scholarly journals Hydrogel Models with Stiffness Gradients for Interrogating Pancreatic Cancer Cell Fate

2021 ◽  
Vol 8 (3) ◽  
pp. 37
Author(s):  
Chun-Yi Chang ◽  
Chien-Chi Lin
Keyword(s):  
Pancreatic Cancer ◽  
Cell Fate ◽  
Cancer Cell ◽  
Stromal Cells ◽  
Ductal Adenocarcinoma ◽  
Tumor Models ◽  
The Past ◽  
Matrix Properties ◽  
Migration Of Cells

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has seen only modest improvements in patient survival rate over the past few decades. PDAC is highly aggressive and resistant to chemotherapy, owing to the presence of a dense and hypovascularized fibrotic tissue, which is composed of stromal cells and extracellular matrices. Increase deposition and crosslinking of matrices by stromal cells lead to a heterogeneous microenvironment that aids in PDAC development. In the past decade, various hydrogel-based, in vitro tumor models have been developed to mimic and recapitulate aspects of the tumor microenvironment in PDAC. Advances in hydrogel chemistry and engineering should provide a venue for discovering new insights regarding how matrix properties govern PDAC cell growth, migration, invasion, and drug resistance. These engineered hydrogels are ideal for understanding how variation in matrix properties contributes to the progressiveness of cancer cells, including durotaxis, the directional migration of cells in response to a stiffness gradient. This review surveys the various hydrogel-based, in vitro tumor models and the methods to generate gradient stiffness for studying migration and other cancer cell fate processes in PDAC.

scholarly journals Systematic Generation of Patient-Derived Tumor Models in Pancreatic Cancer

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 142 ◽  
Author(s):  
Karl Roland Ehrenberg ◽  
Jianpeng Gao ◽  
Felix Oppel ◽  
Stephanie Frank ◽  
Na Kang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Decision Making ◽  
Primary Cultures ◽  
Ductal Adenocarcinoma ◽  
In Vitro Cultivation ◽  
Tumor Models ◽  
Primary Tumors ◽  
Immunodeficient Mice ◽  
Resected Patient

In highly aggressive malignancies like pancreatic cancer (PC), patient-derived tumor models can serve as disease-relevant models to understand disease-related biology as well as to guide clinical decision-making. In this study, we describe a two-step protocol allowing systematic establishment of patient-derived primary cultures from PC patient tumors. Initial xenotransplantation of surgically resected patient tumors (n = 134) into immunodeficient mice allows for efficient in vivo expansion of vital tumor cells and successful tumor expansion in 38% of patient tumors (51/134). Expansion xenografts closely recapitulate the histoarchitecture of their matching patients’ primary tumors. Digestion of xenograft tumors and subsequent in vitro cultivation resulted in the successful generation of semi-adherent PC cultures of pure epithelial cell origin in 43.1% of the cases. The established primary cultures include diverse pathological types of PC: Pancreatic ductal adenocarcinoma (86.3%, 19/22), adenosquamous carcinoma (9.1%, 2/22) and ductal adenocarcinoma with oncocytic IPMN (4.5%, 1/22). We here provide a protocol to establish quality-controlled PC patient-derived primary cell cultures from heterogeneous PC patient tumors. In vitro preclinical models provide the basis for the identification and preclinical assessment of novel therapeutic opportunities targeting pancreatic cancer.

scholarly journals EI24 Suppresses Tumorigenesis in Pancreatic Cancer via Regulating c-Myc

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yi Zang ◽  
Lei Zhu ◽  
Tong Li ◽  
Qi Wang ◽  
Juanjuan Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Transmembrane Protein ◽  
Beclin 1 ◽  
Ductal Adenocarcinoma ◽  
Antitumor Effects ◽  
Pancreatic Cancer Cells

The EI24 autophagy-associated transmembrane protein is frequently associated with tumor growth and patient survival. In the present study, we found that EI24 was downregulated in pancreatic ductal adenocarcinoma (PDAC) tissues compared with adjacent normal tissues and was associated with cancer cell differentiation. Overexpression of EI24 suppressed cancer cell growth in vitro and in vivo and induced cell cycle S phase arrest, with no impact on caspase-dependent apoptosis. EI24 overexpression also resulted in reduced c-Myc expression, an oncogene in PDAC, accompanied with increased LC3B-II formation, increased Beclin-1, and diminished p62. Together, we propose that EI24 suppresses cell proliferation and prompts cell cycle arrest in pancreatic cancer cells by activating the autophagic lysosomal degradation of c-Myc. Our results suggest a potential mechanism underlying the antitumor effects of EI24 in PDAC and provide insight into the crosstalk between autophagy and cell proliferation involving a possible EI24/Beclin-1/p62/c-Myc signaling pathway.

scholarly journals A pancreas tumor derived organoid study: from drug screen to precision medicine

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jia Yao ◽  
Man Yang ◽  
Lawrence Atteh ◽  
Pinyan Liu ◽  
Yongcui Mao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Tumor ◽  
Ductal Adenocarcinoma ◽  
Drug Screen ◽  
Appreciable Change ◽  
The Past ◽  
Pancreas Tumor ◽  
New Strategy ◽  
Systemic Therapies

AbstractPancreatic ductal adenocarcinoma (PDAC) one of the deadliest malignant tumor. Despite considerable progress in pancreatic cancer treatment in the past 10 years, PDAC mortality has shown no appreciable change, and systemic therapies for PDAC generally lack efficacy. Thus, developing biomarkers for treatment guidance is urgently required. This review focuses on pancreatic tumor organoids (PTOs), which can mimic the characteristics of the original tumor in vitro. As a powerful tool with several applications, PTOs represent a new strategy for targeted therapy in pancreatic cancer and contribute to the advancement of the field of personalized medicine.

scholarly journals Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo

PLoS ONE ◽  
2009 ◽  
Vol 4 (7) ◽  
pp. e6278 ◽  
Author(s):  
Beatrice Cousin ◽  
Emmanuel Ravet ◽  
Sandrine Poglio ◽  
Fabienne De Toni ◽  
Mélanie Bertuzzi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Adipose Tissue ◽  
Cancer Cell ◽  
Stromal Cells ◽  
Pancreatic Cancer Cell ◽  
Human Adipose Tissue ◽  
Cancer Cell Death

scholarly journals TRIM29 as a Novel Biomarker in Pancreatic Adenocarcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Hongli Sun ◽  
Xianwei Dai ◽  
Bing Han
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Multivariate Logistic Regression Analysis ◽  
Immunohistochemical Analysis ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Tripartite Motif

Background and Aim. Tripartite motif-containing 29 (TRIM29) is structurally a member of the tripartite motif family of proteins and is involved in diverse human cancers. However, its role in pancreatic cancer remains unclear.Methods. The expression pattern of TRIM29 in pancreatic ductal adenocarcinoma was assessed by immunocytochemistry. Multivariate logistic regression analysis was used to investigate the association between TRIM29 and clinical characteristics.In vitroanalyses by scratch wound healing assay and invasion assays were performed using the pancreatic cancer cell lines.Results. Immunohistochemical analysis showed TRIM29 expression in pancreatic cancer tissues was significantly higher  (n=186)than that in matched adjacent nontumor tissues. TRIM29 protein expression was significantly correlated with lymph node metastasis(P=0.019). Patients with positive TRIM29 expression showed both shorter overall survival and shorter recurrence-free survival than those with negative TRIM29 expression. Multivariate analysis revealed that TRIM29 was an independent factor for pancreatic cancer over survival (HR=2.180, 95% CI: 1.324–4.198,P=0.011).In vitro,TRIM29 knockdown resulted in inhibition of pancreatic cancer cell proliferation, migration, and invasion.Conclusions. Our results indicate that TRIM29 promotes tumor progression and may be a novel prognostic marker for pancreatic ductal adenocarcinoma.

scholarly journals Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Maria Saliakoura ◽  
Matteo Rossi Sebastiano ◽  
Ioanna Nikdima ◽  
Chiara Pozzato ◽  
Georgia Konstantinidou
Keyword(s):  
Pancreatic Cancer ◽  
Fatty Acids ◽  
Cancer Cell ◽  
Human Cancer ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Extracellular Lipid ◽  
Autophagy Inhibition

Abstract Background KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer. Methods To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the KrasG12D/+;p53flox/flox;Pdx1-CreERT2 (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice. Results Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment. Conclusions Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.

scholarly journals Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fumihiko Matsuzawa ◽  
Hirofumi Kamachi ◽  
Tatsuzo Mizukami ◽  
Takahiro Einama ◽  
Futoshi Kawamata ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Morphological Changes ◽  
Pancreatic Cancer Cells ◽  
Cell Invasiveness ◽  
And Migration ◽  
Migration Capacity

Abstract Background Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. Methods We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. Results Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. Conclusions Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

scholarly journals Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Theresa Weickert ◽  
Judith S. Hecker ◽  
Michèle C. Buck ◽  
Christina Schreck ◽  
Jennifer Rivière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Cell Types ◽  
Bone Marrow Niche ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

scholarly journals Forkhead box B2 inhibits the malignant characteristics of the pancreatic cancer cell line Panc‐1 in vitro

2019 ◽  
Vol 24 (10) ◽  
pp. 674-681
Author(s):  
Hiroki Fukuchi ◽  
Yukinobu Hayashida ◽  
Kunio Inoue ◽  
Yoshifusa Sadamura
Keyword(s):  
Pancreatic Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Forkhead Box
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