bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2024‒10‒20
27 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition.
  2. Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model.
  3. Quantification of nutrient fluxes during acute exercise in mice.
  4. Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment.
  5. Mitophagy as a guardian against cellular aging.
  6. Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming.
  7. Integrating priorities at the intersection of cancer and neuroscience.
  8. Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
  9. Modeling lung adenocarcinoma metastases using patient-derived organoids.
  10. ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma.
  11. Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution.
  12. Pathophysiology of Peritoneal Metastasis.
  13. Autophagy and cancer therapy.
  14. GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models.
  15. PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
  16. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
  17. Making lipids very unhappy to discover how they bind to proteins.
  18. Catabolism of extracellular glutathione supplies amino acids to support tumor growth.
  19. Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation.
  20. Caveolin-1 expression is a predictor of survival and recurrence patterns in resected pancreatic ductal adenocarcinoma.
  21. Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy.
  22. Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.
  23. Histomorphological scoring of murine colitis models: A practical guide for the evaluation of colitis and colitis-associated cancer.
  24. Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation.
  25. Leader Cells: Invade and Evade-The Frontline of Cancer Progression.
  26. High Frequency MHz-Order Vibration Enables Cell Membrane Remodelling and Lipid Microdomain Manipulation.
  27. Illuminating cellular architecture and dynamics with fluorescence polarization microscopy.
  1. Cancer Res. 2024 Oct 16.
    KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition.
    Sigrid K Fey, Arafath K Najumudeen, Dale M Watt, Laura M Millett, Catriona A Ford, Kathryn Gilroy, Rosalin J Simpson, Kathy McLay, Rosanna Upstill-Goddard, David Chang, William Clark, Colin Nixon, Joanna L Birch, Simon T Barry, Jennifer P Morton, Andrew D Campbell, Owen J Sansom.
      Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2709
  2. Elife. 2024 Oct 18. pii: RP93312. [Epub ahead of print]13
    Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model.
    Tristan Gicquel, Fabio Marchiano, Gabriela Reyes-Castellanos, Stephane Audebert, Luc Camoin, Bianca H Habermann, Benoit Giannesini, Alice Carrier.
      Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber's size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.
    Keywords:  cachexia; cancer biology; energy metabolism; mitochondria; mouse; muscle wasting; pancreatic cancer
    DOI:  https://doi.org/10.7554/eLife.93312
  3. Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]
    Quantification of nutrient fluxes during acute exercise in mice.
    Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany.
      Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.
    Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
  4. Life Sci Alliance. 2025 Jan;pii: e202403053. [Epub ahead of print]8(1):
    Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment.
    Libi Anandi, Jeremy Garcia, Manon Ros, Libuše Janská, Josephine Liu, Carlos Carmona-Fontaine.
      Ischemic conditions such as hypoxia and nutrient starvation, together with interactions with stromal cells, are critical drivers of metastasis. These conditions arise deep within tumor tissues, and thus, observing nascent metastases is exceedingly challenging. We thus developed the 3MIC-an ex vivo model of the tumor microenvironment-to study the emergence of metastatic features in tumor cells in a 3-dimensional (3D) context. Here, tumor cells spontaneously create ischemic-like conditions, allowing us to study how tumor spheroids migrate, invade, and interact with stromal cells under different metabolic conditions. Consistent with previous data, we show that ischemia increases cell migration and invasion, but the 3MIC allowed us to directly observe and perturb cells while they acquire these pro-metastatic features. Interestingly, our results indicate that medium acidification is one of the strongest pro-metastatic cues and also illustrate using the 3MIC to test anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC can help dissecting the complexity of the tumor microenvironment for the direct observation and perturbation of tumor cells during the early metastatic process.
    DOI:  https://doi.org/10.26508/lsa.202403053
  5. Autophagy. 2024 Oct 14. 1-3
    Mitophagy as a guardian against cellular aging.
    Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  6. Sci Adv. 2024 Oct 18. 10(42): eadp0684
    Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming.
    Noelle R J Thielman, Vanessa Funes, Sanjana Davuluri, Hector E Ibanez, Wei-Chih Sun, Juan Fu, Keyu Li, Stephen Muth, Xingyi Pan, Kenji Fujiwara, Dwayne L Thomas Ii, MacKenzie Henderson, Selina Shiqing Teh, Qingfeng Zhu, Elizabeth Thompson, Elizabeth M Jaffee, Alex Kolodkin, Fengxi Meng, Lei Zheng.
      Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRASMUT-dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRASMUT-dependent manner.
    DOI:  https://doi.org/10.1126/sciadv.adp0684
  7. Cancer Cell. 2024 Oct 15. pii: S1535-6108(24)00362-3. [Epub ahead of print]
    Integrating priorities at the intersection of cancer and neuroscience.
    William L Hwang, Ella N Perrault, Alexander Birbrair, Brandi J Mattson, David H Gutmann, Donald J Mabbott, Edna Cukierman, Elizabeth A Repasky, Erica K Sloan, Hui Zong, Ihsan Ekin Demir, Jami L Saloman, Jeremy C Borniger, Jian Hu, Jorg Dietrich, Joshua J Breunig, Kaan Çifcibaşı, Khalil Ali Ahmad Kasm, Manuel Valiente, Max Wintermark, Munjal M Acharya, Nicole N Scheff, Nisha J D'Silva, Paola D Vermeer, Richard J Wong, Sebastien Talbot, Shawn L Hervey-Jumper, Timothy C Wang, Yi Ye, Yuan Pan, Yuri L Bunimovich, Moran Amit.
      Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.
    DOI:  https://doi.org/10.1016/j.ccell.2024.09.014
  8. EMBO J. 2024 Oct 17.
    Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
    Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima.
      During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.
    Keywords:  Autophagy; Liquid–Liquid Phase Separation; Mitophagy; Optineurin; Wetting
    DOI:  https://doi.org/10.1038/s44318-024-00272-5
  9. Cell Rep Med. 2024 Oct 15. pii: S2666-3791(24)00522-6. [Epub ahead of print]5(10): 101777
    Modeling lung adenocarcinoma metastases using patient-derived organoids.
    Yuan Liu, Manendra Lankadasari, Joel Rosiene, Kofi E Johnson, Juan Zhou, Samhita Bapat, Lai-Fong L Chow-Tsang, Huasong Tian, Brooke Mastrogiacomo, Di He, James G Connolly, Harry B Lengel, Raul Caso, Elizabeth G Dunne, Cameron N Fick, Gaetano Rocco, Smita Sihag, James M Isbell, Mathew J Bott, Bob T Li, Piro Lito, Cameron W Brennan, Mark H Bilsky, Natasha Rekhtman, Prasad S Adusumilli, Marty W Mayo, Marcin Imielinski, David R Jones.
      Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized lung adenocarcinoma (LUAD) patient-derived organoids (PDOs), we establish an in vivo metastasis model that preserves the biologic features of human metastases. Results of whole-genome and RNA sequencing establish that our in vivo PDO metastasis model can be used to study clonality and tumor evolution and to identify biomarkers related to organotropism. Investigation of the response of KRASG12C PDOs to sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD.
    Keywords:  coculture; drug resistance; immune priming; in vivo LUAD metastasis; lung adenocarcinoma; metastasis marker; patient-derived organoids; tumor evolution
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101777
  10. bioRxiv. 2024 Oct 08. pii: 2024.10.04.616725. [Epub ahead of print]
    ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma.
    Dhana Sekhar Reddy Bandi, Ganji Purnachandra Nagaraju, Sujith Sarvesh, Julienne L Carstens, Jeremy B Foote, Emily C Graff, Yu-Hua D Fang, Adam B Keeton, Xi Chen, Kristy L Berry, Sejong Bae, Mehmet Akce, Greg Gorman, Karina J Yoon, Upender Manne, Micheal R Boyd, Donald J Buchsbaum, Asfar S Azmi, Yulia Y Maxuitenko, Gary A Piazza, Bassel F El-Rayes.
      Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRAS G12D , KRAS G12V , KRAS G12C , or KRAS G13Q mutations. ADT-1004 treatment increased CD4 + and CD8 + T cells in the TME consistent with exhaustion and increased MHCII + M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RAS WT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development.Significance: ADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.
    DOI:  https://doi.org/10.1101/2024.10.04.616725
  11. Nat Struct Mol Biol. 2024 Oct 18.
    Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution.
    Yugo Miyata, Katsuya Takahashi, Yongchan Lee, Cheryl S Sultan, Risa Kuribayashi, Masatomo Takahashi, Kosuke Hata, Takeshi Bamba, Yoshihiro Izumi, Kehong Liu, Tomoko Uemura, Norimichi Nomura, So Iwata, Shigekazu Nagata, Tomohiro Nishizawa, Katsumori Segawa.
      Phospholipids are asymmetrically distributed in the plasma membrane (PM), with phosphatidylcholine and sphingomyelin abundant in the outer leaflet. However, the mechanisms by which their distribution is regulated remain unclear. Here, we show that transmembrane protein 63B (TMEM63B) functions as a membrane structure-responsive lipid scramblase localized at the PM and lysosomes, activating bidirectional lipid translocation upon changes in membrane curvature and thickness. TMEM63B contains two intracellular loops with palmitoylated cysteine residue clusters essential for its scrambling function. TMEM63B deficiency alters phosphatidylcholine and sphingomyelin distributions in the PM. Persons with heterozygous mutations in TMEM63B are known to develop neurodevelopmental disorders. We show that V44M, the most frequent substitution, confers constitutive scramblase activity on TMEM63B, disrupting PM phospholipid asymmetry. We determined the cryo-electron microscopy structures of TMEM63B in its open and closed conformations, uncovering a lipid translocation pathway formed in response to changes in the membrane environment. Together, our results identify TMEM63B as a membrane structure-responsive scramblase that controls PM lipid distribution and we reveal the molecular basis for lipid scrambling and its biological importance.
    DOI:  https://doi.org/10.1038/s41594-024-01411-6
  12. J Surg Oncol. 2024 Oct 13.
    Pathophysiology of Peritoneal Metastasis.
    Jesse Demuytere, Sam Ernst, Wim Ceelen.
      Peritoneal metastasis is the result of a complex, stepwise process that involves multiple, spatially and temporally distinct interactions between the primary cancer, disseminated cancer cells or clusters, and the mesothelial lining of the peritoneal cavity and intraperitoneal organs. The biology of peritoneal metastasis, long a neglected field of research, is now increasingly being unraveled. Here, we provide an update on the mechanisms that drive the journey that eventually leads to widespread peritoneal metastatic disease.
    Keywords:  metastasis; pathophysiology; peritoneal
    DOI:  https://doi.org/10.1002/jso.27890
  13. Cancer Lett. 2024 Oct 10. pii: S0304-3835(24)00680-3. [Epub ahead of print] 217285
    Autophagy and cancer therapy.
    Julio M Pimentel, Jun Ying Zhou, Gen Sheng Wu.
      Autophagy is an intracellular degradation process that sequesters cytoplasmic components in double-membrane vesicles known as autophagosomes, which are degraded upon fusion with lysosomes. This pathway maintains the integrity of proteins and organelles while providing energy and nutrients to cells, particularly under nutrient deprivation. Deregulation of autophagy can cause genomic instability, low protein quality, and DNA damage, all of which can contribute to cancer. Autophagy can also be overactivated in cancer cells to aid in cancer cell survival and drug resistance. Emerging evidence indicates that autophagy has functions beyond cargo degradation, including roles in tumor immunity and cancer stem cell survival. Additionally, autophagy can also influence the tumor microenvironment. This feature warrants further investigation of the role of autophagy in cancer, in which autophagy manipulation can improve cancer therapies, including cancer immunotherapy. This review discusses recent findings on the regulation of autophagy and its role in cancer therapy and drug resistance.
    Keywords:  autophagy; cancer; resistance; therapy
    DOI:  https://doi.org/10.1016/j.canlet.2024.217285
  14. MAbs. 2024 Jan-Dec;16(1):16(1): 2416453
    GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models.
    Yu Huang, Jinyong Wang, Xiling Wei, Hui Zhang, Wei Shang, Xiangling Zhang, Lanjiao Zhai, Xi Chen, Huiming Li, Suofu Qin.
      Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. In vitro, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.
    Keywords:  Cachexia; Cancer; Chemotherapy; GDF15; Nanobody
    DOI:  https://doi.org/10.1080/19420862.2024.2416453
  15. Cell. 2024 Oct 15. pii: S0092-8674(24)01094-8. [Epub ahead of print]
    PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
    Shubham Singh, Ulrich E Dransfeld, Yohannes A Ambaw, Joshua Lopez-Scarim, Robert V Farese, Tobias C Walther.
      Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer's disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.
    Keywords:  Alzheimer’s disease; dementia; gangliosides; lipid metabolism; lysosome; neurodegeneration; phospholipid
    DOI:  https://doi.org/10.1016/j.cell.2024.09.036
  16. Cell. 2024 Oct 14. pii: S0092-8674(24)01090-0. [Epub ahead of print]
    IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer.
    Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E Dobrolecki, Weijie Zhang, Dong Han, Na Zhao, Eric Jaehnig, Jingyi Wang, Weiche Wu, Davis A Graham, Yumei Li, Rui Chen, Weiyi Peng, Yiwen Chen, Andre Catic, Zhibin Zhang, Bing Zhang, Anthony M Mustoe, Albert C Koong, George Miles, Michael T Lewis, Meng C Wang, Susan M Rosenberg, Bert W O'Malley, Thomas F Westbrook, Han Xu, Xiang H-F Zhang, C Kent Osborne, Jin Billy Li, Matthew J Ellis, Mothaffar F Rimawi, Jeffrey M Rosen, Xi Chen.
      Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53-/- TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1high immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.
    Keywords:  ER stress; IRE1α; PD-L1-negative breast cancer; dsRNA; pyroptosis
    DOI:  https://doi.org/10.1016/j.cell.2024.09.032
  17. J Cell Biol. 2024 Nov 04. pii: e202410022. [Epub ahead of print]223(11):
    Making lipids very unhappy to discover how they bind to proteins.
    Christopher Stefan, Roberto Covino.
      Membrane lipid composition is maintained by conserved lipid transfer proteins, but computational approaches to study their lipid-binding mechanisms are limiting. Srinivasan et al. (https://doi.org/10.1083/jcb.202312055) develop a clever molecular dynamics simulations assay to accurately model lipid-binding poses in lipid transfer proteins.
    DOI:  https://doi.org/10.1083/jcb.202410022
  18. bioRxiv. 2024 Oct 11. pii: 2024.10.10.617667. [Epub ahead of print]
    Catabolism of extracellular glutathione supplies amino acids to support tumor growth.
    Fabio Hecht, Marco Zocchi, Emily T Tuttle, Nathan P Ward, Bradley Smith, Yun Pyo Kang, Juliana Cazarin, Zamira G Soares, Mete Emir Ozgurses, Huiping Zhao, Colin Sheehan, Fatemeh Alimohammadi, Lila D Munger, Dhvani Trivedi, Gloria Asantewaa, Sara K Blick-Nitko, Jason J Zoeller, Ying Chen, Vasilis Vasiliou, Bradley M Turner, Alexander Muir, Jonathan L Coloff, Joshua Munger, Gina M DeNicola, Isaac S Harris.
      Restricting amino acids from tumors is an emerging therapeutic strategy with significant promise. While typically considered an intracellular antioxidant with tumor-promoting capabilities, glutathione (GSH) is a tripeptide of cysteine, glutamate, and glycine that can be catabolized, yielding amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here, we find that GSH catabolism promotes tumor growth. We show that depletion of intracellular GSH does not perturb tumor growth, and extracellular GSH is highly abundant in the tumor microenvironment, highlighting the potential importance of GSH outside of tumors. We find supplementation with GSH can rescue cancer cell survival and growth in cystine-deficient conditions, and this rescue is dependent on the catabolic activity of γ-glutamyltransferases (GGTs). Finally, pharmacologic targeting of GGTs' activity prevents the breakdown of circulating GSH, lowers tumor cysteine levels, and slows tumor growth. Our findings indicate a non-canonical role for GSH in supporting tumors by acting as a reservoir of amino acids. Depriving tumors of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Further, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.
    DOI:  https://doi.org/10.1101/2024.10.10.617667
  19. Am J Cancer Res. 2024 ;14(9): 4523-4536
    Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation.
    Vida Tajiknia, Maximilian Pinho-Schwermann, Praveen R Srinivasan, Liz Hernandez Borrero, Leiqing Zhang, Kelsey E Huntington, Wafik S El-Deiry.
      KRAS mutations occur in ~40-50% of mCRC and are associated with aggressive disease that is refractory to anti-EGFR therapies. Pancreatic cancer harbors ~90% KRAS driver gene mutation frequency. Small molecules targeting KRAS G12C gained FDA approval for KRAS G12C-mutated NSCLC. ONC212, a fluorinated imipridone with nM anti-cancer activity has preclinical efficacy against pancreatic cancer and other malignancies. MRTX1133, identified as a noncovalent selective KRAS G12D inhibitor that suppresses G12D signaling by binding to the switch II pocket thereby inhibiting protein-protein interactions. We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. IC50 sensitivities ranged from 7 to 12 µM for 5-FU, 0.2-0.8 µM for ONC212, and > 100 nM to > 5,000 nM for MRTX1133 (G12D N = 4: LS513 > 100, HPAF-II > 1,000, SNUC2B > 5,000, PANC-1 > 5,000). For non-G12D, the range of IC50 for MRTX1133 was > 1,000 to > 5,000 nM for CRC lines with G12V, G13D, or WT KRAS (N = 7). Synergies between MRTX1133 plus 5-FU or ONC212 were observed regardless of KRAS G12D mutation with combination indices of < 0.5 indicating strong synergy. Observed synergies were greater with MRTX1133 plus ONC212 compared to MRTX1133 plus 5-FU. pERK was suppressed with mutant but not wild-type KRAS at nM MRTX1133 doses. Immunostimulatory profiles included reduction in IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha and increase in IL-18/IL-1F4 with MRTX treatments and combinations. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.
    Keywords:  KRAS G12D; MRTX1133; ONC212; colorectal cancer; cytokine; drug synergy; pancreatic cancer
    DOI:  https://doi.org/10.62347/DVXL1377
  20. Pancreatology. 2024 Oct 01. pii: S1424-3903(24)00751-8. [Epub ahead of print]
    Caveolin-1 expression is a predictor of survival and recurrence patterns in resected pancreatic ductal adenocarcinoma.
    Yuki Hirose, Atsushi Oba, Manabu Takamatsu, Tsuyoshi Hamada, Tsuyoshi Takeda, Tatsunori Suzuki, Aya Maekawa, Yuki Kitano, Shoki Sato, Kosuke Kobayashi, Kojiro Omiya, Yoshihiro Ono, Takafumi Sato, Hiromichi Ito, Takashi Sasaki, Masato Ozaka, Kengo Takeuchi, Naoki Sasahira, Yosuke Inoue, Toshifumi Wakai, Yu Takahashi.
      BACKGROUND/OBJECTIVE: Caveolin-1 (Cav1) expressed in cancer cells (cCav1) or cancer-associated fibroblasts (fCav1) exerts either pro- or anti-tumorigenic effects depending on the cancer type or stage of cancer. We aimed to clarify the impact of cCav1 or fCav1 on survival, recurrence patterns, and efficacy of neoadjuvant chemotherapy (NAC) in resected pancreatic ductal adenocarcinoma (PDAC).METHODS: Tissue microarrays were constructed including 615 patients who underwent curative resection for PDAC. Cav1 expression was evaluated by immunohistochemistry. Patients were divided into two groups based on Cav1 expression in cancer cells (cCav1high vs. cCav1low) or cancer-associated fibroblasts (fCav1high vs. fCav1low).
    RESULTS: Among all 615 patients, 40.7% were cCav1high and 72.7% were fCav1high. cCav1high was associated with worse overall survival (OS) (p = 0.001) and recurrence-free survival (RFS) (p = 0.001) than cCav1low, and was an independent prognostic factor in multivariate analysis of OS and RFS (OS: p = 0.001, hazard ratio [HR] 1.361; RFS: p = 0.001, HR 1.348). Among 596 patients with resectable/borderline resectable PDAC, cCav1high patients with NAC showed better OS than those without, while there was no significant difference between cCav1low patients with NAC and those without. cCav1high was associated with early recurrence (< 6 months) and liver metastasis after resection. Multivariate analysis revealed cCav1high as an independent predictor of liver metastasis.
    CONCLUSIONS: cCav1high correlated with worse survival, early recurrence, and liver metastasis after resection for PDAC, while NAC improved survival in cCav1high patients. The Evaluation of cCav1 status could provide additional information contributing to the personalized management of PDAC.
    Keywords:  Caveolin-1; Chemo-resistance; Liver metastasis; Pancreatic ductal adenocarcinoma; Survival
    DOI:  https://doi.org/10.1016/j.pan.2024.10.001
  21. Signal Transduct Target Ther. 2024 Oct 14. 9(1): 272
    Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy.
    Yu Xiao, Tao Pan, Wuren Da, Yuanding Liu, Shuangya Chen, Daiquan Chen, Keying Liu, Yihan Zheng, Daolong Xie, Yuan Gao, Haiyan Xu, Yang Sun, Weihong Tan.
      Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer's specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer's targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.
    DOI:  https://doi.org/10.1038/s41392-024-01973-3
  22. Nat Cancer. 2024 Oct 16.
    Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.
    Khalil Kass Youssef, Nitin Narwade, Aida Arcas, Angel Marquez-Galera, Raúl Jiménez-Castaño, Cristina Lopez-Blau, Hassan Fazilaty, David García-Gutierrez, Amparo Cano, Joan Galcerán, Gema Moreno-Bueno, Jose P Lopez-Atalaya, M Angela Nieto.
      Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination.
    DOI:  https://doi.org/10.1038/s43018-024-00839-5
  23. Exp Mol Pathol. 2024 Oct 16. pii: S0014-4800(24)00057-1. [Epub ahead of print]140 104938
    Histomorphological scoring of murine colitis models: A practical guide for the evaluation of colitis and colitis-associated cancer.
    Marianne Remke, Tanja Groll, Thomas Metzler, Elisabeth Urbauer, Janine Kövilein, Theresa Schnalzger, Jürgen Ruland, Dirk Haller, Katja Steiger.
      BACKGROUND AND AIMS: Histomorphology is a powerful and cost-efficient tool for evaluating inflammatory and neoplastic conditions. Inflammatory bowel disease (IBD) is a widespread condition with globally rising incidences, and a lot of research is done to better understand the pathogenesis of IBD and to identify potential therapeutic approaches. However, standardized and reproducible scores for the histomorphological evaluation of murine IBD models are lacking. Therefore, we aimed to develop an easy-to-use and reproducible score for standardized assessment of colitis and associated cancer models.METHODS: In this study, samples from three different colitis models with and without associated cancer formation were analyzed to develop a universal, robust, and reproducible score for the grading of murine colitis models using the following three parameters: 1. Extent of leucocyte infiltration, 2. Tissue damage, 3. Architectural disruption of the mucosa.
    RESULTS: A scoring system was established for different kinds of colitis models (genetically induced enterocolitis, genetically induced metabolic injury, and chemically induced colitis-associated cancer) and all stages of the disease, from mild inflammatory changes to severe inflammation with neoplastic changes as the extreme extent of IBD. The scoring scheme is easy to use, can easily be learned, and proves to have a high interrater reliability.
    CONCLUSIONS: We propose a robust histological scoring system for the assessment of murine colitis and colitis-associated cancer models, giving more researchers access to conclusive and reliable histological assessment.
    Keywords:  Animal models; Experimental pathology; Inflammation; Inflammatory bowel diseases
    DOI:  https://doi.org/10.1016/j.yexmp.2024.104938
  24. J Cell Biol. 2025 Jan 06. pii: e202312141. [Epub ahead of print]224(1):
    Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation.
    Pei Yee Tey, Almut Dufner, Klaus-Peter Knobeloch, Jonathan N Pruneda, Michael J Clague, Sylvie Urbé.
      The immune checkpoint regulator CTLA4 is an unusually short-lived membrane protein. Here, we show that its lysosomal degradation is dependent on ubiquitylation at lysine residues 203 and 213. Inhibition of the v-ATPase partially restores CTLA4 levels following cycloheximide treatment, but also reveals a fraction that is secreted in exosomes. The endosomal deubiquitylase, USP8, interacts with CTLA4, and its loss enhances CTLA4 ubiquitylation in cancer cells, mouse CD4+ T cells, and cancer cell-derived exosomes. Depletion of the USP8 adapter protein, HD-PTP, but not ESCRT-0 recapitulates this cellular phenotype but shows distinct properties vis-à-vis exosome incorporation. Re-expression of wild-type USP8, but neither a catalytically inactive nor a localization-compromised ΔMIT domain mutant can rescue delayed degradation of CTLA4 or counteract its accumulation in clustered endosomes. UbiCRest analysis of CTLA4-associated ubiquitin chain linkages identifies a complex mixture of conventional Lys63- and more unusual Lys27- and Lys29-linked polyubiquitin chains that may underly the rapidity of protein turnover.
    DOI:  https://doi.org/10.1083/jcb.202312141
  25. Int J Mol Sci. 2024 Sep 30. pii: 10554. [Epub ahead of print]25(19):
    Leader Cells: Invade and Evade-The Frontline of Cancer Progression.
    Brittany R Doran, Laura R Moffitt, Amy L Wilson, Andrew N Stephens, Maree Bilandzic.
      Metastasis is the leading cause of cancer-related mortality; however, a complete understanding of the molecular programs driving the metastatic cascade is lacking. Metastasis is dependent on collective invasion-a developmental process exploited by many epithelial cancers to establish secondary tumours and promote widespread disease. The key drivers of collective invasion are "Leader Cells", a functionally distinct subpopulation of cells that direct migration, cellular contractility, and lead trailing or follower cells. While a significant body of research has focused on leader cell biology in the traditional context of collective invasion, the influence of metastasis-promoting leader cells is an emerging area of study. This review provides insights into the expanded role of leader cells, detailing emerging evidence on the hybrid epithelial-mesenchymal transition (EMT) state and the phenotypical plasticity exhibited by leader cells. Additionally, we explore the role of leader cells in chemotherapeutic resistance and immune evasion, highlighting their potential as effective and diverse targets for novel cancer therapies.
    Keywords:  cancer; chemoresistance; collective invasion; keratin 14; leader cell; metastasis
    DOI:  https://doi.org/10.3390/ijms251910554
  26. Biophys J. 2024 Oct 15. pii: S0006-3495(24)00679-9. [Epub ahead of print]
    High Frequency MHz-Order Vibration Enables Cell Membrane Remodelling and Lipid Microdomain Manipulation.
    Lizebona A Ambattu, Blanca Del Rosal, Charlotte E Conn, Leslie Y Yeo.
      We elucidate the mechanism underpinning a recently discovered phenomenon in which cells respond to MHz-order mechanostimuli. Deformations induced along the plasma membrane under these external mechanical cues are observed to decrease the membrane tension, which, in turn, drives transient and reversible remodelling of its lipid structure. In particular, the increase and consequent coalescence of ordered lipid microdomains leads to closer proximity to mechanosensitive ion channels-Piezo1, in particular-that due to crowding, results in their activation to mobilise influx of calcium (Ca2+) ions into the cell. It is such modulation of this second messenger that is responsible for the downstream signalling and cell fates that ensue. Additionally, we show that such spatiotemporal control over the membrane microdomains in cells-without necessitating biochemical factors-facilitates aggregation and association of intrinsically-disordered tau proteins in neuroblastoma cells, and their transformation to pathological conditions implicated in neurodegenerative diseases, thereby paving the way for the development of therapeutic intervention strategies.
    DOI:  https://doi.org/10.1016/j.bpj.2024.10.007
  27. J Cell Sci. 2024 Oct 15. pii: jcs261947. [Epub ahead of print]137(20):
    Illuminating cellular architecture and dynamics with fluorescence polarization microscopy.
    William F Dean, Alexa L Mattheyses.
      Ever since Robert Hooke's 17th century discovery of the cell using a humble compound microscope, light-matter interactions have continuously redefined our understanding of cell biology. Fluorescence microscopy has been particularly transformative and remains an indispensable tool for many cell biologists. The subcellular localization of biomolecules is now routinely visualized simply by manipulating the wavelength of light. Fluorescence polarization microscopy (FPM) extends these capabilities by exploiting another optical property - polarization - allowing researchers to measure not only the location of molecules, but also their organization or alignment within larger cellular structures. With only minor modifications to an existing fluorescence microscope, FPM can reveal the nanoscale architecture, orientational dynamics, conformational changes and interactions of fluorescently labeled molecules in their native cellular environments. Importantly, FPM excels at imaging systems that are challenging to study through traditional structural approaches, such as membranes, membrane proteins, cytoskeletal networks and large macromolecular complexes. In this Review, we discuss key discoveries enabled by FPM, compare and contrast the most common optical setups for FPM, and provide a theoretical and practical framework for researchers to apply this technique to their own research questions.
    Keywords:  Cellular architecture; Fluorescence polarization; Macromolecular complex; Microscopy; Quantitative fluorescence
    DOI:  https://doi.org/10.1242/jcs.261947
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