Pancreatic cancer pathology viewed in the light of evolution

Noë, Michaël; Hong, Seung Mo; Wood, Laura D.; Thompson, Elizabeth D.; Roberts, Nicholas J.; Goggins, Michael; Klein, Alison P.; Eshleman, James R.; Kern, Scott E.; Hruban, Ralph H.

doi:10.1007/s10555-020-09953-z

Cited by 7 publications

(6 citation statements)

References 125 publications

(174 reference statements)

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“…Tumor progression is an evolutionary and ecological process [ 11 , 17 , 57 ]. At the cellular selection level, only the cell population that is best adjusted to survive in a microenvironmental ecosystem will persist.…”

Section: Discussionmentioning

confidence: 99%

“…For a cell population to persist, it must be able to evolve to maintain its fitness and adapt necessary phenotype and metabolic rewiring to be more successful in thriving and progressing within a new or changing microenvironment. However, Noë et al recently stated that much of today’s discourse on PDAC fails to include an evolutionary perspective [ 57 ]. They suggested that PDAC cells should be viewed as evolving living organisms interacting with their microenvironment [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, Noë et al recently stated that much of today’s discourse on PDAC fails to include an evolutionary perspective [ 57 ]. They suggested that PDAC cells should be viewed as evolving living organisms interacting with their microenvironment [ 57 ]. In this study, PDAC cells exhibited almost totally different responses and adaptations to the acute and chronic acidic microenvironmental pressure (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Identification of distinct slow mode of reversible adaptation of pancreatic ductal adenocarcinoma to the prolonged acidic pH microenvironment

Liao

et al. 2022

J Exp Clin Cancer Res

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Background Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm with high metastatic potential and poor clinical outcome. Like other solid tumors, PDAC in the early stages is often asymptomatic, and grows very slowly under a distinct acidic pHe (extracellular pH) microenvironment. However, most previous studies have only reported the fate of cancerous cells upon cursory exposure to acidic pHe conditions. Little is known about how solid tumors—such as the lethal PDAC originating within the pancreatic duct-acinar system that secretes alkaline fluids—evolve to withstand and adapt to the prolonged acidotic microenvironmental stress. Methods Representative PDAC cells were exposed to various biologically relevant periods of extracellular acidity. The time effects of acidic pHe stress were determined with respect to tumor cell proliferation, phenotypic regulation, autophagic control, metabolic plasticity, mitochondrial network dynamics, and metastatic potentials. Results Unlike previous short-term analyses, we found that the acidosis-mediated autophagy occurred mainly as an early stress response but not for later adaptation to microenvironmental acidification. Rather, PDAC cells use a distinct and lengthy process of reversible adaptive plasticity centered on the early fast and later slow mitochondrial network dynamics and metabolic adjustment. This regulates their acute responses and chronic adaptations to the acidic pHe microenvironment. A more malignant state with increased migratory and invasive potentials in long-term acidosis-adapted PDAC cells was obtained with key regulatory molecules being closely related to overall patient survival. Finally, the identification of 34 acidic pHe-related genes could be potential targets for the development of diagnosis and treatment against PDAC. Conclusions Our study offers a novel mechanism of early rapid response and late reversible adaptation of PDAC cells to the stress of extracellular acidosis. The presence of this distinctive yet slow mode of machinery fills an important knowledge gap in how solid tumor cells sense, respond, reprogram, and ultimately adapt to the persistent microenvironmental acidification.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of distinct slow mode of reversible adaptation of pancreatic ductal adenocarcinoma to the prolonged acidic pH microenvironment

Liao

et al. 2022

J Exp Clin Cancer Res

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“…KRAS mutations are the first genetic changes during disease progression, being commonly detected in early PanIN lesions, and are found in more than 95% of PDAC cases [ 31 ]. Constitutive activation of KRAS and persistent stimulation of downstream pathways sustains tumor cell proliferation, migration, metastasis and metabolic reprogramming, along with the evasion of the anti-tumor immune response [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. With the idea that secreted proteins may reach the systemic circulation, and thus be detected in plasma, we tested whether candidate PDAC biomarkers can be identified in the secretome of recently transformed pancreatic cells transduced with the oncogenic KRAS G12V .…”

Section: Introductionmentioning

confidence: 99%

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

Kamal

Siddiqui

Belgiovine

et al. 2022

Cancers

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KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRASG12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I–IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging.

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“…Due to the difficulty of early diagnosis and the limited effectiveness of treatment with surgery, radiotherapy and chemotherapy, patients with pancreatic cancer have a poor prognosis and high mortality rate, with an overall survival rate of only 8% at 5 years ( 1 ). Ductal adenocarcinoma of the pancreas is the most common type, accounting for 95% of all cases of pancreatic cancer ( 2 ). Most patients with pancreatic cancer are diagnosed at an advanced stage, so only 15–20% of patients with pancreatic cancer can undergo surgery.…”

Section: Introductionmentioning

confidence: 99%

Eukaryotic translation initiation factor 2α kinase 2 in pancreatic cancer: An approach towards managing clinical prognosis and molecular immunological characterization

Du,

Wang,

et al. 2023

Oncol Lett

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Most patients with pancreatic cancer are already in the late stages of the disease when they are diagnosed, and pancreatic cancer is a deadly disease with a poor prognosis. With the advancement of research, immunotherapy has become a new focus in the treatment of tumors. To the best of our knowledge, there is currently no reliable diagnostic or prognostic marker for pancreatic cancer; therefore, the present study investigated the potential of eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) as a predictive and diagnostic marker for pancreatic cancer. Immunohistochemical staining of clinical samples independently verified that EIF2AK2 expression was significantly higher in clinically operated pancreatic cancer tissues than in adjacent pancreatic tissues., and EIF2AK2 expression and differentially expressed genes (DEGs) were identified using downloadable RNA sequencing data from The Cancer Genome Atlas and Genomic Tumor Expression Atlas. In addition, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses and immune cell infiltration were used for functional enrichment analysis of EIF2AK2-associated DEGs. The clinical importance of EIF2AK2 was also determined using Kaplan-Meier survival, Cox regression and time-dependent survival receiver operating characteristic curve analyses, and a predictive nomogram model was generated. Finally, the functional role of EIF2AK2 was assessed in PANC-1 cells using a short hairpin RNA-EIF2AK2 knockdown approach, including CCK-8, wound healing assay, cell cycle and apoptosis assays. The findings suggested that EIF2AK2 may have potential as a diagnostic and prognostic biomarker for patients with pancreatic cancer. Furthermore, EIF2AK2 may provide a new therapeutic target for patients with pancreatic cancer.

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Pancreatic cancer pathology viewed in the light of evolution

Cited by 7 publications

References 125 publications

Identification of distinct slow mode of reversible adaptation of pancreatic ductal adenocarcinoma to the prolonged acidic pH microenvironment

Identification of distinct slow mode of reversible adaptation of pancreatic ductal adenocarcinoma to the prolonged acidic pH microenvironment

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

Eukaryotic translation initiation factor 2α kinase 2 in pancreatic cancer: An approach towards managing clinical prognosis and molecular immunological characterization

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