Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models.
| Title: | Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models. |
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| Authors: | Struth E; Department of Physics, University of Massachusetts Boston, Boston, MA, 02125, USA.; Labaf M; Department of Mathematics, University of Massachusetts Boston, Boston, MA, 02125, USA.; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA.; Karimnia V; Department of Physics, University of Massachusetts Boston, Boston, MA, 02125, USA.; Liu Y; Department of Physics, University of Massachusetts Boston, Boston, MA, 02125, USA.; Cramer G; Department of Physics, University of Massachusetts Boston, Boston, MA, 02125, USA.; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Dahl JB; Department of Engineering, University of Massachusetts Boston, Boston, MA, 02125, USA.; Slack FJ; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School Initiative for RNA Medicine, Boston, MA, 02115, USA.; Zarringhalam K; Department of Mathematics, University of Massachusetts Boston, Boston, MA, 02125, USA.; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA.; Celli JP; Department of Physics, University of Massachusetts Boston, Boston, MA, 02125, USA. jonathan.celli@umb.edu.; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA. jonathan.celli@umb.edu. |
| Source: | Scientific reports [Sci Rep] 2024 Sep 05; Vol. 14 (1), pp. 20698. Date of Electronic Publication: 2024 Sep 05. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : Nature Publishing Group, copyright 2011- |
| MeSH Terms: | Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/metabolism ; Stromal Cells*/metabolism ; Fibroblasts*/metabolism ; Carcinoma, Pancreatic Ductal*/pathology ; Carcinoma, Pancreatic Ductal*/metabolism ; Coculture Techniques* ; Drug Resistance, Neoplasm* ; Cell Communication*; Cancer-Associated Fibroblasts/metabolism ; Cancer-Associated Fibroblasts/pathology ; Pancreatic Stellate Cells/metabolism ; Pancreatic Stellate Cells/drug effects ; Extracellular Matrix/metabolism ; Humans ; Cell Line, Tumor ; Tumor Microenvironment |
| Abstract: | Interactions between tumor and stromal cells are well known to play prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs, though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use time lapse imaging and image analysis to study how co-culture geometry impacts interactions between epithelial and stromal cells. We show that extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1) result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility. We analyze these interactions in co-cultures using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. We further contrast co-cultures of PANC1 with those containing a drug resistant subline (PANC1-OR) previously established in our lab and find that heterotypic cell-cell interactions are suppressed in the latter relative to the parental line. We use RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also correlated with reduction in the hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation.; (© 2024. The Author(s).) |
| Comments: | Update of: bioRxiv. 2024 Jul 17:2024.07.14.602133. doi: 10.1101/2024.07.14.602133.. (PMID: 39071263) |
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| Grant Information: | R35 CA232105 United States CA NCI NIH HHS; R35CA232105 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); U54CA156734 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) |
| Entry Date(s): | Date Created: 20240905 Date Completed: 20240905 Latest Revision: 20250720 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11377574 |
| DOI: | 10.1038/s41598-024-71372-9 |
| PMID: | 39237667 |
| Database: | MEDLINE |
Journal Article