scholarly journals Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chenxi Tian ◽  
Ying Huang ◽  
Karl R. Clauser ◽  
Steffen Rickelt ◽  
Allison N. Lau ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stromal Cells ◽  
Proteinase Activity ◽  
Ductal Adenocarcinoma ◽  
Fibrillar Collagen ◽  
Fibrillar Collagens ◽  
Tumor Growth And Metastasis

AbstractPancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.

scholarly journals Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells

2019 ◽  
Vol 116 (39) ◽  
pp. 19609-19618 ◽  
Author(s):  
Chenxi Tian ◽  
Karl R. Clauser ◽  
Daniel Öhlund ◽  
Steffen Rickelt ◽  
Ying Huang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Quantitative Mass Spectrometry ◽  
Chronic Pancreatitis Patient ◽  
Ecm Proteins ◽  
Poor Patient ◽  
Poor Patient Survival

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.

scholarly journals Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

2020 ◽  
Author(s):  
Pei-Yun Tsai ◽  
Min-Sik Lee ◽  
Unmesh Jadhav ◽  
Insia Naqvi ◽  
Shariq Madha ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Glutamine Synthetase ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Ductal Adenocarcinoma ◽  
Nutrient Deprivation ◽  
Open Chromatin ◽  
Nucleotide Synthesis ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.SignificancePancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with no effective therapies. PDA aggressiveness partly stems from its ability to grow within a uniquely dense stroma restricting nutrient access. This study demonstrates that PDA clones that survive chronic nutrient deprivation acquire reversible non-genetic adaptations allowing them to switch between metabolic states optimal for growth under nutrient-replete or nutrient-deprived conditions. One contributing factor to this adaptation mTORC1 activation, which stabilizes glutamine synthetase (GS) necessary for glutamine generation in nutrient-deprived cancer cells. Our findings imply that although total GS levels may not be a prognostic marker for aggressive disease, GS inhibition is of high therapeutic value, as it targets specific cell clusters adapted to nutrient starvation, thus mitigating tumor growth.

scholarly journals Pancreatic Ductal Adenocarcinoma Mice Lacking Mucin 1 Have a Profound Defect in Tumor Growth and Metastasis

2011 ◽  
Vol 71 (13) ◽  
pp. 4432-4442 ◽  
Author(s):  
Dahlia M. Besmer ◽  
Jennifer M. Curry ◽  
Lopamudra D. Roy ◽  
Teresa L. Tinder ◽  
Mahnaz Sahraei ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Mucin 1 ◽  
Tumor Growth And Metastasis

scholarly journals A positive feedback between HIF1α and lysyl oxidase-like 2 dictates the Warburg Effect in Pancreatic Cancer

2021 ◽  
Author(s):  
Rongkun Li ◽  
Yahui Wang ◽  
Lili Zhu ◽  
Xiaoxin Zhang ◽  
Dejun Liu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Positive Feedback ◽  
Warburg Effect ◽  
Lysyl Oxidase ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Cancer Aggressiveness ◽  
Tumor Growth And Metastasis ◽  
The Warburg Effect

Abstract Background Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. Methods The expression pattern and prognostic value of LOXL2 was analyzed by immunohistochemistry. The effects of LOXL2 on cancer cell proliferation, migration, and invasion in vitro, tumor growth and metastasis in vivo were investigated by genetic manipulation of LOXL2 expression in human PDAC cell lines. The effects of LOXL2 on aerobic glycolysis were examined by glucose uptake, lactate production, and Seahorse Flux Analyzer. Quantitative real-time PCR, western blotting, immunofluorescence and other techniques were conducted to identify molecular mechanism. Results Lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in pancreatic ductal adenocarcinoma (PDAC). LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop is existed between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Conclusion Our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.

Abstract 1070: Pancreatic Ductal Adenocarcinoma (PDA) mice lacking Mucin 1 has a profound defect in tumor growth and metastasis

2011 ◽  
Author(s):  
Dahlia Besmer ◽  
Lopamudra Das Roy ◽  
Jennifer Curry ◽  
Teresa Tinder ◽  
Mahnaz Manouchehrabadi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Mucin 1 ◽  
Tumor Growth And Metastasis

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Heidi Roth ◽  
Fatema Bhinderwala ◽  
Rodrigo Franco ◽  
You Zhou ◽  
Robert Powers
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
The Impact

Abstract BackgroundAt less than 7%, pancreatic ductal adenocarcinoma (PDAC) has one of the poorest 5-year cancer survival rates and is set to be the leading cause of cancer related deaths by 2030. The co-chaperone protein DNAJA1 (HSP40) is downregulated four-fold in pancreatic cancer cells, but its impact on pancreatic ductal adenocarcinoma (PDAC) progression remains unclear.MethodsDNAJA1 was overexpressed in pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2, through retroviral transfection. The impact of overexpressing DNAJA1 was investigated using a combination of untargeted metabolomics, stable isotope resolved metabolomics (SIRM), confocal microscopy, flow-cytometry, and cell-based assays.ResultsPancreatic cancer cells overexpressing DNAJA1 exhibited a global metabolomic change. Specifically, differential output from Warburg glycolysis, an increase in redox currency, and an alteration in amino acid levels were observed in both overexpression cell lines. DNAJA1 overexpression also led to mitochondrial fusion, an increase in the expression of Bcl-2, a modest protection from redox induced cell death, a loss of structural integrity due to the loss of actin fibers, and an increase in cell invasiveness in BxPC-3. These differences were more pronounced in BxPC-3, which contains a loss-of-function mutation in the tumor suppressing gene SMAD4.ConclusionsThe overexpression of DNAJA1 promoted cellular proliferation, redox tolerance, invasiveness, and anti-apoptosis, which suggests DNAJA1 has numerous regulatory roles. Overall, our findings suggest a proto-oncogenic role of DNAJA1 in PDAC progression and suggests DNAJA1 may function synergistically with other proteins with altered activity in pancreatic cancer cell lines.

scholarly journals The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment

2020 ◽  
Vol 19 ◽  
pp. 153303382092096
Author(s):  
Hongzhi Sun ◽  
Bo Zhang ◽  
Haijun Li
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stromal Cells ◽  
Genomic Analysis ◽  
Ductal Adenocarcinoma ◽  
Genetic Mutations ◽  
Cellular Processes ◽  
Dismal Prognosis ◽  
Mutant Genes

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

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