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Recreating this unique PDAC stromal architecture and its desmoplastic microenvironment in vitro is key to discover innovative treatments. However, this still remains highly challenging to realize. Herein, organotypic 3D microtumors that recapitulate PDAC\u2010stroma spatial bioarchitecture, as well as its biomolecular, metabolic, and desmoplastic signatures, are bioengineered. Such newly engineered platforms, termed stratified microenvironment spheroid models \u2013 STAMS \u2013 mimic the spatial stratification of cancer\u2010stromal cells, exhibit a reproducible morphology and sub\u2010millimeter size. In culture, 3D STAMS secrete the key molecular biomarkers found in human pancreatic cancer, namely TGF\u2010\u03b2, FGF\u20102, IL\u20101\u03b2, and MMP\u20109, among others. This is accompanied by an extensive desmoplastic reaction where collagen and glycosaminoglycans (GAGs) de novo deposition is observed. These stratified models also recapitulate the resistance to various chemotherapeutics when compared to standard cancer\u2013stroma random 3D models. Therapeutics resistance is further evidenced upon STAMS inclusion in a tumor extracellular matrix (ECM)\u2010mimetic hydrogel matrix, reinforcing the importance of mimicking PDAC\u2010stroma bioarchitectural features in vitro. The 3D STAMS technology represents a next generation of biomimetic testing platforms with improved potential for advancing high\u2010throughput screening and preclinical validation of innovative pancreatic cancer therapies.<\/jats:p>","DOI":"10.1002\/smtd.202001207","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T02:20:44Z","timestamp":1613010044000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Stratified 3D Microtumors as Organotypic Testing Platforms for Screening Pancreatic Cancer Therapies"],"prefix":"10.1002","volume":"5","author":[{"given":"Maria V.","family":"Monteiro","sequence":"first","affiliation":[{"name":"Department of Chemistry, CICECO \u2010 Aveiro Institute of Materials University of Aveiro Campus Universit\u00e1rio de Santiago  Aveiro 3810\u2010193 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