bims-cagime 2023-09-24 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2023‒09‒24
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

A mechanism that ensures non-selective cytoplasm degradation by autophagy.
Dietary fat and lipid metabolism in the tumor microenvironment.
Cell senescence, the senescence-associated secretory phenotype, and cancers.
Past and Future Directions for Research on Cellular Senescence.
Manipulating mitochondrial electron flow enhances tumor immunogenicity.
ATPase-regulated autophagosome biogenesis.
Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.
Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
GelMap: intrinsic calibration and deformation mapping for expansion microscopy.
PD-1 blockade induces reactivation of non-productive T cell responses characterized by NF-kB signaling in patients with pancreatic cancer.
BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma.
Autotaxin secretion is a stromal mechanism of adaptive resistance to TGFβ inhibition in pancreatic ductal adenocarcinoma.
The human cell count and size distribution.
Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration.
Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
The collagen landscape in cancer: profiling collagens in tumors and in circulation reveals novel markers of cancer-associated fibroblast subtypes.
Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy.
Modelling three-dimensional cancer-associated cachexia and therapy: The molecular basis and therapeutic potential of interleukin-6 transignalling blockade.
STAT3 is a genetic modifier of TGF-beta induced EMT in KRAS mutant pancreatic cancer.
Fructose-induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy.
CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.
Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes.
Protocol for quantifying the in vivo rate of protein degradation in mice using a pulse-chase technique.
Beclin1 is essential for the pancreas development.
The cell-cycle choreography of H3 variants shapes the genome.
Tumor lipid metabolism: a mechanistic link between diet and cancer progression.
Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages.
Regulation of nucleo-cytosolic 26S proteasome translocation by aromatic amino acids via mTOR is essential for cell survival under stress.
Using DeepContact with Amira graphical user interface.
Adventures With Parasites, Metabolism, Inborn Errors, and Cancer: The 2023 Lasker-Koshland Special Achievement Award in Medical Science.
Validity of computed tomography defined body composition as a prognostic factor for functional outcome after kidney transplantation.

Nat Commun. 2023 09 19. 14(1): 5815

A mechanism that ensures non-selective cytoplasm degradation by autophagy.

Tetsuya Kotani, Yuji Sakai, Hiromi Kirisako, Chika Kakuta, Soichiro Kakuta, Yoshinori Ohsumi, Hitoshi Nakatogawa.

In autophagy, a membrane cisterna called the isolation membrane expands, bends, becomes spherical, and closes to sequester cytoplasmic constituents into the resulting double-membrane vesicle autophagosome for lysosomal/vacuolar degradation. Here, we discover a mechanism that allows the isolation membrane to expand with a large opening to ensure non-selective cytoplasm sequestration within the autophagosome. A sorting nexin complex that localizes to the opening edge of the isolation membrane plays a critical role in this process. Without the complex, the isolation membrane expands with a small opening that prevents the entry of particles larger than about 25 nm, including ribosomes and proteasomes, although autophagosomes of nearly normal size eventually form. This study sheds light on membrane morphogenesis during autophagosome formation and selectivity in autophagic degradation.

DOI: https://doi.org/10.1038/s41467-023-41525-x
Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984

Dietary fat and lipid metabolism in the tumor microenvironment.

Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.

  Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.

Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
PLoS Biol. 2023 Sep 21. 21(9): e3002326

Cell senescence, the senescence-associated secretory phenotype, and cancers.

Larissa G P Langhi Prata, Tamar Tchkonia, James L Kirkland.

Cellular senescence is a cell fate caused by multiple stresses. A 2008 article in PLOS Biology reported a senescence-associated secretory phenotype that can promote inflammation and cancer, eventually enabling the development of senolytic drugs.

DOI: https://doi.org/10.1371/journal.pbio.3002326
Cold Spring Harb Perspect Med. 2023 Sep 21. pii: a041205. [Epub ahead of print]

Past and Future Directions for Research on Cellular Senescence.

Yi Zhu, Zacharias P Anastasiadis, Jair Machado Espindola Netto, Tamara Evans, Tamar Tchkonia, James L Kirkland.

Cellular senescence was initially described in the early 1960s by Hayflick and Moorehead. They noted sustained cell-cycle arrest after repeated subculturing of human primary cells. Over half a century later, cellular senescence has become recognized as one of the fundamental pillars of aging. Developing senotherapeutics, interventions that selectively eliminate or target senescent cells, has emerged as a key focus in health research. In this article, we note major milestones in cellular senescence research, discuss current challenges, and point to future directions for this rapidly growing field.

DOI: https://doi.org/10.1101/cshperspect.a041205
Science. 2023 Sep 22. 381(6664): 1316-1323

Manipulating mitochondrial electron flow enhances tumor immunogenicity.

Kailash Chandra Mangalhara, Siva Karthik Varanasi, Melissa A Johnson, Mannix J Burns, Gladys R Rojas, Pau B Esparza Moltó, Alva G Sainz, Nimesha Tadepalle, Keene L Abbott, Gaurav Mendiratta, Dan Chen, Yagmur Farsakoglu, Tenzin Kunchok, Filipe Araujo Hoffmann, Bianca Parisi, Mercedes Rincon, Matthew G Vander Heiden, Marcus Bosenberg, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel.

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

DOI: https://doi.org/10.1126/science.abq1053
Autophagy. 2023 Sep 18. 1-2

ATPase-regulated autophagosome biogenesis.

Viola Nähse, Kay O Schink, Harald Stenmark.

  Omega-shaped domains of the endoplasmic reticulum, known as omegasomes, have been suggested to contribute to autophagosome biogenesis, although their exact function is not known. Omegasomes are characterized by the presence of the double FYVE domain containing protein ZFYVE1/DFCP1, but it has remained a paradox that depletion of ZFYVE1 does not prevent bulk macroautophagy/autophagy. We recently showed that ZFYVE1 contains an N-terminal ATPase domain which dimerizes upon ATP binding. Mutations in the ATPase domain that inhibit ATP binding or hydrolysis do not prevent omegasome expansion and maturation. However, omegasome constriction is inhibited by these mutations, which results in an increased lifetime and thereby higher number of omegasomes. Interestingly, whereas ZFYVE1 knockout or mutations do not significantly affect bulk autophagy, selective autophagy of mitochondria, protein aggregates and micronuclei is inhibited. We propose that ATP binding and hydrolysis control the di- or multimerization state of ZFYVE1 which could provide the mechanochemical energy to drive large omegasome constriction and autophagosome completion.

Keywords:  Aggrephagy; Atpase; autophagosome; micronucleophagy; mitophagy; omegasome

DOI:  https://doi.org/10.1080/15548627.2023.2255967
JCI Insight. 2023 Sep 21. pii: e163022. [Epub ahead of print]

Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.

Fumimasa Kitamura, Takashi Semba, Noriko Yasuda-Yoshihara, Kosuke Yamada, Akiho Nishimura, Juntaro Yamasaki, Osamu Nagano, Tadahito Yasuda, Atsuko Yonemura, Yilin Tong, Huaitao Wang, Takahiko Akiyama, Kazuki Matsumura, Norio Uemura, Rumi Itoyama, Luke Bu, Lingfeng Fu, Xichen Hu, Feng Wei, Kosuke Mima, Katsunori Imai, Hiromitsu Hayashi, Yo-Ichi Yamashita, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto.

  Glycolysis is highly enhanced in Pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for PDAC patients, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides new insights into crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.

Keywords:  Cancer; Metabolism; Oncology

DOI:  https://doi.org/10.1172/jci.insight.163022
Cancer Discov. 2023 Sep 20.

Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.

Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W LaFleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe.

The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.

DOI: https://doi.org/10.1158/2159-8290.CD-22-1301
Nat Methods. 2023 Sep 18.

GelMap: intrinsic calibration and deformation mapping for expansion microscopy.

Hugo G J Damstra, Josiah B Passmore, Albert K Serweta, Ioannis Koutlas, Mithila Burute, Frank J Meye, Anna Akhmanova, Lukas C Kapitein.

Expansion microscopy (ExM) is a powerful technique to overcome the diffraction limit of light microscopy by physically expanding biological specimen in three dimensions. Nonetheless, using ExM for quantitative or diagnostic applications requires robust quality control methods to precisely determine expansion factors and to map deformations due to anisotropic expansion. Here we present GelMap, a flexible workflow to introduce a fluorescent grid into pre-expanded hydrogels that scales with expansion and reports deformations. We demonstrate that GelMap can be used to precisely determine the local expansion factor and to correct for deformations without the use of cellular reference structures or pre-expansion ground-truth images. Moreover, we show that GelMap aids sample navigation for correlative uses of expansion microscopy. Finally, we show that GelMap is compatible with expansion of tissue and can be readily implemented as a quality control step into existing ExM workflows.

DOI: https://doi.org/10.1038/s41592-023-02001-y
Clin Cancer Res. 2023 Sep 21.

PD-1 blockade induces reactivation of non-productive T cell responses characterized by NF-kB signaling in patients with pancreatic cancer.

Lestat R Ali, Patrick J Lenehan, Victoire Cardot-Ruffino, Andressa Dias Costa, Matthew H G Katz, Todd W Bauer, Jonathan A Nowak, Brian M Wolpin, Thomas A Abrams, Anuj Patel, Thomas E Clancy, Jiping Wang, Joseph D Mancias, Matthew J Reilley, Chee-Chee H Stucky, Tanios S Bekaii-Saab, Rawad Elias, Nipun Merchant, Craig L Slingluff, Osama E Rahma, Stephanie K Dougan.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease where bulky tumor burden and limited time to develop anti-tumor T cells may have contributed to poor clinical efficacy. Here we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti-PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors.EXPERIMENTAL DESIGN: We used single cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor.
RESULTS: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T cell clonotypes observed in the tumor.
CONCLUSIONS: Cytotoxic T cells in the blood of PDAC patients remain sensitive to reinvigoration by PD-1 blockade and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti-PD-1 reinvigoration and marks these T cells as non-productive contributors to anti-tumor immunity.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1444
Gastroenterology. 2023 Sep 20. pii: S0016-5085(23)05012-6. [Epub ahead of print]

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma.

Yuliang Feng, Liuyang Cai, Martin Pook, Feng Liu, Chao-Hui Chang, Mai Abdel Mouti, Reshma Nibhani, Stefania Militi, James Dunford, Martin Philpott, Yanbo Fan, Guo-Chang Fan, Qi Liu, Jun Qi, Cheng Wang, Wanzi Hong, Hannah Morgan, Mingyang Wang, Sakthivel Sadayappan, Anil G Jegga, Udo Oppermann, Yigang Wang, Wei Huang, Lei Jiang, Siim Pauklin.

  BACKGROUND AND AIMS: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood which hampers the development of novel strategies for eliminating CSCs.METHODS: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway.
RESULTS: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to Gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.
CONCLUSIONS: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Keywords:  Cancer Therapy; Epigenetics; Pancreatic cancer; TGFβ/Activin-SMAD2/3; cancer stem cells

DOI:  https://doi.org/10.1053/j.gastro.2023.09.021
Cancer Res. 2023 Sep 22.

Autotaxin secretion is a stromal mechanism of adaptive resistance to TGFβ inhibition in pancreatic ductal adenocarcinoma.

Silvia Pietrobono, Fabio Sabbadini, Monica Bertolini, Domenico Mangiameli, Veronica De Vita, Federica Fazzini, Giulia Lunardi, Simona Casalino, Enza Scarlato, Valeria Merz, Camilla Zecchetto, Alberto Quinzii, Giusy Di Conza, Michael Lahn, Davide Melisi.

The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase 2 H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine to gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer associated fibroblasts (CAFs) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NF-κB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NF-κB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared to those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0104
Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2303077120

The human cell count and size distribution.

Ian A Hatton, Eric D Galbraith, Nono S C Merleau, Teemu P Miettinen, Benjamin McDonald Smith, Jeffery A Shander.

  Cell size and cell count are adaptively regulated and intimately linked to growth and function. Yet, despite their widespread relevance, the relation between cell size and count has never been formally examined over the whole human body. Here, we compile a comprehensive dataset of cell size and count over all major cell types, with data drawn from >1,500 published sources. We consider the body of a representative male (70 kg), which allows further estimates of a female (60 kg) and 10-y-old child (32 kg). We build a hierarchical interface for the cellular organization of the body, giving easy access to data, methods, and sources (https://humancelltreemap.mis.mpg.de/). In total, we estimate total body counts of ≈36 trillion cells in the male, ≈28 trillion in the female, and ≈17 trillion in the child. These data reveal a surprising inverse relation between cell size and count, implying a trade-off between these variables, such that all cells within a given logarithmic size class contribute an equal fraction to the body's total cellular biomass. We also find that the coefficient of variation is approximately independent of mean cell size, implying the existence of cell-size regulation across cell types. Our data serve to establish a holistic quantitative framework for the cells of the human body, and highlight large-scale patterns in cell biology.

Keywords:  cell biomass; cell count; cell size; size distribution; size homeostasis

DOI:  https://doi.org/10.1073/pnas.2303077120
Cell Metab. 2023 Sep 15. pii: S1550-4131(23)00331-5. [Epub ahead of print]

Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration.

Maike Becker, Sini S Joseph, Francisco Garcia-Carrizo, Robby Z Tom, Daria Opaleva, Isabelle Serr, Matthias H Tschöp, Tim J Schulz, Susanna M Hofmann, Carolin Daniel.

  Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.

Keywords:  IL6Ra signaling; exercise; immune tissue crosstalk; immune-metabolic crosstalk; immunometabolism; injury; muscle function; niche-specific Tregs; tissue Tregs; voluntary wheel running

DOI:  https://doi.org/10.1016/j.cmet.2023.08.010
bioRxiv. 2023 Sep 05. pii: 2023.09.01.555986. [Epub ahead of print]

Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.

Spencer D Shelton, Sara House, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra.

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.

DOI: https://doi.org/10.1101/2023.09.01.555986
J Pathol. 2023 Sep 20.

The collagen landscape in cancer: profiling collagens in tumors and in circulation reveals novel markers of cancer-associated fibroblast subtypes.

Jeppe Thorlacius-Ussing, Christina Jensen, Neel I Nissen, Thomas R Cox, Raghu Kalluri, Morten Karsdal, Nicholas Willumsen.

  Cancer-associated fibroblasts (CAFs) deposit and remodel collagens in the tumor stroma, impacting cancer progression and efficacy of interventions. CAFs are the focus of new therapeutics with the aim of normalizing the tumor microenvironment. To do this, a better understanding of CAF heterogeneity and collagen composition in cancer is needed. In this study, we sought to profile the expression of collagens at multiple levels with the goal of identifying cancer biomarkers. We investigated the collagen expression pattern in various cell types and CAF subtypes in a publicly available single-cell RNA sequencing (RNA-seq) dataset of pancreatic ductal adenocarcinoma. Next, we investigated the collagen expression profile in tumor samples across cancer types from The Cancer Genome Atlas (TCGA) database and evaluated if specific patterns of collagen expression were associated with prognosis. Finally, we profiled circulating collagen peptides using a panel of immunoassays to measure collagen fragments in the serum of cancer patients. We found that pancreatic stellate cells and fibroblasts were the primary producers of collagens in the pancreas. COL1A1, COL3A1, COL5A1, COL6A1 were expressed in all CAF subtypes, whereas COL8A1, COL10A1, COL11A1, COL12A1 were specific to myofibroblast CAFs (myCAF) and COL14A1 specific to inflammatory CAFs (iCAF). In TCGA database, myCAF collagens COL10A1 and COL11A1 were elevated across solid tumor types, and multiple associations between high expression and worse survival were found. Finally, circulating collagen biomarkers were elevated in the serum of patients with cancer relative to healthy controls with COL11A1 (myCAF) having the best diagnostic accuracy of the markers measured. In conclusion, CAFs express a noncanonical collagen profile with specific collagen subtypes associated with iCAFs and myCAFs in PDAC. These collagens are deregulated at the cellular, tumor, and systemic levels across different solid tumors and associate with survival. These findings could lead to new discoveries such as novel biomarkers and therapeutic targets. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  biomarkers; cancer; cancer-associated fibroblasts; collagen; extracellular matrix

DOI:  https://doi.org/10.1002/path.6207
Cancer Lett. 2023 Sep 20. pii: S0304-3835(23)00347-6. [Epub ahead of print] 216396

Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy.

Zhangyi Luo, Katherine M Eichinger, Anju Zhang, Song Li.

  Recent discoveries in cancer metabolism have revealed promising metabolic targets to modulate cancer progression, drug response, and anti-cancer immunity. Combination therapy, consisting of metabolic inhibitors and chemotherapeutic or immunotherapeutic agents, offers new opportunities for improved cancer therapy. However, it also presents challenges due to the complexity of cancer metabolic pathways and the metabolic interactions between tumor cells and immune cells. Many studies have been published demonstrating potential synergy between novel inhibitors of metabolism and chemo/immunotherapy, yet our understanding of the underlying mechanisms remains limited. Here, we review the current strategies of altering the metabolic pathways of cancer to improve the anti-cancer effects of chemo/immunotherapy. We also note the need to differentiate the effect of metabolic inhibition on cancer cells and immune cells and highlight nanotechnology as an emerging solution. Improving our understanding of the complexity of the metabolic pathways in different cell populations and the anti-cancer effects of chemo/immunotherapy will aid in the discovery of novel strategies that effectively restrict cancer growth and augment the anti-cancer effects of chemo/immunotherapy.

Keywords:  Cancer Metabolism; Cancer nanotechnology; Chemotherapy; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2023.216396
J Cachexia Sarcopenia Muscle. 2023 Sep 20.

Modelling three-dimensional cancer-associated cachexia and therapy: The molecular basis and therapeutic potential of interleukin-6 transignalling blockade.

Marianna Cosentino, Laura Forcina, Mariam Zouhair, Ludovica Apa, Desirèe Genovese, Caterina Boccia, Emanuele Rizzuto, Antonio Musarò.

  BACKGROUND: Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin-6 (IL-6) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways.METHODS: We employed a three-dimensional ex vivo muscle engineered tissue (X-MET) to model cancer-associated cachexia and to study the effectiveness of selective inhibition of IL-6 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X-MET model. A dose of 1.2 ng/mL of glycoprotein-130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL-6 transignalling.
RESULTS: C26-conditioned medium induced a cachectic-like phenotype in the X-MET, leading to a decline of muscle mass (-60%; P < 0.001), a reduction in myosin expression (-92.4%; P < 0.005) and a reduction of the contraction frequency spectrum (-94%). C26-conditioned medium contains elevated amounts of IL-6 (8.61 ± 4.09 pg/mL) and IL6R (56.85 ± 10.96 pg/mL). These released factors activated the signal transducer and activator of transcription 3 (STAT3) signalling in the C26_CM X-MET system (phosphorylated STAT3/TOTAL +54.6%; P < 0.005), which in turn promote an enhancement of Il-6 (+69.2%; P < 0.05) and Il6r (+43%; P < 0.05) gene expression, suggesting the induction of a feed-forward loop. The selective neutralization of IL-6 transignalling, by gp130Fc, in C26_CM X-MET prevented the hyperactivation of STAT3 (-55.8%; P < 0.005), countered the reduction of cross-sectional area (+28.2%; P < 0.05) and reduced the expression of proteolytic factors including muscle ring finger-1 (-88%; P < 0.005) and ATROGIN1 (-92%; P < 0.05), thus preserving the robustness and increasing the contractile force (+20%) of the three-dimensional muscle system. Interestingly, the selective inhibition of IL-6 transignalling modulated gene regulatory networks involved in myogenesis and apoptosis, normalizing the expression of pro-apoptotic miRNAs, including miR-31 (-53.2%; P < 0.05) and miR-34c (-65%; P < 0.005), and resulting in the reduction of apoptotic pathways highlighted by the sensible reduction of cleaved caspase 3 (-92.5%; P < 0.005) in gp130Fc-treated C26_CM X-MET.
CONCLUSIONS: IL-6 transignalling appeared as a promising target to counter cancer cachexia-related alterations. The X-MET model has proven to be a reliable drug-screening tool to identify novel therapeutic approaches and to test them in preclinical studies, significantly reducing the use of animal models.

Keywords:  IL-6 transignalling blockade; cancer cachexia; drug screening; muscle wasting; three-dimensional skeletal muscle model

DOI:  https://doi.org/10.1002/jcsm.13329
bioRxiv. 2023 Sep 05. pii: 2023.09.01.555946. [Epub ahead of print]

STAT3 is a genetic modifier of TGF-beta induced EMT in KRAS mutant pancreatic cancer.

Stephen D'Amico, Varvara Kirillov, Oleksi Petrenko, Nancy C Reich.

Oncogenic mutations in KRAS are among the most common in cancer. Classical models suggest that loss of epithelial characteristics and the acquisition of mesenchymal traits are associated with cancer aggressiveness and therapy resistance. However, the mechanistic link between these phenotypes and mutant KRAS biology remains to be established. Here we identify STAT3 as a genetic modifier of TGF-beta-induced epithelial to mesenchymal transition. Gene expression profiling of pancreatic cancer cells identifies more than 200 genes commonly regulated by STAT3 and oncogenic KRAS. Functional classification of STAT3 responsive program reveals its major role in tumor maintenance and epithelial homeostasis. The signatures of STAT3-activated cell states can be projected onto human KRAS mutant tumors, suggesting that they faithfully reflect characteristics of human disease. These observations have implications for therapeutic intervention and tumor aggressiveness.Significance: The identification of the molecular and genetic characteristics of tumors is essential for understanding disease progression and aggressiveness. KRAS mutations are the most frequent oncogenic drivers in human cancer. In this study we demonstrate that the ubiquitously expressed transcription factor STAT3 is a genetic modifier of TGF-beta-induced EMT, and thereby oncogenic KRAS dependency. Both in vitro and in vivo studies demonstrate that STAT3 responsive program is an inherent part of oncogenic KRAS outcome.

DOI: https://doi.org/10.1101/2023.09.01.555946
Cancer Res. 2023 Sep 22.

Fructose-induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy.

Yanfen Cui, Jianfei Tian, Zhaosong Wang, Hui Guo, He Zhang, Zhiyong Wang, Hui Liu, Weijie Song, Liming Liu, Ruinan Tian, Xiaoyan Zuo, Sixin Ren, Ruifang Niu, Fei Zhang.

Excessive fructose intake is associated with the occurrence, progression, and poor prognosis of various tumors. A better understanding of the mechanisms underlying the functions of fructose in cancer could facilitate the development of better treatment and prevention strategies. In this study, we investigated the functional association between fructose utilization and pancreatic ductal adenocarcinoma (PDAC) progression. Fructose could be taken up and metabolized by PDAC cells and provided an adaptive survival mechanism for PDAC cells under glucose deficient conditions. GLUT5-mediated fructose metabolism maintained the survival, proliferation, and invasion capacities of PDAC cells in vivo and in vitro. Fructose metabolism not only provided ATP and biomass to PDAC cells but also conferred metabolic plasticity to the cells, making them more adaptable to the tumor microenvironment. Mechanistically, fructose activated AMPK-mTORC1 signaling pathway to inhibit glucose deficiency-induced autophagic cell death. Moreover, the fructose specific transporter GLUT5 was highly expressed in PDAC tissues and was an independent marker of disease progression in PDAC patients. These findings provide mechanistic insights into the role of fructose in promoting PDAC progression and offer potential strategies for targeting metabolism to treat PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0464
Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2302878120

CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.

Zheng Liu, Wenjie Liu, Wei Wang, Yibao Ma, Yufeng Wang, David L Drum, Jinyang Cai, Hallie Blevins, Eun Lee, Syed Shah, Paul B Fisher, Xinhui Wang, Xianjun Fang, Chunqing Guo, Xiang-Yang Wang.

  Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.

Keywords:  cancer metabolism; carnitine palmitoyltransferase 1A; cellular immunotherapy; fatty acid oxidation; therapeutic resistance

DOI:  https://doi.org/10.1073/pnas.2302878120
Cancer Chemother Pharmacol. 2023 Sep 19.

Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes.

Anna Maria Militello, Giulia Orsi, Alessandro Cavaliere, Monica Niger, Antonio Avallone, Lisa Salvatore, Giampaolo Tortora, Ilario Giovanni Rapposelli, Guido Giordano, Silvia Noventa, Elisa Giommoni, Silvia Bozzarelli, Marina Macchini, Umberto Peretti, Letizia Procaccio, Alberto Puccini, Stefano Cascinu, Cristina Montagna, Michele Milella, Michele Reni.

  PURPOSE: The clinical outcome and the efficacy of chemotherapy in pancreatic cancer patients with BRCA1/2 Variants of Unknown Significance (VUS) is unknown. We explored the effects of chemotherapy with or without Platinum in non metastatic and metastatic pancreatic cancer patients with BRCA1/2 VUS.METHODS: A retrospective analysis of non-metastatic or metastatic pancreatic cancer patients with gBRCA1/2 VUS treated in 13 Italian centers between November 2015 and December 2020 was performed. All patients were assessed for toxicity and RECIST 1.1 response. Metastatic patients were evaluated for survival outcome.
RESULTS: 30 pancreatic cancer patients with gBRCA1/2 VUS were considered: 20 were M+ and 10 were non-M+. Pl-CT was recommended to 16 patients: 10 M+ (6 FOLFIRINOX and 4 PAXG) and 6 non-M+ (3 FOLFIRINOX and 3 PAXG); 11 patients received Nabpaclitaxel-Gemcitabine (AG; 8 M+) and 3 patients (2 M+) were treated with Gemcitabine (G). The RECIST 1.1 response rate was 27% for AG and 44% for Pl-CT (22% for (m) FOLFIRINOX and 71% PAXG). 1 year Progression-Free Survival was 37.5% for patients treated with AG and 33% in the Pl-CT subgroup. Median Overall Survival (OS) was 23.5 months for patients treated with AG and 14 months for the Pl-CT subgroup. 1 Year and 2 Year OS were numerically better for AG (1 Year OS: 75% vs 60% and 2 Year OS: 50% and 20% in AG and Pl-CT subgroups, respectively) as well.
CONCLUSIONS: Pl-CT does not seem to be associated with a better outcome compared to AG chemotherapy in PDAC patients with BRCA 1/2 VUS.

Keywords:  BRCA Variants of Unknown Significance (VUS); Chemotherapy response; Chemotherapy toxicity; Pancreatic cancer; Platinum chemotherapy

DOI:  https://doi.org/10.1007/s00280-023-04585-w
STAR Protoc. 2023 Sep 19. pii: S2666-1667(23)00541-5. [Epub ahead of print]4(4): 102574

Protocol for quantifying the in vivo rate of protein degradation in mice using a pulse-chase technique.

Jamie E Hibbert, Kent W Jorgenson, Wenyuan G Zhu, Nathaniel D Steinert, Troy A Hornberger.

  The ability to measure the in vivo rate of protein degradation is a major limitation in numerous fields of biology. Here, we present a protocol for quantifying this rate in mice using a pulse-chase technique that utilizes an azide-bearing non-canonical amino acid called azidohomoalanine (AHA). We describe steps for using chow containing AHA to pulse-label the animal's proteome. We then detail the quantification of AHA-labeled proteins in whole-tissue lysates or histological sections using a copper-catalyzed azide-alkyne cycloaddition 'click' reaction. For complete details on the use and execution of this protocol, please refer to Steinert et al. (2023).1.

Keywords:  Cell Biology; Metabolism; Molecular Biology; Protein Biochemistry

DOI:  https://doi.org/10.1016/j.xpro.2023.102574
Dev Biol. 2023 Sep 20. pii: S0012-1606(23)00162-8. [Epub ahead of print]

Beclin1 is essential for the pancreas development.

Sally Mehanna, Satoko Arakawa, Mai Imasaka, Wenting Chen, Yuto Nakanishi, Hiroshi Nishiura, Shigeomi Shimizu, Masaki Ohmuraya.

  Beclin1 (Becn1) is a multifunctional protein involved in autophagy regulation, membrane trafficking, and tumor suppression. In this study, we examined the roles of Becn1 in the pancreas development by generating mice with conditional deletion of Becn1 in the pancreas using pancreatic transcriptional factor 1a (Ptf1a)-Cre mice (Becn1f/f; Ptf1aCre/+). Surprisingly, loss of Becn1 in the pancreas resulted in severe pancreatic developmental defects, leading to insufficient exocrine and endocrine pancreatic function. Approximately half of Becn1f/f; Ptf1aCre/+ mice died immediately after birth. However, duodenum and neural tissue development were almost normal, indicating that pancreatic insufficiency was the cause of death. These findings demonstrated a novel role for Becn1 in pancreas morphogenesis, differentiation, and growth, and suggested that loss of this factor leaded to pancreatic agenesis at birth.

Keywords:  Autophagy; Beclin1; Pancreatic agenesis; Pdx1; Ptf1a

DOI:  https://doi.org/10.1016/j.ydbio.2023.09.008
Mol Cell. 2023 Sep 14. pii: S1097-2765(23)00694-9. [Epub ahead of print]

The cell-cycle choreography of H3 variants shapes the genome.

Kamila Delaney, Nicole Weiss, Geneviève Almouzni.

  Histone variants provide versatility in the basic unit of chromatin, helping to define dynamic landscapes and cell fates. Maintaining genome integrity is paramount for the cell, and it is intimately linked with chromatin dynamics, assembly, and disassembly during DNA transactions such as replication, repair, recombination, and transcription. In this review, we focus on the family of H3 variants and their dynamics in space and time during the cell cycle. We review the distinct H3 variants' specific features along with their escort partners, the histone chaperones, compiled across different species to discuss their distinct importance considering evolution. We place H3 dynamics at different times during the cell cycle with the possible consequences for genome stability. Finally, we examine how their mutation and alteration impact disease. The emerging picture stresses key parameters in H3 dynamics to reflect on how when they are perturbed, they become a source of stress for genome integrity.

Keywords:  DNA replication; H3 histone variants; chromatin dynamics

DOI:  https://doi.org/10.1016/j.molcel.2023.08.030
Curr Opin Biotechnol. 2023 Sep 13. pii: S0958-1669(23)00103-9. [Epub ahead of print]84 102993

Tumor lipid metabolism: a mechanistic link between diet and cancer progression.

Yu-Jin Jeong, Thomas J Rogers, Carolyn E Anderson, Evan C Lien.

The potential for 'anti-cancer' diets to markedly alter cancer risk and prognosis has captured the imagination of patients, physicians, and researchers alike, but many of these dietary recommendations come from correlative studies that attribute certain diets to altered cancer risk. While provocative, little is known about the molecular mechanisms behind how these dietary interventions impact cancer progression. Within this context, however, changes in tumor lipid metabolism are emerging as a key contributor. In this review, we examine the current understanding of lipid metabolism in the tumor microenvironment (TME), suggesting how diet-induced changes in lipid composition may regulate tumor progression and therapeutic efficacy. By dissecting various cellular pathways involved in lipid metabolism, we highlight how diet modulates the balance between saturated and unsaturated fatty acid (FA) species in tumors to impact cancer cell and stromal cell function. Finally, we describe how current cancer therapies may synergize with diet to improve therapeutic efficacy.

DOI: https://doi.org/10.1016/j.copbio.2023.102993
Nat Aging. 2023 Sep 18.

Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages.

Nilushi S De Silva, Johan Siewiera, Chantal Alkhoury, Guilherme P F Nader, Francesca Nadalin, Kevin de Azevedo, Mickaël Couty, Helena M Izquierdo, Anvita Bhargava, Cécile Conrad, Mathieu Maurin, Konstantina Antoniadou, Charles Fouillade, Arturo Londono-Vallejo, Rayk Behrendt, Karine Bertotti, Cindy Serdjebi, François Lanthiez, Lisa Gallwitz, Paul Saftig, Beatriz Herrero-Fernández, Angela Saez, José María González-Granado, Guillaume van Niel, Alexandre Boissonnas, Matthieu Piel, Nicolas Manel.

Aging is characterized by gradual immune dysfunction and increased disease risk. Genomic instability is considered central to the aging process, but the underlying mechanisms of DNA damage are insufficiently defined. Cells in confined environments experience forces applied to their nucleus, leading to transient nuclear envelope rupture (NER) and DNA damage. Here, we show that Lamin A/C protects lung alveolar macrophages (AMs) from NER and hallmarks of aging. AMs move within constricted spaces in the lung. Immune-specific ablation of lamin A/C results in selective depletion of AMs and heightened susceptibility to influenza virus-induced pathogenesis and lung cancer growth. Lamin A/C-deficient AMs that persist display constitutive NER marks, DNA damage and p53-dependent senescence. AMs from aged wild-type and from lamin A/C-deficient mice share a lysosomal signature comprising CD63. CD63 is required to limit damaged DNA in macrophages. We propose that NER-induced genomic instability represents a mechanism of aging in AMs.

DOI: https://doi.org/10.1038/s43587-023-00488-w
Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00652-4. [Epub ahead of print]83(18): 3333-3346.e5

Regulation of nucleo-cytosolic 26S proteasome translocation by aromatic amino acids via mTOR is essential for cell survival under stress.

Ido Livneh, Victoria Cohen-Kaplan, Bertrand Fabre, Ifat Abramovitch, Chen Lulu, Nishanth Belugali Nataraj, Ikrame Lazar, Tamar Ziv, Yosef Yarden, Yaniv Zohar, Eyal Gottlieb, Aaron Ciechanover.

  The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm-a response regulated by newly identified mTOR-agonistic amino acids-Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear sequestration of the proteasome following mTOR activation by YWF inhibits this proteolytic adaptive mechanism, leading to cell death, which establishes this newly identified pathway as a key stress-coping mechanism.

Keywords:  UPS; aromatic amino acids; mTOR; proteasome dynamics; protein quality control; proteolysis; stress response

DOI:  https://doi.org/10.1016/j.molcel.2023.08.016
STAR Protoc. 2023 Sep 15. pii: S2666-1667(23)00525-7. [Epub ahead of print]4(4): 102558

Using DeepContact with Amira graphical user interface.

Liqing Liu, Hongjun Wu, Shuxin Yang, Ke Yi, Junjie Hu, Li Xiao, Tao Xu.

  DeepContact is a deep learning software for high-throughput quantification of membrane contact site (MCS) in 2D electron microscopy images. This protocol will guide users through incorporating available DeepContact models in Amira's artificial intelligence module, thereby allowing invoking of DeepContact functions in organelle segmentation and quantifying of MCS with a user-friendly graphical user interface of Amira software. For complete details on the use and execution of this protocol, please refer to Liu et al. (2022).1.

Keywords:  Cell Biology; Computer Sciences; Microscopy

DOI:  https://doi.org/10.1016/j.xpro.2023.102558
JAMA. 2023 Sep 21.

Adventures With Parasites, Metabolism, Inborn Errors, and Cancer: The 2023 Lasker-Koshland Special Achievement Award in Medical Science.

Piet Borst.

DOI: https://doi.org/10.1001/jama.2023.15784
J Cachexia Sarcopenia Muscle. 2023 Sep 20.

Validity of computed tomography defined body composition as a prognostic factor for functional outcome after kidney transplantation.

Tim D A Swaab, Evelien E Quint, Lisa B Westenberg, Marcel Zorgdrager, Dorry L Segev, Mara A McAdams-DeMarco, Stephan J L Bakker, Alain R Viddeleer, Robert A Pol.

  BACKGROUND: The prevalence of sarcopenia is markedly higher in kidney transplant candidates than in the general population. It is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which increases the risk of adverse postoperative outcomes.METHODS: We studied the impact of computed tomography defined preoperative sarcopenia, defined as a skeletal muscle index below age and gender specific cut-off values, on postoperative physical functional outcomes (grip strength, 4-m walking test, timed up and go, and sit to stand) at 6 months follow up.
RESULTS: A total of 107 patients transplanted between 2015 and 2019 were included in this single-centre study. Mean age was 60.3 (±13.1), and 68.2% of patients were male. Ten patients (9.4%) were identified as sarcopenic. Sarcopenic patients were younger (55.6 (±15.1) vs. 60.8 (±12.9) years), more likely to be female (60.0% vs. 28.9%), and had an increased dialysis vintage (19 [2.5-32.8] vs. 9 [0.0-21.0] months) in comparison with their non-sarcopenic counterparts. In univariate analysis, they had a significantly lower body mass index and skeletal muscle area (P ≤ 0.001). In multivariate regression analysis, skeletal muscle index was significantly associated with grip strength (β = 0.690, R2 = 0.232) and timed up and go performance (β = -0.070, R2 = 0.154).
CONCLUSIONS: We identified a significant association between sarcopenia existing pre-transplantation and poorer 6 months post-transplantation physical functioning with respect to hand grip strength and timed up and go tests in kidney transplant recipients. These results could be used to preoperatively identify patients with an increased risk of poor postoperative physical functional outcome, allowing for preoperative interventions to mitigate these risks.

Keywords:  Computed tomography; Kidney transplantation; Physical functioning; Sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13316