{"orcid":"0000-0001-5145-4609","last_name":"Merrin","id":"4515C308-F248-11E8-B48F-1D18A9856A87","first_name":"Jack","full_name":"Merrin, Jack"},{"first_name":"Robert P.","full_name":"Jenkins, Robert P.","last_name":"Jenkins"},{"last_name":"Sahai","full_name":"Sahai, Erik","first_name":"Erik"},{"full_name":"Sixt, Michael K","first_name":"Michael K","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","last_name":"Sixt","orcid":"0000-0002-6620-9179"},{"first_name":"Edouard B","id":"3A9DB764-F248-11E8-B48F-1D18A9856A87","full_name":"Hannezo, Edouard B","last_name":"Hannezo","orcid":"0000-0001-6005-1561"}],"scopus_import":"1","publication_identifier":{"eissn":["2375-2548"]},"day":"09","article_processing_charge":"Yes","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"PlanS_conform":"1","type":"journal_article"},{"date_published":"2025-09-25T00:00:00Z","language":[{"iso":"eng"}],"has_accepted_license":"1","fulldoi":"https://doi.org/10.1101/2025.05.20.655037","ddc":["539","570"],"day":"25","type":"preprint","article_processing_charge":"No","corr_author":"1","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2025.05.20.655037"}],"author":[{"last_name":"Dunajova","full_name":"Dunajova, Zuzana","first_name":"Zuzana","id":"4B39F286-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Tasciyan, Saren","first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-1671-393X","last_name":"Tasciyan"},{"last_name":"Majek","first_name":"Juraj","id":"3e6d9473-f38e-11ec-8ae0-c4e05a8aa9e1","full_name":"Majek, Juraj"},{"id":"4515C308-F248-11E8-B48F-1D18A9856A87","first_name":"Jack","full_name":"Merrin, Jack","orcid":"0000-0001-5145-4609","last_name":"Merrin"},{"last_name":"Sahai","first_name":"Erik","full_name":"Sahai, Erik"},{"orcid":"0000-0002-6620-9179","last_name":"Sixt","full_name":"Sixt, Michael K","first_name":"Michael K","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0001-6005-1561","last_name":"Hannezo","id":"3A9DB764-F248-11E8-B48F-1D18A9856A87","first_name":"Edouard B","full_name":"Hannezo, Edouard B"}],"oa_version":"Preprint","publication":"bioRxiv","related_material":{"record":[{"relation":"research_data","id":"21439","status":"public"},{"status":"public","id":"22963","relation":"later_version"},{"relation":"dissertation_contains","status":"public","id":"21423"}]},"das_tickbox":"1","oa":1,"date_updated":"2026-10-29T23:31:07Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2026-03-11T08:40:06Z","department":[{"_id":"GradSch"},{"_id":"EdHa"},{"_id":"MiSi"},{"_id":"NanoFab"},{"_id":"AnSa"}],"_id":"21427","month":"09","project":[{"name":"Pushing from within: Control of cell shape, integrity and motility by cytoskeletal pushing forces","grant_number":"101071793","_id":"bd91e723-d553-11ed-ba76-fe7eeb2185fd"},{"name":"Motile active matter models of migrating cells and chiral filaments","_id":"34d75525-11ca-11ed-8bc3-89b6307fee9d","grant_number":"26360"}],"status":"public","acknowledgement":"European Research Council, https://ror.org/0472cxd90, 101071793\r\nAustrian Academy of Sciences, 26360","abstract":[{"text":"While tumor malignancy has been extensively studied under the prism of genetic and epigenetic heterogeneity, tumor cell states also critically depend on reciprocal interactions with the microenvironment. This raises the hitherto untested possibility that heterogeneity of the untransformed tumor stroma can actively fuel malignant progression. As biological heterogeneity is inherently difficult to control, we adopted a reductionist approach and let tumor cells invade micro-engineered environments harboring obstacles with precision-controlled geometry. We find that not only the presence of obstacles, but more surprisingly their spatial disorder, causes a drastic shift from a collective to a single-cell mode of invasion – comparable in strength to cadherin loss. Combining live-imaging and perturbation experiments with minimal biophysical modeling, we demonstrate that cell detachments result both from local geometrical constraints and a global integration of spatial disorder over time. We show that different types of microenvironments map onto different universality classes of invasion dynamics - homogeneous substrates follow Kardar–Parisi–Zhang (KPZ) scaling, while disordered ones exhibit exponents consistent with KPZ with quenched disorder (KPZq). Our findings highlight generic physical principles for how the mode of cancer cell invasion depends on environmental heterogeneity, with potential implications to understand tumor evolution in vivo.","lang":"eng"}],"title":"Substrate heterogeneity promotes cancer cell dissemination through interface roughening","citation":{"ista":"Dunajova Z, Tasciyan S, Majek J, Merrin J, Sahai E, Sixt MK, Hannezo EB. Substrate heterogeneity promotes cancer cell dissemination through interface roughening. bioRxiv, <a href=\"https://doi.org/10.1101/2025.05.20.655037\">10.1101/2025.05.20.655037</a>.","ama":"Dunajova Z, Tasciyan S, Majek J, et al. Substrate heterogeneity promotes cancer cell dissemination through interface roughening. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2025.05.20.655037\">10.1101/2025.05.20.655037</a>","mla":"Dunajova, Zuzana, et al. “Substrate Heterogeneity Promotes Cancer Cell Dissemination through Interface Roughening.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2025.05.20.655037\">10.1101/2025.05.20.655037</a>.","chicago":"Dunajova, Zuzana, Saren Tasciyan, Juraj Majek, Jack Merrin, Erik Sahai, Michael K Sixt, and Edouard B Hannezo. “Substrate Heterogeneity Promotes Cancer Cell Dissemination through Interface Roughening.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2025.05.20.655037\">https://doi.org/10.1101/2025.05.20.655037</a>.","apa":"Dunajova, Z., Tasciyan, S., Majek, J., Merrin, J., Sahai, E., Sixt, M. K., &#38; Hannezo, E. B. (n.d.). Substrate heterogeneity promotes cancer cell dissemination through interface roughening. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2025.05.20.655037\">https://doi.org/10.1101/2025.05.20.655037</a>","short":"Z. Dunajova, S. Tasciyan, J. Majek, J. Merrin, E. Sahai, M.K. Sixt, E.B. Hannezo, BioRxiv (n.d.).","ieee":"Z. Dunajova <i>et al.</i>, “Substrate heterogeneity promotes cancer cell dissemination through interface roughening,” <i>bioRxiv</i>. ."},"publication_status":"draft","OA_place":"repository","year":"2025","tmp":{"image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"doi":"10.1101/2025.05.20.655037"},{"publication":"Biophysical Journal","oa_version":"Published Version","file_date_updated":"2024-07-16T12:09:55Z","intvolume":"       123","das_tickbox":"0","date_updated":"2026-09-24T10:26:59Z","file":[{"success":1,"date_updated":"2024-07-16T12:09:55Z","file_id":"17266","file_name":"2024_BiophysicalJournal_Azadbakht.pdf","creator":"dernst","checksum":"1c8fe1cf950394875b65b90da86428ff","file_size":3189926,"relation":"main_file","access_level":"open_access","date_created":"2024-07-16T12:09:55Z","content_type":"application/pdf"}],"isi":1,"oa":1,"date_created":"2024-01-21T23:00:56Z","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","department":[{"_id":"AnSa"}],"article_type":"original","ec_funded":1,"_id":"14844","month":"02","quality_controlled":"1","issue":"3","status":"public","publisher":"Elsevier","project":[{"call_identifier":"H2020","_id":"eba2549b-77a9-11ec-83b8-a81e493eae4e","grant_number":"802960","name":"Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines"}],"acknowledgement":"We gratefully acknowledge useful discussions with Casper van der Wel, help by Yogesh Shelke with PAA coverslip preparation, and support by Rachel Doherty with particle functionalization. A.A. and D.J.K. would like to thank Timon Idema and George Dadunashvili for initial attempts to simulate the experimental system. D.J.K. would like to thank the physics department at Leiden University for funding the PhD position of A.A. B.M. and A.Š. acknowledge funding by the European Union’s Horizon 2020 research and innovation programme (ERC starting grant no. 802960).","title":"Nonadditivity in interactions between three membrane-wrapped colloidal spheres","abstract":[{"text":"Many cell functions require a concerted effort from multiple membrane proteins, for example, for signaling, cell division, and endocytosis. One contribution to their successful self-organization stems from the membrane deformations that these proteins induce. While the pairwise interaction potential of two membrane-deforming spheres has recently been measured, membrane-deformation-induced interactions have been predicted to be nonadditive, and hence their collective behavior cannot be deduced from this measurement. We here employ a colloidal model system consisting of adhesive spheres and giant unilamellar vesicles to test these predictions by measuring the interaction potential of the simplest case of three membrane-deforming, spherical particles. We quantify their interactions and arrangements and, for the first time, experimentally confirm and quantify the nonadditive nature of membrane-deformation-induced interactions. We furthermore conclude that there exist two favorable configurations on the membrane: (1) a linear and (2) a triangular arrangement of the three spheres. Using Monte Carlo simulations, we corroborate the experimentally observed energy minima and identify a lowering of the membrane deformation as the cause for the observed configurations. The high symmetry of the preferred arrangements for three particles suggests that arrangements of many membrane-deforming objects might follow simple rules.","lang":"eng"}],"publication_status":"published","citation":{"ista":"Azadbakht A, Meadowcroft B, Majek J, Šarić A, Kraft DJ. 2024. Nonadditivity in interactions between three membrane-wrapped colloidal spheres. Biophysical Journal. 123(3), 307–316.","ama":"Azadbakht A, Meadowcroft B, Majek J, Šarić A, Kraft DJ. Nonadditivity in interactions between three membrane-wrapped colloidal spheres. <i>Biophysical Journal</i>. 2024;123(3):307-316. doi:<a href=\"https://doi.org/10.1016/j.bpj.2023.12.020\">10.1016/j.bpj.2023.12.020</a>","mla":"Azadbakht, Ali, et al. “Nonadditivity in Interactions between Three Membrane-Wrapped Colloidal Spheres.” <i>Biophysical Journal</i>, vol. 123, no. 3, Elsevier, 2024, pp. 307–16, doi:<a href=\"https://doi.org/10.1016/j.bpj.2023.12.020\">10.1016/j.bpj.2023.12.020</a>.","chicago":"Azadbakht, Ali, Billie Meadowcroft, Juraj Majek, Anđela Šarić, and Daniela J. Kraft. “Nonadditivity in Interactions between Three Membrane-Wrapped Colloidal Spheres.” <i>Biophysical Journal</i>. Elsevier, 2024. <a href=\"https://doi.org/10.1016/j.bpj.2023.12.020\">https://doi.org/10.1016/j.bpj.2023.12.020</a>.","apa":"Azadbakht, A., Meadowcroft, B., Majek, J., Šarić, A., &#38; Kraft, D. J. (2024). Nonadditivity in interactions between three membrane-wrapped colloidal spheres. <i>Biophysical Journal</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.bpj.2023.12.020\">https://doi.org/10.1016/j.bpj.2023.12.020</a>","short":"A. Azadbakht, B. Meadowcroft, J. Majek, A. Šarić, D.J. Kraft, Biophysical Journal 123 (2024) 307–316.","ieee":"A. Azadbakht, B. Meadowcroft, J. Majek, A. Šarić, and D. J. Kraft, “Nonadditivity in interactions between three membrane-wrapped colloidal spheres,” <i>Biophysical Journal</i>, vol. 123, no. 3. Elsevier, pp. 307–316, 2024."},"researchdata_availability":"no","tmp":{"image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"year":"2024","volume":123,"doi":"10.1016/j.bpj.2023.12.020","pmid":1,"date_published":"2024-02-06T00:00:00Z","external_id":{"pmid":["38158654"],"isi":["001185235900001"]},"language":[{"iso":"eng"}],"has_accepted_license":"1","ddc":["570"],"fulldoi":"https://doi.org/10.1016/j.bpj.2023.12.020","day":"06","type":"journal_article","article_processing_charge":"Yes (in subscription journal)","page":"307-316","supplementarymaterial":"no","publication_identifier":{"issn":["0006-3495"],"eissn":["1542-0086"]},"scopus_import":"1","author":[{"last_name":"Azadbakht","full_name":"Azadbakht, Ali","first_name":"Ali"},{"orcid":"0000-0003-3441-1337","last_name":"Meadowcroft","full_name":"Meadowcroft, Billie","id":"a4725fd6-932b-11ed-81e2-c098c7f37ae1","first_name":"Billie"},{"last_name":"Majek","full_name":"Majek, Juraj","id":"3e6d9473-f38e-11ec-8ae0-c4e05a8aa9e1","first_name":"Juraj"},{"orcid":"0000-0002-7854-2139","last_name":"Šarić","id":"bf63d406-f056-11eb-b41d-f263a6566d8b","first_name":"Anđela","full_name":"Šarić, Anđela"},{"last_name":"Kraft","full_name":"Kraft, Daniela J.","first_name":"Daniela J."}]}]