Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

Pan, Haopeng; Zhu, Shajun; Gong, Tiancheng; Wu, Di; Zhao, Yahong; Yan, Jiashuai; Dai, Chaolun; Huang, Yan; Yang, Yumin; Guo, Yibing

doi:10.1039/d3bm00598d

Cited by 5 publications

(5 citation statements)

References 77 publications

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“…Increase in hydrogel stiffness changed the sensitivity of breast cancer cells to DOX. A stiffened hydrogel was found to decrease the sensitivity of cells to drug, which is consistent with previous reports [ 23 , 52 , 53 ]. Furthermore, the expression of P-gP mRNA increased when cells were incubated in the agarose hydrogels with DOX, which should be because cancer cells exposing to DOX can stimulate P-gP expression [ 34 ].…”

Section: Resultssupporting

confidence: 92%

Effect of Hydrogel Stiffness on Chemoresistance of Breast Cancer Cells in 3D Culture

Zeng,

Chen,

Yoshitomi

et al. 2024

Gels

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Chemotherapy is one of the most common strategies for cancer treatment, whereas drug resistance reduces the efficiency of chemotherapy and leads to treatment failure. The mechanism of emerging chemoresistance is complex and the effect of extracellular matrix (ECM) surrounding cells may contribute to drug resistance. Although it is well known that ECM plays an important role in orchestrating cell functions, it remains exclusive how ECM stiffness affects drug resistance. In this study, we prepared agarose hydrogels of different stiffnesses to investigate the effect of hydrogel stiffness on the chemoresistance of breast cancer cells to doxorubicin (DOX). Agarose hydrogels with a stiffness range of 1.5 kPa to 112.3 kPa were prepared and used to encapsulate breast cancer cells for a three-dimensional culture with different concentrations of DOX. The viability of the cells cultured in the hydrogels was dependent on both DOX concentration and hydrogel stiffness. Cell viability decreased with DOX concentration when the cells were cultured in the same stiffness hydrogels. When DOX concentration was the same, breast cancer cells showed higher viability in high-stiffness hydrogels than they did in low-stiffness hydrogels. Furthermore, the expression of P-glycoprotein mRNA in high-stiffness hydrogels was higher than that in low-stiffness hydrogels. The results suggested that hydrogel stiffness could affect the resistance of breast cancer cells to DOX by regulating the expression of chemoresistance-related genes.

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Section: Resultssupporting

confidence: 92%

Effect of Hydrogel Stiffness on Chemoresistance of Breast Cancer Cells in 3D Culture

Zeng,

Chen,

Yoshitomi

et al. 2024

Gels

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“…Furthermore, here we report that PDAC cells with acquired chemoresistance to gemcitabine and paclitaxel adopt an increased contractile behavior as compared to their parental clones. Previous studies mainly focused on investigating PDAC chemoresistance triggered by culturing drug-sensitive cells on substrates with varying stiffness [9,10,38,39]. For instance, Shah and collaborators characterized some mechanical features of PDAC cells with acquired gemcitabine resistance [15], showing a switch to mesenchymal phenotype and an increased migratory/invasive potential.…”

Section: Discussionmentioning

confidence: 99%

“…The cell line SUIT-2.028 has an epithelial-like phenotype, while PATU-T and SUIT-2.007 were representative of the mesenchymal phenotype. Given that no significant difference was observed between the intermediate stiffness values (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47), and that the stiffest value investigated (142 kPa) has less physiological relevance for PDAC, in what follows we proceeded in comparing the soft and stiff substrates of 11 and 47 kPa only. We first confirmed, as for the non-resistant cells, that PDAC chemoresistant cells had variable cell spreading area, and that the mean force per pillar was a faithful measure of traction forces (see Supplemental Table 4 and Supplemental Figure 4).…”

Section: Pdac Cells Force Generation Is Stiffness-dependentmentioning

confidence: 99%

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel

Gregori,

Bergonzini,

Capula

et al. 2024

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding of some biological mechanisms of chemoresistance, much of those mechanisms remain to be uncovered. Mechanobiology, which studies physical properties of cells, holds promise as a potential target for addressing challenges of chemoresistance in PDAC. Therefore, we here in an initial step, assessed the altered mechanobiology of PDAC cells with acquired chemoresistance to gemcitabine and paclitaxel. Methods: Five PDAC cell lines and six stably-resistant subclones were assessed for force generation on elastic micropillar arrays. Those measurements of mechanical phenotype were complemented by single-cell motility and invasion in collagen matrix were investigated using 2D models and 3D extracellular matrix-mimetic, respectively. Further the nuclear translocation of Yes-associted protein (YAP), as a measure of active mechanical status, was compared, and biomarkers of the epithelial-to-mesenchymal transition (EMT) were evaluated using RT-PCR. Results: PDAC cells with acquired chemoresistance exert higher traction forces than their parental/wild-type (WT) cells. In 2D, single-cell motility was altered for all chemoresistant cells, with a cell-type specific pattern. In 3D, spheroids of chemoresistant PDAC cells were able to invade the matrix, and remodel collagen more than their WT clones. However, YAP nuclear translocation and EMT were not significantly altered in relation to changes in other physical parameters. Conclusion: This is the first study to investigate and report on the altered mechanobiological features for PDAC cells that have acquired chemoresistance. A better understanding of mechanical features could help in identifying future targets to overcome chemoresistance in PDAC.

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“…Our previous studies have shown that a stiff hydrogel can change the sensitivity of tumor cells to chemotherapy drugs, and the potential mechanism maybe changes in the level of autophagy. 11 It has also been suggested that changes in matrix stiffness have been shown to activate intracellular mechanical signal transduction pathways, which in turn affect the nuclear localization of YAP and ultimately regulate the development of different organs. 7 Moreover, YAP signaling has been shown to have different roles at different stages of pancreatic β-cell differentiation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Thus far, many studies have confirmed that in vitro simulation of the matrix stiffness of the ECM can activate organ development signals in vivo, thereby altering cell differentiation or drug sensitivity. Our previous studies have shown that a stiff hydrogel can change the sensitivity of tumor cells to chemotherapy drugs, and the potential mechanism maybe changes in the level of autophagy . It has also been suggested that changes in matrix stiffness have been shown to activate intracellular mechanical signal transduction pathways, which in turn affect the nuclear localization of YAP and ultimately regulate the development of different organs .…”

Section: Introductionmentioning

confidence: 99%

Biomimetic Hydrogels Promote Pseudoislet Formation to Improve Glycemic Control in Diabetic Mice

Zhu,

Xu,

et al. 2024

ACS Biomater. Sci. Eng.

Self Cite

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Islet or β-cell transplantation is currently considered to be the ideal treatment for diabetes, and three-dimensional (3D) bioprinting of a bionic pancreas with physiological stiffness is considered to be promising for the encapsulation and transplantation of β-cells. In this study, a 5%GelMA/2%AlgMA hybrid hydrogel with pancreatic physiological stiffness was constructed and used for β-cell encapsulation, 3D bioprinting, and in vivo transplantation to evaluate glycemic control in diabetic mice. The hybrid hydrogel had good cytocompatibility and could induce insulin-producing cells (IPCs) to form pseudoislet structures and improve insulin secretion. Furthermore, we validated the importance of betacellulin (BTC) in IPCs differentiation and confirmed that IPCs self-regulation was achieved by altering the nuclear and cytoplasmic distributions of BTC expression. In vivo transplantation of diabetic mice quickly restored blood glucose levels. In the future, 3D bioprinting of β-cells using biomimetic hydrogels will provide a promising platform for clinical islet transplantation for the treatment of diabetes.

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Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma

Abstract: Matrix stiffness based on GelMA hydrogel triggers chemoresistance to gemcitabine through autophagy in pancreatic ductal adenocarcinoma.

Cited by 5 publications

References 77 publications

Effect of Hydrogel Stiffness on Chemoresistance of Breast Cancer Cells in 3D Culture

Effect of Hydrogel Stiffness on Chemoresistance of Breast Cancer Cells in 3D Culture

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel

Biomimetic Hydrogels Promote Pseudoislet Formation to Improve Glycemic Control in Diabetic Mice

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