Menekse Ermis a,1, Natashya Falcone a,1, Natan Roberto de Barros a, Marvin Mecwan a, Reihaneh Haghniaz a, Auveen Choroomi a, Mahsa Monirizad a, Yeji Lee b, Jihyeon Song b, Hyun-Jong Cho c, Yangzhi Zhu a, Heemin Kang d, Mehmet R. Dokmeci a, Ali Khademhosseini a, Junmin Lee b,e, Han-Jun Kim a,f
aTerasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
bDepartment of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, 37673, Republic of Korea
cCollege of Pharmacy, Kangwon National University, Chuncheon, Gangwon, 24341, Republic of Korea
dDepartment of Materials Science and Engineering, Korea University, Seoul, 02841, Republic of Korea
eInstitute for Convergence Research and Education in Advanced Technology, Yonsei University, Incheon 21983, Republic of Korea
fCollege of Pharmacy, Korea University, Sejong, 30019, Republic of Korea
1These authors contributed equally to this work.
Corresponding authors: Ali Khademhosseini, Junmin Lee, Han-Jun Kim
The tumor microenvironment consists of diverse, complex etiological factors. The matrix component of pancreatic ductal adenocarcinoma (PDAC) plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness. Although significant efforts have been made to model desmoplastic PDAC, existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC. Here, two major components in desmoplastic pancreatic matrices, hyaluronic acid- and gelatin-based hydrogels, are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts (CAF). Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation. Higher expression levels of markers associated with proliferation, epithelial to mesenchymal transition, mechanotransduction, and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels, while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1 (TGF-β1). The proposed multicellular pancreatic tumor model, in combination with proper mechanical properties and TGF-β1 supplement, makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors, which could be potentially applicable for realizing personalized medicine and drug testing applications.