Review
Oncology
Kostas Palamaris, Evangelos Felekouras, Stratigoula Sakellariou
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy characterized by aggressive behavior and resistance to chemotherapy, with emerging evidence pointing to epithelial to mesenchymal transition (EMT) as a key driver of disease progression and drug resistance. EMT allows cancer cells to transition to a more mesenchymal state, contributing to tumor dissemination and chemoresistance in PDAC.
Article
Cell Biology
Cheng Xiong, Youwei Zhu, Meilin Xue, Yongsheng Jiang, Yiming Zhong, Lingxi Jiang, Minmin Shi, Hao Chen
Summary: This study revealed that TAMs promote PDAC progression through the TGF-beta signaling pathway, and the pro-tumorigenic effects of TAMs or TAM-CM can be abolished by inhibiting the TGF-beta signaling pathway or neutralizing TGF-beta antibody.
Article
Oncology
Yujin Pan, Deyu Li, Jiuhui Yang, Ning Wang, Erwei Xiao, Lianyuan Tao, Xiangming Ding, Peichun Sun, Dongxiao Li
Summary: This study demonstrates the preferability of portal venous for CTC testing and the association of high PoV M-CTC count with increased risk of metastasis and shorter survival time in resectable PDAC patients. PoV CTC phenotype detection shows potential as a reliable and accurate tool for identifying high-risk PDAC patients for better management strategies.
FRONTIERS IN ONCOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Theodore Evan, Victoria Min-Yi Wang, Axel Behrens
Summary: Intratumour heterogeneity (ITH) is an important focus of cancer research, referring to the variation of cancer cells that contribute to tumour evolution, progression, metastasis, and treatment resistance. Not only genetically encoded, the phenotypic heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is also influenced by the complex tumour microenvironment and interactions between tumour and stromal cells. This review discusses different types of phenotypic heterogeneity in PDAC and highlights recent findings on how therapeutic efforts can target and limit cellular heterogeneity to halt PDAC progression.
Review
Oncology
Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Norio Uemura, Yuta Shiraishi, Hiroki Sato, Hideo Baba
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type with high metastatic properties and difficulty in early diagnosis. Most PDAC patients have glucose metabolism disorders, which are closely related to the initiation, development, invasion, and metastasis of PDAC. This review provides valuable insights into the clinical and molecular impacts of glycolysis on PDAC research and treatment.
Review
Biochemistry & Molecular Biology
Yuanyang Wang, Cheng Qin, Gang Yang, Bangbo Zhao, Weibin Wang
Summary: Patients with pancreatic cancer have a poor prognosis due to difficulties in early diagnosis, high metastasis rates, and chemoresistance. Autophagy plays a dual role in cancer development, inhibiting cancer initiation while promoting cancer progression. Inhibiting autophagy can enhance drug efficacy but may also lead to drug resistance in pancreatic cancer.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Article
Oncology
Marie-Lucie Racu, Laetitia Lebrun, Andrea Alex Schiavo, Claude Van Campenhout, Sarah De Clercq, Lara Absil, Esmeralda Minguijon Perez, Calliope Maris, Christine Decaestecker, Isabelle Salmon, Nicky D'Haene
Summary: Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and its incidence is increasing over time. Understanding the molecular mechanisms behind metastasis and chemoresistance in PDAC is crucial, as these are the main causes of death in patients. SMAD4 is deactivated in half of PDAC cases and its loss is associated with worse overall survival and metastasis. SMAD4 is a key transducer in the TGF-beta pathway, which plays a role in epithelial-mesenchymal transition (EMT). EMT is a biological process where epithelial cells lose their characteristics and acquire a more mesenchymal phenotype, leading to increased motility. Recent studies suggest that cells may undergo intermediate states during EMT, known as epithelial-mesenchymal plasticity (EMP), which exhibit enhanced aggressiveness and more efficient metastasis. This review aims to summarize and analyze current knowledge on SMAD4 loss in PDAC patients and investigate its potential role in EMP, in order to better understand its function in PDAC carcinogenesis.
Review
Cell Biology
Tianyi Zhang, Yanxian Ren, Pengfei Yang, Jufang Wang, Heng Zhou
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a high deposition of extracellular matrix (ECM) and poor prognosis. ECM proteins derived from tumor cells reduce the effectiveness of conventional cancer treatment and contribute to tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) in the ECM are promising targets for novel anti-tumor interventions.
CELL DEATH & DISEASE
(2022)
Article
Oncology
Erica S. Tsang, James T. Topham, Joanna M. Karasinska, Michael K. C. Lee, Laura M. Williamson, Shehara Mendis, Robert E. Denroche, Gun Ho Jang, Steve E. Kalloger, Richard A. Moore, Andrew J. Mungall, Oliver F. Bathe, Patricia A. Tang, Faiyaz Notta, Julie M. Wilson, Janessa Laskin, Grainne M. O'Kane, Jennifer J. Knox, Rachel A. Goodwin, Jonathan M. Loree, Steven J. M. Jones, Marco A. Marra, Steven Gallinger, David F. Schaeffer, Daniel J. Renouf
Summary: This study analyzed genomic and transcriptomic data from a large cohort of PDAC patient samples, revealing a distinctive pattern of biallelic CDKN2A mutation and increased expression of FOXC2 in EOPC tumors. The correlation between FOXC2 and EMT pathways represents novel molecular characteristics of EOPC.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Shuai Huang, Xudong Zhang, Kai Luo, Li Jiang, Jianhua Jiang, Renfeng Li
Summary: In this study, OSBP2 was found to be highly expressed in PDAC and its upregulation promoted the progression of PDAC, including increased cell migration, invasion, proliferation, chemotherapy resistance, and decreased apoptosis. Furthermore, overexpression of OSBP2 resulted in downregulation of the cell adhesion molecule E-cadherin and upregulation of other transcription factors. Therefore, OSBP2 may serve as a potential diagnostic and therapeutic target for PDAC.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Agnes Czikora, Katalin Erdelyi, Tamas Ditroi, Noemi Szanto, Eszter Petra Juranyi, Szilard Szanyi, Jozsef Tovari, Tamas Strausz, Peter Nagy
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer type with increasing incidence globally. This study found that the expression levels of cystathionine beta-synthase (CBS) are elevated in metastatic PDAC cells compared to non-metastatic primary tumors. Further investigations revealed that CBS plays a significant role in cancer cell invasion and metastasis, potentially through its involvement in epithelial to mesenchymal transition (EMT) of the cells.
Article
Oncology
Parmanand Malvi, Vipin Rawat, Romi Gupta, Narendra Wajapeyee
Summary: Metabolic reprogramming, characterized by the overexpression of metabolic enzymes, is a key feature of cancer cells. This study focuses on lactate dehydrogenase (LDHA) as an overexpressed enzyme in various cancer types, including pancreatic ductal adenocarcinoma (PDAC), and its role in promoting cancer growth. The study models the adaptation of cancer cells to LDHA inhibition, specifically using the competitive LDHA inhibitor sodium oxamate. Through various molecular analyses, the study identifies significant differences in mRNA expression, chromatin accessibility, and metabolite levels between oxamate-resistant PDAC cells and parental cells. Furthermore, integrated analysis reveals changes in metabolic enzymes that contribute to the observed alterations in metabolites. This study provides insights into the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells, and highlights the need for further functional studies to understand the mechanisms underlying this resistance and optimize the use of LDHA inhibitors in cancer therapy.
FRONTIERS IN ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Shun Wang, Yan Zheng, Feng Yang, Le Zhu, Xiao-Qiang Zhu, Zhe-Fang Wang, Xiao-Lin Wu, Cheng-Hui Zhou, Jia-Yan Yan, Bei-Yuan Hu, Bo Kong, De-Liang Fu, Christiane Bruns, Yue Zhao, Lun-Xiu Qin, Qiong-Zhu Dong
Summary: Pancreatic cancer is increasingly common and often diagnosed at advanced stages with poor prognosis. Due to its high heterogeneity, metabolic reprogramming, and dense stromal environment, current therapies have limited efficacy. Recent advances in understanding the biology and genetics of pancreatic cancer have led to new clinical therapeutic options.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
Article
Oncology
Julie Dardare, Andrea Witz, Margaux Betz, Aurelie Francois, Morgane Meras, Laureline Lamy, Aurelien Lambert, Stephanie Grandemange, Marie Husson, Marie Rouyer, Jessica Demange, Jean-Louis Merlin, Alexandre Harle, Pauline Gilson
Summary: This study investigates the role of DDB2 in pancreatic ductal adenocarcinoma (PDAC). The results show that lower expression of DDB2 is associated with shorter disease-free survival in PDAC patients. Overexpression of DDB2 can decrease cell migration and invasion, and increase sensitivity to certain chemotherapy drugs.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Kai-Zhou Jin, Ying Wu, Xiao-Xiao Zheng, Tian-Jiao Li, Zhen-Yu Liao, Qing-Lin Fei, Hui-Ru Zhang, Sai-Meng Shi, Xin Sha, Xian-Jun Yu, Wei Chen, Long-Yun Ye, Wei-Ding Wu
Summary: Intrinsic drug resistance mechanisms in tumor cells and epithelial-to-mesenchymal transition (EMT) significantly reduce the effectiveness of cancer treatment. This study developed cSN38 nanoparticles and a TGF-beta 1 inhibitor, LY364947, as a strategy to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). The combination of cSN38 and LY364947 nanoparticles improved drug sensitivity, reduced EMT, and inhibited PDAC tumor growth both in vitro and in vivo. These findings highlight the potential of nanoscale therapeutics in combating PDAC.
Article
Cell Biology
Louise K. Metcalfe, Peter R. Shepherd, Greg C. Smith, Nigel Turner
Summary: The Arg457Gln variant in the CREBRF gene is associated with excess body weight and paradoxical reduction in diabetes risk in Pacific/Oceanic populations. A mouse model with the Crebrf Arg458Gln variant showed limited phenotypic effects, suggesting a need to reconsider the mechanistic link between CREBRF function and obesity and diabetes risks in variant allele carriers.
Article
Biochemistry & Molecular Biology
Brenna Osborne, Jane Reznick, Lauren E. Wright, David A. Sinclair, Gregory J. Cooney, Nigel Turner
Summary: This study investigated the effects of liver-specific SIRT3 overexpression on mitochondrial function and metabolism. The results showed that overexpression of SIRT3 increased oxygen consumption and reduced triglyceride accumulation. However, increasing hepatic SIRT3 had limited overall benefits during the development of diet-induced insulin resistance.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Review
Endocrinology & Metabolism
Brendan P. Wilkins, Angela M. Finch, Yan Wang, Nicola J. Smith
Summary: Atherosclerosis is a disease that leads to cardiovascular complications, and statins have limitations in treating all patients. The deletion of GPR146 has been found to reduce serum cholesterol and atherosclerotic plaque burden, making it a potential therapeutic target.
TRENDS IN ENDOCRINOLOGY AND METABOLISM
(2022)
Article
Cell Biology
Margaret A. Mouat, Brendan P. Wilkins, Eileen Ding, Hemna Govindaraju, James L. J. Coleman, Robert M. Graham, Nigel Turner, Nicola J. Smith
Summary: The deletion of GPR37L1 does not significantly affect glucose handling, body weight, and fat mass in mice. However, Gpr37l1(-/-) mice show lower fat mass accumulation and higher ambulatory activity during night hours.
Article
Biochemistry & Molecular Biology
Samuel G. Towarnicki, Neil A. Youngson, Susan M. Corley, Jus C. St John, Richard G. Melvin, Nigel Turner, Margaret J. Morris, J. William O. Ballard
Summary: Studies have shown that ancestral life experiences, particularly stress and diet, can influence the growth, metabolism, and behavior of future generations. This research focuses on the non-genetic inheritance between fertilization and adulthood, revealing that ancestral dietary macronutrient composition and quantity can impact the developmental timing of descendants through changes in specific signaling pathways.
Article
Nutrition & Dietetics
Sarah E. Hancock, Michael G. Friedrich, Todd W. Mitchell, Roger J. W. Truscott, Paul L. Else
Summary: This study examined the changes in phospholipid composition in the mitochondrial and microsomal membranes of the human cerebellum and motor cortex with age, comparing the results with previous analyses of other brain regions.
Article
Genetics & Heredity
Gabriella Assante, Sriram Chandrasekaran, Stanley Ng, Aikaterini Tourna, Carolina H. Chung, Kowsar A. Isse, Jasmine L. Banks, Ugo Soffientini, Celine Filippi, Anil Dhawan, Mo Liu, Steven G. Rozen, Matthew Hoare, Peter Campbell, J. William O. Ballard, Nigel Turner, Margaret J. Morris, Shilpa Chokshi, Neil A. Youngson
Summary: The research demonstrates that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage, thus initiating the development of HCC.
Article
Biochemistry & Molecular Biology
Sarah E. Hancock, Eileen Ding, Emma Johansson Beves, Todd Mitchell, Nigel Turner
Summary: Recent advances in single-cell genomics and transcriptomics have greatly improved our understanding of cellular heterogeneity, but single-cell lipidomics methods have lagged behind. However, we have developed a method combining fluorescence-assisted cell sorting and shotgun lipidomics that allows us to detect and quantify a wide range of phosphatidylcholine and sphingomyelin species from single cells. This method can distinguish between different cell lineages and detect subtle differences in the lipidome between cell lines of the same cancer type. It can also be used in conjunction with other single-cell technologies to provide comprehensive multi-omics data on cells with similar phenotypes, advancing our knowledge on cellular heterogeneity.
JOURNAL OF LIPID RESEARCH
(2023)
Article
Biology
Amanda E. Brandon, Lewin Small, Tuong-Vi Nguyen, Eurwin Suryana, Henry Gong, Christian Yassmin, Sarah E. Hancock, Tamara Pulpitel, Sophie Stonehouse, Letisha Prescott, Melkam A. Kebede, Belinda Yau, Lake-Ee Quek, Greg M. Kowalski, Clinton R. Bruce, Nigel Turner, Gregory J. Cooney
Summary: Obesity is generally associated with insulin resistance and increased risk of developing type 2 diabetes, but there is a subset of obese individuals who remain insulin sensitive. Recent research suggests that high carbohydrate diets can cause obesity in mice without glucose intolerance. This study found that dietary manipulation can influence insulin action independently of adiposity, and specific ceramide species may be associated with these differences.
Article
Endocrinology & Metabolism
Brenna Osborne, Lauren E. Wright, Amanda E. Brandon, Ella Stuart, Lewin Small, Joris Hoeks, Patrick Schrauwen, David A. Sinclair, Magdalene K. Montgomery, Gregory J. Cooney, Nigel Turner
Summary: This study investigated whether specific overexpression of SIRT3 in skeletal muscle could prevent high-fat diet-induced muscle insulin resistance. The results showed that overexpression of SIRT3 did not alleviate muscle insulin resistance induced by high-fat diet and intramuscular triglyceride content was increased. These findings indicate that muscle-specific overexpression of SIRT3 has only minor effects on the acute development of skeletal muscle insulin resistance in high-fat-fed rats.
JOURNAL OF ENDOCRINOLOGY
(2023)
Article
Genetics & Heredity
Adam J. Lawther, Jerzy Zieba, Zhiming Fang, Teri M. Furlong, Illya Conn, Hemna Govindaraju, Laura L. Y. Choong, Nigel Turner, Khawar Sohail Siddiqui, Wallace Bridge, Sam Merlin, Tzipi Cohen Hyams, Murray Killingsworth, Valsamma Eapen, Raymond A. Clarke, Adam K. Walker
Summary: Mitochondrial dysfunction is strongly associated with autism spectrum disorder (ASD), and the IMMP2L gene is linked to autism inheritance. By developing an Immp2lKD knockout mouse model, the researchers found that Immp2l(KD) -/- KO mice did not show any differences in the core behavioral symptoms of ASD, but they exhibited increased auditory stimulus-driven instrumental behavior and amphetamine-induced locomotion. The researchers also discovered that the ROS levels were lowered in the new Immp2l(KD) -/- KO mice, contrary to previous studies on Immp2l-deficient mouse models, and these mice did not display oxidative stress-related phenotypes.
Article
Cell Biology
Lindsay E. Wu, Corrine E. Fiveash, Nicholas L. Bentley, Myung-Jin Kang, Hemna Govindaraju, Jayne A. Barbour, Brendan P. Wilkins, Sarah E. Hancock, Romanthi Madawala, Abhijit Das, Hassina Massudi, Catherine Li, Lynn-Jee Kim, Ashley S. A. Wong, Maria B. Marinova, Ghazal Sultani, Abhirup Das, Neil A. Youngson, David G. Le Couteur, David A. Sinclair, Nigel Turner
Summary: The NAD+-dependent deacylase family of sirtuin enzymes, including SIRT2, play important roles in biological aging, late-life health, and overall lifespan. However, the role of SIRT2 has been less clear. Previous studies showed that transgenic overexpression of SIRT2 can improve health and increase lifespan in a progeria model. In this study, the researchers tested whether SIRT2 overexpression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. They found that SIRT2 overexpression did not have an additional impact on health or lifespan in these mice. Biochemical studies also revealed changes in brain metabolites in SIRT2 overexpressing mice, but these changes did not translate into functional differences.
Article
Cell Biology
Indra Heckenbach, Garik V. Mkrtchyan, Michael Ben Ezra, Daniela Bakula, Jakob Sture Madsen, Malte Hasle Nielsen, Denise Oro, Brenna Osborne, Anthony J. Covarrubias, M. Laura Idda, Myriam Gorospe, Laust Mortensen, Eric Verdin, Rudi Westendorp, Morten Scheibye-Knudsen
Summary: A deep learning predictor based on nuclear morphology can identify senescent cells and is associated with health outcomes in humans.
Article
Clinical Neurology
Gabrielle R. Phillips, Jennifer T. Saville, Sarah E. Hancock, Simon H. J. Brown, Andrew M. Jenner, Catriona McLean, Maria Fuller, Kelly A. Newell, Todd W. Mitchell
Summary: This study investigated the changes in sphingolipid species in the brains of Huntington's disease patients. They found that the caudate region had a shifted sphingolipid profile, favoring long-chain species over very-long-chain species. They also observed a reduced expression of ceramide synthase 1 in the caudate of Huntington's patients, which correlated with a younger age at death and a longer CAG repeat length.
BRAIN COMMUNICATIONS
(2022)