Comprehensive analysis of the transcriptional expressions and prognostic value of S100A family in pancreatic ductal adenocarcinoma

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were analyzed by using the Drugbank database. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

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Comprehensive Analysis of the Transcriptional Expressions and Prognostic Value of S100A Family in Pancreatic Ductal Adenocarcinoma

10.21203/rs.3.rs-149466/v1 ◽

2021 ◽

Author(s):

Hong-Bin Li ◽

Jian-Li Wang ◽

Xiao-Dong Jin ◽

Lei Zhao ◽

Hui-Li Ye ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Value ◽

Pancreatic Cancer Cell ◽

Expression Patterns ◽

Ductal Adenocarcinoma ◽

Tissue Samples ◽

Cancer Types ◽

Cancer Tissues ◽

Refractory Malignancy

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics, and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were also analyzed by using Drugbank. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

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Comprehensive analysis of the transcriptional expressions and prognostic value of S100A family in pancreatic ductal adenocarcinoma

10.21203/rs.3.rs-148631/v1 ◽

2021 ◽

Author(s):

Hongbin Li ◽

Jianli Wang ◽

Xiaodong Jin ◽

Lei Zhao ◽

Huili Ye ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Value ◽

Pancreatic Cancer Cell ◽

Expression Patterns ◽

Ductal Adenocarcinoma ◽

Tissue Samples ◽

Cancer Types ◽

Cancer Tissues ◽

Refractory Malignancy

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory malignancy with poor prognosis. It is urgent to identify novel and valid biomarkers to predict the progress and prognosis of PDAC. The S100A family have been identified as being involved in cell proliferation, migration and differentiation progression of various cancer types. However, the expression patterns and prognostic values of S100As in PDAC remain to be analyzed. Methods We investigated the transcriptional expressions, methylation level and prognostic value of S100As in PDAC patients from the Oncomine, GEPIA2, Linkedomics, and cBioPortal databases. Real-time PCR was used to detect the expressions of S100A2/4/6/10/14/16 in four pancreatic cancer cell lines and pancreatic cancer tissues from PDAC patients undergoing surgery. To verify the results further, immunohistochemistry was used to measure the expression of S100A2/4/6/10/14/16 in 43 PDAC patients’ tissue samples. The drug relations of S100As were also analyzed by using Drugbank. Results The results suggested that, the expression levels of S100A2/4/6/10/14/16 were elevated to PDAC tissues than in normal pancreatic tissues, and the promoter methylation levels of S100A S100A2/4/6/10/14/16 in PDAC (n = 10) were lower compared with normal tissue (n = 184) (P < 0.05). In addition, their expressions were negatively correlated with PDAC patient survival. Conclusions Taken together, these results suggest that S100A2/4/6/10/14/16 might be served as prognostic biomarkers for survivals of PDAC patients.

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ITGA2, LAMB3, and LAMC2 may be the potential therapeutic targets in pancreatic ductal adenocarcinoma: an integrated bioinformatics analysis

Scientific Reports ◽

10.1038/s41598-021-90077-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shajedul Islam ◽

Takao Kitagawa ◽

Byron Baron ◽

Yoshihiro Abiko ◽

Itsuo Chiba ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Bioinformatics Analysis ◽

Therapeutic Targets ◽

Ductal Adenocarcinoma ◽

Integrin Subunit ◽

Hub Genes ◽

Cancerous Tissue ◽

Tissue Samples

AbstractPancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with an abysmal prognosis rate over the last few decades. Early diagnosis and prevention could effectively combat this malignancy. Therefore, it is crucial to discover potential biomarkers to identify asymptomatic premalignant or early malignant tumors of PDAC. Gene expression analysis is a powerful technique to identify candidate biomarkers involved in disease progression. In the present study, five independent gene expression datasets, including 321 PDAC tissues and 208 adjacent non-cancerous tissue samples, were subjected to statistical and bioinformatics analysis. A total of 20 differentially expressed genes (DEGs) were identified in PDAC tissues compared to non-cancerous tissue samples. Gene ontology and pathway enrichment analysis showed that DEGs were mainly enriched in extracellular matrix (ECM), cell adhesion, ECM–receptor interaction, and focal adhesion signaling. The protein–protein interaction network was constructed, and the hub genes were evaluated. Collagen type XII alpha 1 chain (COL12A1), fibronectin 1 (FN1), integrin subunit alpha 2 (ITGA2), laminin subunit beta 3 (LAMB3), laminin subunit gamma 2 (LAMC2), thrombospondin 2 (THBS2), and versican (VCAN) were identified as hub genes. The correlation analysis revealed that identified hub genes were significantly interconnected. Wherein COL12A1, FN1, ITGA2, LAMB3, LAMC2, and THBS2 were significantly associated with PDAC pathological stages. The Kaplan–Meier survival plots revealed that ITGA2, LAMB3, and LAMC2 expression were inversely correlated with a prolonged patient survival period. Furthermore, the Human Protein Atlas database was used to validate the expression and cellular origins of hub genes encoded proteins. The protein expression of hub genes was higher in pancreatic cancer tissue than in normal pancreatic tissue samples, wherein ITGA2, LAMB3, and LAMC2 were exclusively expressed in pancreatic cancer cells. Pancreatic cancer cell-specific expression of these three proteins may play pleiotropic roles in cancer progression. Our results collectively suggest that ITGA2, LAMB3, and LAMC2 could provide deep insights into pancreatic carcinogenesis molecular mechanisms and provide attractive therapeutic targets.

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An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers12030716 ◽

2020 ◽

Vol 12 (3) ◽

pp. 716

Author(s):

Grasieli de Oliveira ◽

Paula Paccielli Freire ◽

Sarah Santiloni Cury ◽

Diogo de Moraes ◽

Jakeline Santos Oliveira ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Value ◽

Meta Analysis ◽

The Cancer Genome Atlas ◽

Secreted Proteins ◽

Ductal Adenocarcinoma ◽

Public Data ◽

Potential Biomarkers

Pancreatic ductal adenocarcinoma (PDAC) is extremely aggressive, has an unfavorable prognosis, and there are no biomarkers for early detection of the disease or identification of individuals at high risk for morbidity or mortality. The cellular and molecular complexity of PDAC leads to inconsistences in clinical validations of many proteins that have been evaluated as prognostic biomarkers of the disease. The tumor secretome, a potential source of biomarkers in PDAC, plays a crucial role in cell proliferation and metastasis, as well as in resistance to treatments, which together contribute to a worse clinical outcome. The massive amount of proteomic data from pancreatic cancer that has been generated from previous studies can be integrated and explored to uncover secreted proteins relevant to the diagnosis and prognosis of the disease. The present study aimed to perform an integrated meta-analysis of PDAC proteome and secretome public data to identify potential biomarkers of the disease. Our meta-analysis combined mass spectrometry data obtained from two systematic reviews of the pancreatic cancer literature, which independently selected 20 studies of the secretome and 35 of the proteome. Next, we predicted the secreted proteins using seven in silico tools or databases, which identified 39 secreted proteins shared between the secretome and proteome data. Notably, the expression of 31 genes of these secretome-related proteins was upregulated in PDAC samples from The Cancer Genome Atlas (TCGA) when compared to control samples from TCGA and The Genotype-Tissue Expression (GTEx). The prognostic value of these 39 secreted proteins in predicting survival outcome was confirmed using gene expression data from four PDAC datasets (validation set). The gene expression of these secreted proteins was able to distinguish high- and low-survival patients in nine additional tumor types from TCGA, demonstrating that deregulation of these secreted proteins may also contribute to the prognosis in multiple cancers types. Finally, we compared the prognostic value of the identified secreted proteins in PDAC biomarkers studies from the literature. This analysis revealed that our gene signature performed equally well or better than the signatures from these previous studies. In conclusion, our integrated meta-analysis of PDAC proteome and secretome identified 39 secreted proteins as potential biomarkers, and the tumor gene expression profile of these proteins in patients with PDAC is associated with worse overall survival.

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ITGA2, LAMB3, and LAMC2 May Be the Potential Therapeutic Targets in Pancreatic Ductal Adenocarcinoma: an Integrated Bioinformatics Analysis

10.21203/rs.3.rs-379158/v1 ◽

2021 ◽

Author(s):

Shajedul Islam ◽

Takao Kitagawa ◽

Byron Baron ◽

Yoshihiro Abiko ◽

Itsuo Chiba ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Bioinformatics Analysis ◽

Therapeutic Targets ◽

Ductal Adenocarcinoma ◽

Integrin Subunit ◽

Hub Genes ◽

Cancerous Tissue ◽

Tissue Samples

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with an abysmal prognosis rate over the last few decades. Early diagnosis and prevention could effectively combat this malignancy. Therefore, it is crucial to discover potential biomarkers to identify asymptomatic premalignant or early malignant tumors of PDAC. Gene expression analysis is a powerful technique to identify candidate biomarkers involved in disease progression. In the present study, five independent gene expression datasets, including 321 PDAC tissues and 208 adjacent non-cancerous tissue samples, were subjected to statistical and bioinformatics analysis. A total of 20 differentially expressed genes (DEGs) were identified in PDAC tissues compared to non-cancerous tissue samples. Gene ontology and pathway enrichment analysis showed that DEGs were mainly enriched in extracellular matrix (ECM), cell adhesion, ECM-receptor interaction, and focal adhesion signaling. The protein protein interaction network was constructed, and the hub genes were evaluated. Collagen type XII alpha 1 chain (COL12A1), fibronectin 1 (FN1), integrin subunit alpha 2 (ITGA2), laminin subunit beta 3 (LAMB3), laminin subunit gamma 2 (LAMC2), thrombospondin 2 (THBS2), and versican (VCAN) were identified as hub genes. The correlation analysis revealed that identified hub genes were significantly interconnected. Wherein COL12A1, FN1, ITGA2, LAMB3, LAMC2, and THBS2 were significantly associated with PDAC pathological stages. The Kaplan-Meier survival plots revealed that ITGA2, LAMB3, and LAMC2 expression were inversely correlated with a prolonged patient survival period. Furthermore, the Human Protein Atlas database was used to validate the expression and cellular origins of hub genes encoded proteins. The protein expression of hub genes was higher in pancreatic cancer tissue than in normal pancreatic tissue samples, wherein ITGA2, LAMB3, and LAMC2 were exclusively expressed in pancreatic cancer cells. Pancreatic cancer cell-specific expression of these three proteins may play pleiotropic roles in cancer progression. Our results collectively suggest that ITGA2, LAMB3, and LAMC2 could provide deep insights into pancreatic carcinogenesis molecular mechanisms and provide attractive therapeutic targets.

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The WNT5A/ROR2 signaling pathway in pancreatic ductal adenocarcinoma (PDAC)

10.21203/rs.3.rs-34447/v1 ◽

2020 ◽

Author(s):

Lydia Remtisch ◽

Georg Wiltberger ◽

Katrin Schierle ◽

Moulla Yousef ◽

René Thieme ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Prognostic Value ◽

Expression Patterns ◽

Tumor Stroma ◽

Pancreatic Tissue ◽

Ductal Adenocarcinoma ◽

Normal Pancreatic Tissue ◽

Variable Expression ◽

Wnt5a Expression

Abstract Background WNT5A/ROR2 signaling pathway has been shown to be involved in many human cancers. Its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified yet. The aim of this study was to determine the prognostic value of WNT5A-expression in conjunction with the ROR2-expression in the same tumor tissues of PDAC patients. Methods We retrospectively analyzed the expression of WNT5A and ROR2 in 117 paraffin-embedded PDAC specimens following surgical pancreatic resection by immunohistochemistry. The prognostic value of WNT5A and ROR2 was assessed using Kaplan-Meier survival curves and multivariate COX regression-models. Results High ROR2-expression was detected in 65.8% (77/117) of PDAC-tumors, in 28.2% (33/117) in tumor-stroma, and in 71.1% (65/90) of normal pancreatic tissue. High WNT5A-expression was found in 76.9% (90/117) of tumors, in 59.0% (69/117) of tumor-stroma, and in 83.0% (73/88) of normal pancreatic tissue. Spearman's correlation co-efficiency demonstrated weak association between ROR2- and WNT5A-expression in tumor (r = 0.184; p = 0.047), and no association in stroma (r = 0.036; p = 0.699). Multivariate analysis showed that regional lymph node invasion and differentiation were independent prognostic factors of survival, while ROR2- and WNT5A-expression not. Conclusions Variable expression patterns for ROR2 and WNT5A were demonstrated in PDAC and normal pancreatic tissues suggesting a role for WNT5A/ROR2 signalling pathway, not only in PDAC but also in the normal pancreatic tissue during inflammation. The lack of prognostic significance for ROR2- and WNT5A-expression in our cohort, either alone or in subgroup analysis, signifies the complexity of their role in PDAC, which is highly dependent on the different molecular receptor-ligand tissue contexts.

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Betulinic Acid Affects the Energy-Related Proteomic Profiling in Pancreatic Ductal Adenocarcinoma Cells

Molecules ◽

10.3390/molecules26092482 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2482

Author(s):

Ching-Feng Chiu ◽

Hsin-Yi Chang ◽

Chun-Yine Huang ◽

Chen-Zou Mau ◽

Tzu-Ting Kuo ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Betulinic Acid ◽

Expression Patterns ◽

Apolipoprotein A1 ◽

Ductal Adenocarcinoma ◽

Therapeutic Window ◽

Pdac Cell ◽

Cell Growth And Migration ◽

Altered Expression ◽

Clinical Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of <8%. Therefore, finding new treatment strategies against PDAC cells is an imperative issue. Betulinic acid (BA), a plant-derived natural compound, has shown great potential to combat cancer owing to its versatile physiological functions. In this study, we observed the impacts of BA on the cell viability and migratory ability of PDAC cell lines, and screened differentially expressed proteins (DEPs) by an LC-MS/MS-based proteomics analysis. Our results showed that BA significantly inhibited the viability and migratory ability of PDAC cells under a relatively low dosage without affecting normal pancreatic cells. Moreover, a functional analysis revealed that BA-induced downregulation of protein clusters that participate in mitochondrial complex 1 activity and oxidative phosphorylation, which was related to decreased expressions of RNA polymerase mitochondrial (POLRMT) and translational activator of cytochrome c oxidase (TACO1), suggesting that the influence on mitochondrial function explains the effect of BA on PDAC cell growth and migration. In addition, BA also dramatically increased Apolipoprotein A1 (APOA1) expression and decreased NLR family CARD domain-containing protein 4 (NLRC4) expression, which may be involved in the dampening of PDAC migration. Notably, altered expression patterns of APOA1 and NLRC4 indicated a favorable clinical prognosis of PDAC. Based on these findings, we identified potential proteins and pathways regulated by BA from a proteomics perspective, which provides a therapeutic window for PDAC.

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Panel of serum miRNAs as potential non-invasive biomarkers for pancreatic ductal adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-82266-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Imteyaz Ahmad Khan ◽

Safoora Rashid ◽

Nidhi Singh ◽

Sumaira Rashid ◽

Vishwajeet Singh ◽

...

Keyword(s):

Next Generation Sequencing ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Ductal Adenocarcinoma ◽

Next Generation ◽

Serum Samples ◽

Tissue Samples ◽

Non Invasive ◽

Specific Symptoms ◽

Generation Sequencing

AbstractEarly-stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to non-specific symptoms. Circulating miRNAs in body fluids have been emerging as potential non-invasive biomarkers for diagnosis of many cancers. Thus, this study aimed to assess a panel of miRNAs for their ability to differentiate PDAC from chronic pancreatitis (CP), a benign inflammatory condition of the pancreas. Next-generation sequencing was performed to identify miRNAs present in 60 FFPE tissue samples (27 PDAC, 23 CP and 10 normal pancreatic tissues). Four up-regulated miRNAs (miR-215-5p, miR-122-5p, miR-192-5p, and miR-181a-2-3p) and four down-regulated miRNAs (miR-30b-5p, miR-216b-5p, miR-320b, and miR-214-5p) in PDAC compared to CP were selected based on next-generation sequencing results. The levels of these 8 differentially expressed miRNAs were measured by qRT-PCR in 125 serum samples (50 PDAC, 50 CP, and 25 healthy controls (HC)). The results showed significant upregulation of miR-215-5p, miR-122-5p, and miR-192-5p in PDAC serum samples. In contrast, levels of miR-30b-5p and miR-320b were significantly lower in PDAC as compared to CP and HC. ROC analysis showed that these 5 miRNAs can distinguish PDAC from both CP and HC. Hence, this panel can serve as a non-invasive biomarker for the early detection of PDAC.

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Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00138.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. G524-G536 ◽

Cited By ~ 12

Author(s):

Sandrina Maertin ◽

Jason M. Elperin ◽

Ethan Lotshaw ◽

Matthias Sendler ◽

Steven D. Speakman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Oxidative Phosphorylation ◽

Pancreatic Ductal Adenocarcinoma ◽

Environmental Stresses ◽

Ductal Adenocarcinoma ◽

Cell Adaptation ◽

Autophagy Inhibition ◽

Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

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