bims-cagime 2023-09-10 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2023–09–10
29 papers selected by
Kıvanç Görgülü, Technical University of Munich

Pancreatic ductal adenocarcinoma with acinar-to-ductal metaplasia-like cancer cells shows increased cellular proliferation.
Epigenetic control of pancreatic cancer metastasis.
ATG3 proteins possess a unique amphipathic α-helix essential for the Atg8/LC3 lipidation reaction.
Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response.
The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.
PTEN activates chaperone-mediated autophagy to regulate metabolism.
Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer.
A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.
Optimising preclinical models of aging for translation to clinical trials.
Physical function endpoints in cancer cachexia clinical trials: Systematic Review 1 of the cachexia endpoints series.
Loss of attachment promotes proline accumulation and excretion in cancer cells.
Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
Viscoelasticity and advective flow of RNA underlies nucleolar form and function.
The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress.
A standardized and reproducible workflow for membrane glass slides in routine histology and spatial proteomics.
Age and obesity-driven changes in the extracellular matrix of the primary tumor and metastatic site influence tumor invasion and metastatic outgrowth.
eIF3d controls the persistent integrated stress response.
Vitamin B6 is governed by the local compartmentalization of metabolic enzymes during growth.
CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1.
Physical forces guide curvature sensing and cell migration mode bifurcating.
Protein intake in cancer: Does it improve nutritional status and/or modify tumour response to chemotherapy?
Live imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation.
CCDC50 promotes tumor growth through regulation of lysosome homeostasis.
Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.
Loss of Pla2r1 decreases cellular senescence and age-related alterations caused by aging and Western diets.
Should I stay or should I go? Spatio-temporal control of cellular anchorage by hematopoietic factors orchestrates tumor metastatic cascade.
Metabolic elasticity: A new measure of age.
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Pancreatology. 2023 Aug 26. pii: S1424-3903(23)01611-3. [Epub ahead of print]

Pancreatic ductal adenocarcinoma with acinar-to-ductal metaplasia-like cancer cells shows increased cellular proliferation.

Reiji Nishimon, Koji Yoshida, Fumiaki Sanuki, Yoshihiro Nakashima, Tomoo Miyake, Tatsuki Sato, Yasuyuki Tomiyama, Sohji Nishina, Takuya Moriya, Akiko Shiotani, Keisuke Hino.

   BACKGROUND/OBJECTIVES: Acinar-to-ductal metaplasia (ADM) has been shown to contribute to the development of pancreatic ductal adenocarcinoma (PDAC) in genetically engineered mouse models, but little is known about whether acinar cell plasticity contributes to carcinogenesis in human PDAC. We aimed to assess whether cancer cells that stain positive for amylase and CK19 (ADM-like cancer cells) are present in human resected PDAC and to investigate their role in tumor progression.
METHODS: We immunohistochemically investigated the presence of ADM-like cancer cells, and compared the clinical and histological parameters of PDAC patients with and without ADM-like cancer cells.
RESULTS: ADM-like cancer cells were detected in 16 of 60 (26.7%) PDAC specimens. Positive staining for anterior gradient protein 2 (AGR2) was observed in 14 of 16 (87.5%) PDAC specimens with ADM-like cancer cells. On the other hand, the intensity of AGR2 expression (negative, low/moderate or high) was lower in PDAC with ADM-like cancer cells (9/7) than in PDAC without these cells (11/33) (P = 0.032). The presence of ADM-like cancer cells was significantly correlated with increased cell proliferation (P = 0.012) and tended to be associated with MUC1 expression (P = 0.067).
CONCLUSIONS: These results indicated that acinar cells may act as the origin of human PDAC, and that their presence may be useful for the stratification of human PDAC to predict prognosis.

Keywords:  Amylase; Anterior gradient protein 2; CK19; Human; MUC1

DOI:  https://doi.org/10.1016/j.pan.2023.08.007
Cancer Metastasis Rev. 2023 Sep 02.

Epigenetic control of pancreatic cancer metastasis.

Lukas Krauß, Carolin Schneider, Elisabeth Hessmann, Dieter Saur, Günter Schneider.

  Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.

Keywords:  Epigenetic; HAT; HDAC; KDM; KMT; Pancreatic cancer metastasis

DOI:  https://doi.org/10.1007/s10555-023-10132-z
Autophagy. 2023 Sep 07. 1-2

ATG3 proteins possess a unique amphipathic α-helix essential for the Atg8/LC3 lipidation reaction.

Taki Nishimura, Gianmarco Lazzeri, Sharon A Tooze, Roberto Covino.

  In our recent paper, we uncovered that ATG3 exhibits a large degree of structural dynamics on autophagic membranes to efficiently carry out LC3 lipidation. ATG3 proteins possess an amphipathic α-helix (AH) identified by a small number of bulky and hydrophobic residues. This biophysical fingerprint allows for transient membrane association of ATG3 and facilitates its enzymatic reaction. This study will pave the way for a structural and mechanistic understanding of how membrane association of ATG proteins is orchestrated during autophagosome formation.

Keywords:  ATG3; All-atom MD simulation; LC3 lipidation; amphipathic α-helix; membrane protein dynamics

DOI:  https://doi.org/10.1080/15548627.2023.2255458
Cell Stress. 2023 Aug 14. 7(8): 59-68

Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response.

Joseph R Merrill, Alessandra Inguscio, Taemoon Chung, Breanna Demestichas, Libia A Garcia, Jill Habel, David Y Lewis, Tobias Janowitz, Scott K Lyons.

  Non-invasive imaging of tumors expressing reporter transgenes is a popular preclinical method for studying tumor development and response to therapy in vivo due to its ability to distinguish signal from tumors over background noise. However, the utilized transgenes, such as firefly luciferase, are immunogenic and, therefore, impact results when expressed in immune-competent hosts. This represents an important limitation, given that cancer immunology and immunotherapy are currently among the most impactful areas of research and therapeutic development. Here we present a non-immunogenic preclinical tumor imaging approach. Based on the expression of murine sodium iodide symporter (mNIS), it facilitates sensitive, non-invasive detection of syngeneic tumor cells in immune-competent tumor models without additional immunogenicity arising from exogenous transgenic protein or selection marker expression. NIS-expressing tumor cells internalize the gamma-emitting [99mTc]pertechnetate ion and so can be detected by SPECT (single photon emission computed tomography). Using a mouse model of pancreatic ductal adenocarcinoma hepatic metastases in immune-competent C57BL/6 mice, we demonstrate that the technique enables the detection of very early metastatic lesions and longitudinal assessment of immunotherapy responses using precise and quantifiable whole-body SPECT/CT imaging.

Keywords:  SPECT; cancer; imaging; immunotherapy; luciferase; metastases; reporter transgene; sodium iodine symporter

DOI:  https://doi.org/10.15698/cst2023.08.288
EMBO Rep. 2023 Sep 06. e57600

The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.

Maude Giroud, Stefan Kotschi, Yun Kwon, Ophélia Le Thuc, Anne Hoffmann, Manuel Gil-Lozano, Michael Karbiener, Juan Carlos Higareda-Almaraz, Sajjad Khani, Daniel Tews, Pamela Fischer-Posovszky, Wenfei Sun, Hua Dong, Adhideb Ghosh, Christian Wolfrum, Martin Wabitsch, Kirsi A Virtanen, Matthias Blüher, Søren Nielsen, Anja Zeigerer, Cristina García-Cáceres, Marcel Scheideler, Stephan Herzig, Alexander Bartelt.

  Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

Keywords:  adipocyte; mitochondrial dynamics; non-coding RNA; obesity; thermogenesis

DOI:  https://doi.org/10.15252/embr.202357600
Autophagy. 2023 Sep 08. 1-2

PTEN activates chaperone-mediated autophagy to regulate metabolism.

S Joseph Endicott, Richard A Miller.

  PTEN is a negative modulator of the INS-PI3K-AKT pathway and is an essential regulator of metabolism and cell growth. PTEN is one of the most commonly mutated tumor suppressors in cancer. However, PTEN overexpression extends the lifespan of both sexes of mice. We recently showed that PTEN is necessary and sufficient to activate chaperone-mediated autophagy (CMA) in the mouse liver and cultured cells. Selective protein degradation via CMA is required to suppress glycolysis and fatty acid synthesis when PTEN is overexpressed. Thus, activation of CMA downstream of PTEN might modulate health and metabolism through selective degradation of key metabolic enzymes.

Keywords:  Aging; PTEN; autophagy; chaperone-mediated autophagy; metabolism

DOI:  https://doi.org/10.1080/15548627.2023.2255966
Cancers (Basel). 2023 Sep 01. pii: 4368. [Epub ahead of print]15(17):

Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer.

Pamela N Klassen, Vickie Baracos, Sunita Ghosh, Lisa Martin, Michael B Sawyer, Vera C Mazurak.

  Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013-2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: -17.8 to +7.3 cm2/m2, ∆ATI: -106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (-3.2 cm2/m2, p < 0.001; -12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (-1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (-11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies.

Keywords:  adipose; cancer cachexia; chemotherapy; computed tomography; pancreatic ductal adenocarcinoma; skeletal muscle; wasting

DOI:  https://doi.org/10.3390/cancers15174368
Carcinogenesis. 2023 Sep 06. pii: bgad056. [Epub ahead of print]

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Matteo Giaccherini, Leonardo Gori, Manuel Gentiluomo, Riccardo Farinella, Klara Cervena, Jurgita Skieceviciene, Frederike Dijk, Gabriele Capurso, Antonis Vezakis, Livia Archibugi, Roger Chammas, Tamás Hussein, Francesca Tavano, Péter Hegyi, Martin Lovecek, Jakob Izbicki, Hermann Brenner, Beatrice Mohelnikova-Duchonova, Giuseppe Dell'Anna, Juozas Kupcinskas, Stefano Ermini, Mateus Nóbrega Aoki, John P Neoptolemos, Maria Gazouli, Claudio Pasquali, Raffaele Pezzilli, Renata Talar-Wojnarowska, Martin Oliverius, Mohammed Al-Saeedi, Maurizio Lucchesi, Niccolò Furbetta, Silvia Carrara, Casper H J van Eijck, Almantas Maleckas, Anna Caterina Milanetto, Rita T Lawlor, Ben Schöttker, Ugo Boggi, Luca Morelli, Laura Ginocchi, Ruggero Ponz de Leon, Cosimo Sperti, Alessandro Zerbi, Paolo Giorgio Arcidiacono, Faik G Uzunoglu, Stefania Bunduc, Bernd Holleczek, Domenica Gioffreda, Ewa Małecka-Wojciesko, Mindaugas Kiudelis, Andrea Szentesi, Hanneke W M van Laarhoven, Pavel Soucek, Mara Götz, Bálint Erőss, Giulia Martina Cavestro, Daniela Basso, Francesco Perri, Stefano Landi, Federico Canzian, Daniele Campa.

  Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case control study comprising four different populations, for a total of 14,538 PDAC cases and 190,657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P=2.46x10 -9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P=1.53x10 -6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of GWAS studies in light of functional data.

Keywords:  Pancreatic ductal adenocarcinoma; association study; genetic susceptibility; missense; single nucleotide polymorphisms

DOI:  https://doi.org/10.1093/carcin/bgad056
Br J Clin Pharmacol. 2023 Sep 07.

Optimising preclinical models of aging for translation to clinical trials.

Sarah J Mitchell, Michael R MacArthur, Alice E Kane.

  Preclinical models have been the backbone of translational research for more than a century. Rats and mice are critical models in the preliminary stages of drug testing, both for determining efficacy and ruling out potential human-relevant toxicities. Historically, most preclinical pharmacological studies have used young, relatively healthy, inbred male models in highly-controlled environments. In the field of geriatric pharmacology, there is a growing focus on the importance of using more appropriate preclinical models both in the testing of therapeutics commonly used in older populations, and in the evaluation of potential geroprotective drug candidates. Here we provide a commentary on optimising preclinical models of ageing for translation to clinical trials. We will discuss approaches to modeling clinically-relevant contexts such as age, sex, genetic diversity, exposures and environment, as well as measures of clinically-relevant outcomes such as frailty and healthspan. We will identify the strengths and limitations of these approaches and areas for improvement. We will also briefly cover new preclinical models that move beyond rodents. We hope this commentary will be a springboard for larger discussions on optimising preclinical aging models for testing therapeutics.

Keywords:  Mouse models; c elegans; frailty; geroscience; healthspan; killifish; polypharmacy; sex

DOI:  https://doi.org/10.1111/bcp.15902
J Cachexia Sarcopenia Muscle. 2023 Sep 06.

Physical function endpoints in cancer cachexia clinical trials: Systematic Review 1 of the cachexia endpoints series.

Cancer Cachexia Endpoints Working Group

  In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.

Keywords:  cachexia; cancer; endpoints; physical function; trials

DOI:  https://doi.org/10.1002/jcsm.13321
Sci Adv. 2023 Sep 08. 9(36): eadh2023

Loss of attachment promotes proline accumulation and excretion in cancer cells.

Steven E Pilley, Marc Hennequart, Anke Vandekeere, Julianna Blagih, Nathalie M Legrave, Sarah-Maria Fendt, Karen H Vousden, Christiaan F Labuschagne.

Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.

DOI: https://doi.org/10.1126/sciadv.adh2023
Nat Struct Mol Biol. 2023 Sep 07.

Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.

Anika Seel, Francesco Padovani, Moritz Mayer, Alissa Finster, Daniela Bureik, Felix Thoma, Christof Osman, Till Klecker, Kurt M Schmoller.

To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.

DOI: https://doi.org/10.1038/s41594-023-01091-8
Nat Commun. 2023 Sep 06. 14(1): 5195

A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.

Corina E Antal, Tae Gyu Oh, Stefan Aigner, En-Ching Luo, Brian A Yee, Tania Campos, Hervé Tiriac, Katherine L Rothamel, Zhang Cheng, Henry Jiao, Allen Wang, Nasun Hah, Elizabeth Lenkiewicz, Jan C Lumibao, Morgan L Truitt, Gabriela Estepa, Ester Banayo, Senada Bashi, Edgar Esparza, Ruben M Munoz, Jolene K Diedrich, Nicole M Sodir, Jasmine R Mueller, Cory R Fraser, Erkut Borazanci, David Propper, Daniel D Von Hoff, Christopher Liddle, Ruth T Yu, Annette R Atkins, Haiyong Han, Andrew M Lowy, Michael T Barrett, Dannielle D Engle, Gerard I Evan, Gene W Yeo, Michael Downes, Ronald M Evans.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

DOI: https://doi.org/10.1038/s41467-023-40798-6
Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00642-1. [Epub ahead of print]83(17): 3095-3107.e9

Viscoelasticity and advective flow of RNA underlies nucleolar form and function.

Joshua A Riback, Jorine M Eeftens, Daniel S W Lee, Sofia A Quinodoz, Anita Donlic, Natalia Orlovsky, Lennard Wiesner, Lien Beckers, Lindsay A Becker, Amy R Strom, Ushnish Rana, Michele Tolbert, Byron W Purse, Ralph Kleiner, Richard Kriwacki, Clifford P Brangwynne.

  The nucleolus is the largest biomolecular condensate and facilitates transcription, processing, and assembly of ribosomal RNA (rRNA). Although nucleolar function is thought to require multiphase liquid-like properties, nucleolar fluidity and its connection to the highly coordinated transport and biogenesis of ribosomal subunits are poorly understood. Here, we use quantitative imaging, mathematical modeling, and pulse-chase nucleotide labeling to examine nucleolar material properties and rRNA dynamics. The mobility of rRNA is several orders of magnitude slower than that of nucleolar proteins, with rRNA steadily moving away from the transcriptional sites in a slow (∼1 Å/s), radially directed fashion. This constrained but directional mobility, together with polymer physics-based calculations, suggests that nascent rRNA forms an entangled gel, whose constant production drives outward flow. We propose a model in which progressive maturation of nascent rRNA reduces its initial entanglement, fluidizing the nucleolar periphery to facilitate the release of assembled pre-ribosomal particles.

Keywords:  biomolecular condensate; liquid-liquid phase separation; membraneless organelle; nucleolus; ribonucleoprotein assembly; ribosome biogenesis; transcription; viscoelasticity

DOI:  https://doi.org/10.1016/j.molcel.2023.08.006
Nat Aging. 2023 Sep 04.

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress.

Carlos Anerillas, Krystyna Mazan-Mamczarz, Allison B Herman, Rachel Munk, Kwan-Wood Gabriel Lam, Miguel Calvo-Rubio, Amanda Garrido, Dimitrios Tsitsipatis, Jennifer L Martindale, Gisela Altés, Martina Rossi, Yulan Piao, Jinshui Fan, Chang-Yi Cui, Supriyo De, Kotb Abdelmohsen, Rafael de Cabo, Myriam Gorospe.

Sublethal cell damage can trigger senescence, a complex adaptive program characterized by growth arrest, resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, verteporfin (VPF), selectively triggered apoptotic cell death largely by derepressing DDIT4, which in turn inhibited mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, triggering ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased the numbers of senescent cells in the organs of old mice and mice exhibiting doxorubicin-induced senescence. Moreover, VPF treatment reduced immune cell infiltration and pro-fibrotic transforming growth factor-β signaling in aging mouse lungs, improving tissue homeostasis. We present an alternative senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.

DOI: https://doi.org/10.1038/s43587-023-00480-4
Mol Cell Proteomics. 2023 Sep 06. pii: S1535-9476(23)00154-8. [Epub ahead of print] 100643

A standardized and reproducible workflow for membrane glass slides in routine histology and spatial proteomics.

Thierry M Nordmann, Lisa Schweizer, Andreas Metousis, Marvin Thielert, Edwin Rodriguez, Lise Mette Rahbek-Gjerdrum, Pia-Charlotte Stadler, Michael Bzorek, Andreas Mund, Florian A Rosenberger, Matthias Mann.

  Defining the molecular phenotype of single cells in-situ is key for understanding tissue architecture in health and disease. Advanced imaging platforms have recently been joined by spatial omics technologies, promising unparalleled insights into the molecular landscape of biological samples. Furthermore, high-precision laser microdissection of tissue on membrane glass slides is a powerful method for spatial omics technologies and single-cell type spatial proteomics in particular. However, current histology protocols have not been compatible with glass membrane slides and laser microdissection for automated staining platforms and routine histology procedures. This has prevented the combination of advanced staining procedures with laser microdissection. In this study we describe a novel method for handling glass membrane slides that enables automated, eight-color multiplexed immunofluorescence staining and high-quality imaging followed by precise laser-guided extraction of single cells. The key advance is the glycerol-based modification of heat-induced epitope retrieval protocols, termed 'G-HIER'. We find that this altered antigen-retrieval solution prevents membrane distortion. Importantly, G-HIER is fully compatible with current antigen retrieval workflows and mass spectrometry-based proteomics and does not affect proteome depth or quality. To demonstrate the versatility of G-HIER for spatial proteomics, we apply the recently introduced Deep Visual Proteomics technology to perform single-cell type analysis of adjacent suprabasal and basal keratinocytes of human skin. G-HIER overcomes previous incompatibility of standard and advanced staining protocols with membrane glass slides and enables robust integration with routine histology procedures, high-throughput multiplexed imaging and sophisticated downstream spatial omics technologies.

Keywords:  Antigen retrieval; Deep Visual Proteomics; Glycerol; Histology; Laser microdissection; Membrane slides; Proteomics; Spatial proteomics

DOI:  https://doi.org/10.1016/j.mcpro.2023.100643
bioRxiv. 2023 Aug 25. pii: 2023.08.24.554492. [Epub ahead of print]

Age and obesity-driven changes in the extracellular matrix of the primary tumor and metastatic site influence tumor invasion and metastatic outgrowth.

Sydney J Conner, Justinne R Guarin, Hannah B Borges, Kenneth J Salhany, Diamond N Mensah, Grace A Hamilton, Giang H Le, Madeleine J Oudin.

Younger age and obesity increase the incidence and metastasis of triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The extracellular matrix (ECM) promotes tumor invasion and metastasis. We characterized the effect of age and obesity on the ECM of mammary fat pads, lungs, and liver using a diet-induced obesity (DIO) model. At 4 week intervals, we either injected the mammary fat pads with allograft tumor cells to characterize tumor growth and metastasis or isolated the mammary fat pads and livers to characterize the ECM. Age had no effect on tumor growth but increased lung and liver metastasis after 16 weeks. Obesity increased tumor growth starting at 12 weeks, increased liver metastasis only at 4 weeks, and weight gain correlated to increased lung but not liver metastasis. Utilizing whole decellularized ECM coupled with proteomics, we found that early stages of obesity were sufficient to induce changes in the ECM composition and invasive potential of mammary fat pads with increased abundance of pro-invasive ECM proteins Collagen IV and Collagen VI. We identified cells of stromal vascular fraction and adipose stem and progenitor cells as primarily responsible for secreting Collagen IV and VI, not adipocytes. We characterized the changes in ECM in the lungs and liver, and determined that older age decreases the metastatic potential of lung and liver ECM while later-stage obesity increases the metastatic potential. These data implicate ECM changes in the primary tumor and metastatic microenvironment as mechanisms by which age and obesity contribute to breast cancer progression.
Significance: Younger age and obesity increase the incidence and metastasis of triple-negative breast cancer. Our data suggest that changes in the breast, lung and liver ECM are driving some of these effects.

DOI: https://doi.org/10.1101/2023.08.24.554492
Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00643-3. [Epub ahead of print]

eIF3d controls the persistent integrated stress response.

Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee.

  Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.

Keywords:  ATF4; GCN2; RNA methylation; eIF3d; integrated stress response; m(6)A; translation regulation

DOI:  https://doi.org/10.1016/j.molcel.2023.08.008
Sci Adv. 2023 Sep 08. 9(36): eadi2232

Vitamin B6 is governed by the local compartmentalization of metabolic enzymes during growth.

Carolina N Franco, Laurence J Seabrook, Steven T Nguyen, Ying Yang, Melissa Campos, Qi Fan, Andrew C Cicchetto, Mei Kong, Heather R Christofk, Lauren V Albrecht.

Vitamin B6 is a vital micronutrient across cell types and tissues, and dysregulated B6 levels contribute to human disease. Despite its importance, how B6 vitamer levels are regulated is not well understood. Here, we provide evidence that B6 dynamics are rapidly tuned by precise compartmentation of pyridoxal kinase (PDXK), the rate-limiting B6 enzyme. We show that canonical Wnt rapidly led to the accumulation of inactive B6 by shunting cytosolic PDXK into lysosomes. PDXK was modified with methyl-arginine Degron (MrDegron), a protein tag for lysosomes, which enabled delivery via microautophagy. Hyperactive lysosomes resulted in the continuous degradation of PDXK and B6 deficiency that promoted proliferation in Wnt-driven colorectal cancer (CRC) cells. Pharmacological or genetic disruption of the coordinated MrDegron proteolytic pathway was sufficient to reduce CRC survival in cells and organoid models. In sum, this work contributes to the repertoire of micronutrient-regulated processes that enable cancer cell growth and provides insight into the functional impact of B6 deficiencies for survival.

DOI: https://doi.org/10.1126/sciadv.adi2232
Cancer Cell. 2023 Aug 31. pii: S1535-6108(23)00284-2. [Epub ahead of print]

CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1.

Beiping Miao, Zhaoqing Hu, Riccardo Mezzadra, Lotte Hoeijmakers, Astrid Fauster, Shangce Du, Zhi Yang, Melanie Sator-Schmitt, Helena Engel, Xueshen Li, Caroline Broderick, Guangzhi Jin, Raquel Gomez-Eerland, Lisette Rozeman, Xin Lei, Hitoshi Matsuo, Chen Yang, Ingrid Hofland, Dennis Peters, Annegien Broeks, Elke Laport, Annika Fitz, Xiyue Zhao, Mohamed A A Mahmoud, Xiujian Ma, Sandrine Sander, Hai-Kun Liu, Guoliang Cui, Yu Gan, Wei Wu, Yanling Xiao, Albert J R Heck, Wenxian Guan, Scott W Lowe, Hugo M Horlings, Cun Wang, Thijn R Brummelkamp, Christian U Blank, Ton N M Schumacher, Chong Sun.

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.

DOI: https://doi.org/10.1016/j.ccell.2023.08.008
PNAS Nexus. 2023 Aug;2(8): pgad237

Physical forces guide curvature sensing and cell migration mode bifurcating.

Luyi Feng, Tiankai Zhao, Hongmei Xu, Xuechen Shi, Changhao Li, K Jimmy Hsia, Sulin Zhang.

  The ability of cells to sense and adapt to curvy topographical features has been implicated in organ morphogenesis, tissue repair, and tumor metastasis. However, how individual cells or multicellular assemblies sense and differentiate curvatures remains elusive. Here, we reveal a curvature sensing mechanism in which surface tension can selectively activate either actin or integrin flows, leading to bifurcating cell migration modes: focal adhesion formation that enables cell crawling at convex front edges and actin cable assembly that pulls cells forward at concave front edges. The molecular flows and curved front morphogenesis are sustained by coordinated cellular tension generation and transmission. We track the molecular flows and mechanical force transduction pathways by a phase-field model, which predicts that multicellular curvature sensing is more efficient than individual cells, suggesting collective intelligence of cells. The unique ability of cells in curvature sensing and migration mode bifurcating may offer insights into emergent collective patterns and functions of living active systems at different length scales.

Keywords:  cell migration; molecular flow; phase-field modeling; surface tension

DOI:  https://doi.org/10.1093/pnasnexus/pgad237
J Cachexia Sarcopenia Muscle. 2023 Sep 04.

Protein intake in cancer: Does it improve nutritional status and/or modify tumour response to chemotherapy?

Martin Boutière, Cécile Cottet-Rousselle, Céline Coppard, Karine Couturier, Catherine Féart, Morgane Couchet, Christelle Corne, Christophe Moinard, Charlotte Breuillard.

   BACKGROUND: Combating malnutrition and cachexia is a core challenge in oncology. To limit muscle mass loss, the use of proteins in cancer is encouraged by experts in the field, but it is still debated due to their antagonist effects. Indeed, a high protein intake could preserve lean body mass but may promote tumour growth, whereas a low-protein diet could reduce tumour size but without addressing cachexia. Here we used a realistic rodent model of cancer and chemotherapy to evaluate the influence of different protein intakes on cachexia, tumour response to chemotherapy and immune system response. The goal is to gain a closer understanding of the effect of protein intake in cancer patients undergoing chemotherapy.
METHODS: Female Fischer 344 rats were divided into six groups: five groups (n = 14 per group) with cancer (Ward colon tumour) and chemotherapy were fed with isocaloric diets with 8%, 12%, 16%, 24% or 32% of caloric intake from protein and one healthy control group (n = 8) fed a 16% protein diet, considered as a standard diet. Chemotherapy included two cycles, 1 week apart, each consisting of an injection of CPT-11 (50 mg/kg) followed by 5-fluorouracil (50 mg/kg) the day after. Food intake, body weight, and tumour size were measured daily. On day 9, the rats were euthanized and organs were weighed. Body composition was determined and protein content and protein synthesis (SUnSET method) were measured in the muscle, liver, intestine, and tumour. Immune function was explored by flow cytometry.
RESULTS: Cancer and chemotherapy led to a decrease in body weight characterized by a decrease of both fat mass (-56 ± 3%, P < 0.05) and fat-free mass (-8 ± 1%, P < 0.05). Surprisingly, there was no effect of protein diet on body composition, muscle or tumour parameters (weight, protein content, or protein synthesis) but a high cumulative protein intake was positively associated with a high relative body weight and high fat-free mass. The immune system was impacted by cancer and chemotherapy but not by the different amount of protein intake.
CONCLUSIONS: Using a realistic model of cancer and chemotherapy, we demonstrated for the first time that protein intake did not positively or negatively modulate tumour growth. Moreover, our results suggested that a high cumulative protein intake was able to improve moderately nutritional status in chemotherapy treated cancer rodents. Although this work cannot be evaluated clinically for ethical reasons, it nevertheless brings an essential contribution to nutrition management for cancer patients.

Keywords:  Cachexia; Cancer; Chemotherapy; Malnutrition; Protein diet; Tumour

DOI:  https://doi.org/10.1002/jcsm.13276
J Cell Sci. 2023 Sep 06. pii: jcs.261225. [Epub ahead of print]

Live imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation.

Juma Ward, Paul Martin.

  Previous clinical studies and work in mouse models have indicated that platelets and microclots may function as enablers in the recruitment of immune cells to the pre-metastatic cancer niche leading to efficacious extravasation of cancer cells through the vessel wall. Here we investigate the interaction between platelets, endothelial cells, inflammatory cells and engrafted human and zebrafish cancer cells by live imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging of each lineage reveals their dynamic behaviour and potential roles in these events, and we test function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrin, and warfarin treatment to inhibit clotting, both abrogate extravasation of cancer cells. Inflammatory phenotype appears fundamental, and we show that forcing a pro-inflammatory, TNFa+ve phenotype is inhibitory to extravasation of cancer cells.

Keywords:  Cancer; Coagulation; Inflammation; Zebrafish

DOI:  https://doi.org/10.1242/jcs.261225
EMBO Rep. 2023 Sep 06. e56948

CCDC50 promotes tumor growth through regulation of lysosome homeostasis.

Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou.

  The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.

Keywords:  CCDC50; cell death; lysophagy; lysosome damage; melanoma

DOI:  https://doi.org/10.15252/embr.202356948
Nat Cancer. 2023 Sep 07.

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.

Xu Zhou, Jingyu An, Roma Kurilov, Benedikt Brors, Kai Hu, Teresa Peccerella, Stephanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Dirk Theile, Max Sauter, Jürgen Burhenne, Shigenori Ei, Ulrike Heger, Oliver Strobel, Simon T Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus Büchler, Thilo Hackert, Franco Fortunato, John P Neoptolemos, Peter Bailey.

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

DOI: https://doi.org/10.1038/s43018-023-00628-6
Aging Cell. 2023 Sep 04. e13971

Loss of Pla2r1 decreases cellular senescence and age-related alterations caused by aging and Western diets.

Amélie Massemin, Delphine Goehrig, Jean-Michel Flaman, Sara Jaber, Audrey Griveau, Sophia Djebali, Elisabeth Marcos, Léa Payen, Jacqueline Marvel, Romain Parent, Serge Adnot, Philippe Bertolino, Jennifer Rieusset, Antonin Tortereau, David Vindrieux, David Bernard.

  Cellular senescence is induced by many stresses including telomere shortening, DNA damage, oxidative, or metabolic stresses. Senescent cells are stably cell cycle arrested and they secrete many factors including cytokines and chemokines. Accumulation of senescent cells promotes many age-related alterations and diseases. In this study, we investigated the role of the pro-senescent phospholipase A2 receptor 1 (PLA2R1) in regulating some age-related alterations in old mice and in mice subjected to a Western diet, whereas aged wild-type mice displayed a decreased ability to regulate their glycemia during glucose and insulin tolerance tests, aged Pla2r1 knockout (KO) mice efficiently regulated their glycemia and displayed fewer signs of aging. Loss of Pla2r1 was also found protective against the deleterious effects of a Western diet. Moreover, these Pla2r1 KO mice were partially protected from diet-induced senescent cell accumulation, steatosis, and fibrosis. Together these results support that Pla2r1 drives several age-related alterations, especially in the liver, arising during aging or through a Western diet.

Keywords:  Western diet; aging; cellular senescence; liver

DOI:  https://doi.org/10.1111/acel.13971
Mol Cancer. 2023 Sep 07. 22(1): 149

Should I stay or should I go? Spatio-temporal control of cellular anchorage by hematopoietic factors orchestrates tumor metastatic cascade.

Veronica Marabitti, Ignazio Caruana, Francesca Nazio.

  The term "metastatic cascade" defines a process whereby few tumor cells complete a sequence of steps to leave the primary tumor to reach one or more sites elsewhere in the body, usually through the bloodstream to develop one or several metastases. Due to the nature and plasticity of cancer, unfortunately no specific and functional anti-metastatic drugs are available. In this Commentary, we are highlighting how four essential factors are able to induce adhesion-to-suspension transition (herein referred to as AST) in human cancer cells and how this process may play a key role in tumor metastasis. We further underlined the potential role of hematopoietic transcriptional regulators in reprogramming anchorage dependency of cells, supporting the possible targeting of AST factors as promising therapeutic strategy to overcome metastasis in solid tumor cells.

Keywords:  Cancer dissemination; Hematopoietic factors; Metastasis; New drug-development

DOI:  https://doi.org/10.1186/s12943-023-01851-6
Cell Metab. 2023 09 05. pii: S1550-4131(23)00301-7. [Epub ahead of print]35(9): 1495-1497

Metabolic elasticity: A new measure of age.

Samuel Bennett, Shogo Sato.

Promoting healthy aging is contingent on understanding the underlying mechanisms for the age-associated decline in metabolic physiology. Through developing a novel concept of "metabolic elasticity" to evaluate metabolic adaptability in response to cyclical changes in energy balance, Zhou et al. present an impactful gauge of metabolic health that is particularly relevant to aging.

DOI: https://doi.org/10.1016/j.cmet.2023.08.006
Nat Genet. 2023 Sep;55(9): 1448-1461

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

GWA-PA Consortium

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

DOI: https://doi.org/10.1038/s41588-023-01462-3