Differential Effects of Confinement on the Dynamics of Normal and Tumor-Derived Pancreatic Ductal Organoids
Year: 2024
Type: article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the epithelia comprising the ductal network of the pancreas. During disease progression, PDAC tumors recruit fibroblasts that promote fibrosis, increasing local tissue stiffness and subjecting epithelial cells to increased compressive forces. Previous in vitro studies have documented cytoskeletal and nuclear adaptation following compressive stresses in two-dimensional (2D) and three-dimensional (3D) environments. However, a comparison of the responses of normal and tumor-derived ductal epithelia to physiologically relevant confinement remains underexplored, especially in 3D organoids. Here we control confinement with an engineered 3D microenvironment composed of Matrigel mixed with a low yield stress granular microgel. Normal and tumor-derived murine pancreas organoids (normal and tumor) were cultured for 48 h within this composite 3D environment or in pure Matrigel to investigate the effects of confinement on morphogenesis and lumen expansion. In confinement, tumor organoids (mT) formed a lumen that expanded rapidly, whereas normal organoids (mN) expanded more slowly. Moreover, a majority of normal organoids in more-confined conditions exhibited an inverted apicobasal polarity compared to those in less-confined conditions. Tumor organoids exhibited a collective "pulsing" behavior that increased in confinement. These pulses generated forces sufficient to locally overcome the yield stress of the microgels in the direction of organoid expansion. Normal organoids more commonly exhibit unidirectional rotation. Our in vitro microgel confinement platform enabled the discovery of two distinct modes of collective force generation in organoids that may shed light on the mutual interactions between tumors and the microenvironment. These insights into in vitro dynamics may deepen our understanding of how the confinement of healthy cells within a fibrotic tumor niche disrupts tissue organization and function in vivo.
Source: ACS Applied Bio Materials
Authors: Jonah M. Rosas, Joseph P. Campanale, Jacob L. Harwood, Lufei Li, Rachel Bae, Shujun Cheng, Julia M. Tsou, Kathi M. Kaiser, Dannielle D. Engle, Denise J. Montell, Angela A. Pitenis
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Hispanic Scholarship Fund, National Science Foundation, American Cancer Society, Bill and Melinda Gates Foundation, National Institutes of Health, University of California, Santa Barbara, Materials Research Science and Engineering Center, Harvard University, National Institute of General Medical Sciences, Division of Materials Research, Division of Civil, Mechanical and Manufacturing Innovation
Awards: G1141670404, G2232042528, Materials Research Science and Engineering Center at UCSB, G3387330441, G3664610177, G401861217, G4281768896, CAREER: Dynamics of Fragile Interfaces, G527763833, G6282714480, G6671297155, Coordination of collective motility by cell polarity signaling, G9000146344, G928865086
OpenAlex ID: W4404627333