bims-cagime 2024-07-21 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2024–07–21
34 papers selected by
Kıvanç Görgülü, Technical University of Munich

Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia.
Earliest Metabolic Changes Associated with the Initiation of Pancreatic Cancer.
A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention.
Computing the influence of lipids and lipid complexes on membrane mechanics.
Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake.
Predicting lipid sorting in curved membranes.
Free energy calculations for membrane morphological transformations and insights to physical biology and oncology.
De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane.
Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.
Modeling asymmetric cell membranes at all-atom resolution.
In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.
Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.
Is There a Mathematician on Board?
Modelling the spatiotemporal dynamics of senescent cells in wound healing, chronic wounds, and fibrosis.
The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.
Mechanical evolution of metastatic cancer cells in three-dimensional microenvironment.
Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation.
An E3 ligase and autophagy adaptor regulates tau proteostasis through nested phase separation.
Effect of smoking cessation on the likelihood of pancreatitis and pancreatic cancer.
GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase.
CryoDRGN-ET: deep reconstructing generative networks for visualizing dynamic biomolecules inside cells.
The WAVE complex forms linear arrays at negative membrane curvature to instruct lamellipodia formation.
Striking senescence with sodium transporter inhibition.
Imaging Interorganelle Phospholipid Transport by Extended Synaptotagmins Using Bioorthogonally Tagged Lipids.
Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds.
Survival benefit associated with screening of patients at elevated risk for pancreatic cancer.
The Human Body Is Made of Bags: We are like levers and computers, but above all, humans are bags of biology.
Key considerations for investigating and interpreting autophagy in skeletal muscle.
Imaging Tumor Metabolism.
A fibronectin gradient remodels mixed-phase mesoderm.
FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis.
The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers.
qMAP enabled microanatomical mapping of human skin aging.
Cryo-Fluorescence Tomography as a Tool for Visualizing Whole-Body Inflammation Using Perfluorocarbon Nanoemulsion Tracers.

Cancer Res. 2024 Jul 15. 84(14): 2297-2312

Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia.

Thorsten Neuß, Min-Chun Chen, Nils Wirges, Sinem Usluer, Rupert Oellinger, Svenja Lier, Michael Dudek, Tobias Madl, Martin Jastroch, Katja Steiger, Werner Schmitz, Henrik Einwächter, Roland M Schmid.

Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis. Significance: Metabolic reprogramming from oxidative phosphorylation to glycolysis mediated by MYC plays a crucial role in the development of pancreatic cancer, revealing a mechanism driving tumorigenesis and potential therapeutic targets. See related commentary by Storz, p. 2225.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2213
Cancer Res. 2024 Jul 15. 84(14): 2225-2226

Earliest Metabolic Changes Associated with the Initiation of Pancreatic Cancer.

Peter Storz.

Pancreatic cancer is usually detected at a late stage, when tumors have already metastasized; therefore, it has a poor prognosis with a 5-year survival rate of 11% to 12%. A key to targeting this high mortality is to develop methods for detecting the disease at a stage in which it is still local to the pancreas. However, this needs a better understanding of the events that govern pancreatic cancer oncogenesis. In this issue of Cancer Research, Neuß and colleagues report metabolic changes associated with acinar-to-ductal metaplasia (ADM), an initiating event that leads to the formation of precursor lesions for pancreatic ductal adenocarcinoma (PDAC). Their findings reveal a switch to aerobic glycolysis, increased c-MYC signaling, and increased serine metabolism as driving factors for the ADM process. These findings are important as they demonstrate that metabolic changes that drive the proliferation and metastasis of full-blown PDAC begin in the earliest lesions. The data not only provide insights into how PDAC develops but also a potential explanation for previously described findings, such as circulating lesion cells can be detected even when no carcinoma in situ is present. In summary, this article is highly relevant for furthering our understanding of how metabolic reprogramming drives the earliest events leading to PDAC development and could lay the groundwork for developing methods for early detection or intervention. See related article by Neuß et al., p. 2297.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0874
Cancer Discov. 2024 Jul 22.

A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention.

Norihiro Yamaguchi, Y Gloria Wu, Ethan Ravetch, Mai Takahashi, Abdul G Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Shigeaki Umeda, Elisa de Stanchina, Ivo C Lorenz, Christine A Iacobuzio-Donahue, Sohail F Tavazoie.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer secreted protein that becomes over-expressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia induced factor-1a (HIF1a) nuclear retention and function. NPTX1 is over-expressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1a hypoxic response in PDAC.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1323
Methods Enzymol. 2024 ;pii: S0076-6879(24)00126-5. [Epub ahead of print]701 515-540

Computing the influence of lipids and lipid complexes on membrane mechanics.

Amirali Hossein, Kayla Sapp, Alexander Sodt.

  Methodology for extracting the spontaneous curvature, bending modulus, and neutral surface of a lipid bilayer is described. The "SPEX" method is a robust technique for computing the bilayer bending modulus while allowing for resolution of the spontaneous curvature of specific interacting lipids and complexes, and the dependence of spontaneous curvature on wavelength. The method is described referring to the publicly available MembraneAnalysis.jl software package.

Keywords:  Bending modulus; Bilayer mechanics; Neutral surface; Spontaneous curvature

DOI:  https://doi.org/10.1016/bs.mie.2024.04.002
Carcinogenesis. 2024 Jul 15. pii: bgae045. [Epub ahead of print]

Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake.

Fangquan Chen, Hu Tang, Junhao Lin, Limin Xiang, Yanjiao Lu, Rui Kang, Daolin Tang, Jiao Liu.

  Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.

Keywords:  alkaliptosis; drug resistance; macropinocytosis; pancreatic cancer

DOI:  https://doi.org/10.1093/carcin/bgae045
Methods Enzymol. 2024 ;pii: S0076-6879(24)00117-4. [Epub ahead of print]701 287-307

Predicting lipid sorting in curved membranes.

Jackson Crowley, Cécile Hilpert, Luca Monticelli.

  Most biological membranes are curved, and both lipids and proteins play a role in generating curvature. For any given membrane shape and composition, it is not trivial to determine whether lipids are laterally distributed in a homogeneous or inhomogeneous way, and whether the inter-leaflet distribution is symmetric or not. Here we present a simple computational tool that allows to predict the preference of any lipid type for membranes with positive vs. negative curvature, for any given value of curvature. The tool is based on molecular dynamics simulations of tubular membranes with hydrophilic pores. The pores allow spontaneous, barrierless flip-flop of most lipids, while also preventing differences in pressure between the inner and outer water compartments and minimizing membrane asymmetric stresses. Specifically, we provide scripts to build and analyze the simulations. We test the tool by performing simulations on simple binary lipid mixtures, and we show that, as expected, lipids with negative intrinsic curvature distribute to the tubule inner leaflet, the more so when the radius of the tubular membrane is small. Compared to other existing computational methods, relying on membrane buckles and tethers, our method is based on spontaneous inter-leaflet transport of lipids, and therefore allows to explore lipid distribution in asymmetric membranes. The method can easily be adapted to work with any molecular dynamics code and any force field.

Keywords:  Biological membrane; Computer simulation; Lipid bilayer; Lipid flip- flop; Lipid membrane; Lipid sorting; Membrane curvature; Molecular dynamics

DOI:  https://doi.org/10.1016/bs.mie.2024.03.022
Methods Enzymol. 2024 ;pii: S0076-6879(24)00123-X. [Epub ahead of print]701 359-386

Free energy calculations for membrane morphological transformations and insights to physical biology and oncology.

Kshitiz Parihar, Seung-Hyun Ko, Ryan Bradley, Phillip Taylor, N Ramakrishnan, Tobias Baumgart, Wei Guo, Valerie M Weaver, Paul A Janmey, Ravi Radhakrishnan.

  In this chapter, we aim to bridge basic molecular and cellular principles surrounding membrane curvature generation with rewiring of cellular signals in cancer through multiscale models. We describe a general framework that integrates signaling with other cellular functions like trafficking, cell-cell and cell-matrix adhesion, and motility. The guiding question in our approach is: how does a physical change in cell membrane configuration caused by external stimuli (including those by the extracellular microenvironment) alter trafficking, signaling and subsequent cell fate? We answer this question by constructing a modeling framework based on stochastic spatial continuum models of cell membrane deformations. We apply this framework to explore the link between trafficking, signaling in the tumor microenvironment, and cell fate. At each stage, we aim to connect the results of our predictions with cellular experiments.

Keywords:  Curvature sensing; Dynamically triangulated Monte Carlo; Free energy methods; Membrane morphological transitions; Trafficking; Vesiculation

DOI:  https://doi.org/10.1016/bs.mie.2024.03.028
J Cell Biol. 2024 Oct 07. pii: e202402035. [Epub ahead of print]223(10):

De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane.

Kieop Park, Aastha Garde, Siddharthan B Thendral, Adam W J Soh, Qiuyi Chi, David R Sherwood.

To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid-producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC's invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.

DOI: https://doi.org/10.1083/jcb.202402035
Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2319782121

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.

Daniel Maxim Iascone, Xue Zhang, Patricia Brafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L Zhang, Sukanya Madhwal, Kieona Cook, Pavel Pivarshev, Ben Z Stanger, Stewart Anderson, Chi V Dang, Amita Sehgal.

  Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

Keywords:  adenocarcinoma; cancer; circadian rhythms; luciferase; metabolism

DOI:  https://doi.org/10.1073/pnas.2319782121
Methods Enzymol. 2024 ;pii: S0076-6879(24)00093-4. [Epub ahead of print]701 157-174

Modeling asymmetric cell membranes at all-atom resolution.

Jessica Bodosa, Anthony J Pane, Jeffery B Klauda.

  Molecular dynamics (MD) simulations are a useful tool when studying the properties of membranes as they allow for a molecular view of lipid interactions with proteins, nucleic acids, or small molecules. While model membranes are usually symmetric in their lipid composition between leaflets and include a small number of lipid components, physiological membranes are highly complex and vary in the level of asymmetry. Simulation studies have shown that changes in leaflet asymmetry can alter the properties of a membrane. It is therefore necessary to carefully build asymmetric membranes to accurately simulate membranes. This chapter carefully describes the different methods for building asymmetric membranes and the advantages/disadvantages of each method. The simplest methods involve building a membrane with either an equal number of lipids per leaflet or an equal initial surface area (SA) estimated by the area per lipid. More detailed methods include combining two symmetric membranes of equal SA or altering an asymmetric membrane and adjusting the number of lipids after equilibration to minimize an observable such as differential stress (0-DS). More complex methods that require specific simulation software are also briefly described. The challenges and assumptions are listed for each method which should help guide the researcher to choose the best method for their unique MD simulation of an asymmetric membrane.

Keywords:  Area per lipid; Complex membranes; Differential stress; Lipid flip-flop; Membrane asymmetry; Membrane coupling; Molecular dynamics

DOI:  https://doi.org/10.1016/bs.mie.2024.03.009
Nature. 2024 Jul 17.

In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution.

Peter F Renz, Umesh Ghoshdastider, Simona Baghai Sain, Fabiola Valdivia-Francia, Ameya Khandekar, Mark Ormiston, Martino Bernasconi, Clara Duré, Jonas A Kretz, Minkyoung Lee, Katie Hyams, Merima Forny, Marcel Pohly, Xenia Ficht, Stephanie J Ellis, Andreas E Moor, Ataman Sendoel.

The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1-3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial-mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.

DOI: https://doi.org/10.1038/s41586-024-07663-y
Am J Physiol Cell Physiol. 2024 Jul 16.

Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.

Thomas D Cardaci, Brandon N VanderVeen, Alexander R Huss, Brooke M Bullard, Kandy T Velazquez, Norma Frizzell, James A Carson, Robert L Price, E Angela Murphy.

  Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. While its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular LD content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis Lung Carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n=20) were implanted with LLC cells [106] in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red o/lipid staining (tibialis anterior), and protein (gastrocnemius). LLC mice had a greater number (232%; p=0.006) and size (130%; p=0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; p=0.0109) and 'very high' oil-red O positive (178%; p=0.0002) fibers compared to controls and this was inversely correlated with fiber size (R2=0.5294; p<0.0001). Morphological analyses of LDs show increased elongation and complexity (aspect ratio: IMF: 9%, p=0.046) with decreases in circularity (circularity: SS: 6%, p=0.042) or roundness (roundness: Whole: 10%, p=0.033; IMF: 8%, p=0.038) as well as decreased LD-mitochondria touch (-15%; p=0.006), contact length (-38%; p=0.036), and relative contact (86%; p=0.004). Further, dysregulation in lipid metabolism (adiponectin, CPT-1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (p<0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.

Keywords:  Lewis Lung Carcinoma; high-fat diet; lipid deposition; lipid metabolism; muscle wasting

DOI:  https://doi.org/10.1152/ajpcell.00345.2024
Cancer Res. 2024 Jul 15. 84(14): 2229-2230

Is There a Mathematician on Board?

Elana J Fertig.

As convergence science is emerging as a theme in cancer research, scientists from diverse backgrounds, including mathematics, are increasingly entering our research community. The captain of a Southwest Airlines flight recently paged in jest for a mathematician to help support fuel calculations that would enable a flight to arrive safely at the American Association for Cancer Research (AACR) Annual Meeting, epitomizing the need for well-trained mathematicians to address pressing problems. Here, we summarize the roles mathematicians can play in cancer research and the support needed to facilitate their entry into the cancer research field. The inclusion of scientific diversity across quantitative and engineering disciplines is critical for advancing the understanding and treatment of cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1396
bioRxiv. 2024 Jul 08. pii: 2024.07.04.602041. [Epub ahead of print]

Modelling the spatiotemporal dynamics of senescent cells in wound healing, chronic wounds, and fibrosis.

Sharmilla Chandrasegaran, James P Sluka, Daryl Shanley.

Cellular senescence is known to drive age-related pathology through the senescence-associated secretory phenotype (SASP). However, it also plays important physiological roles such as cancer suppression, embryogenesis and wound healing. Wound healing is a tightly regulated process which when disrupted results in conditions such as fibrosis and chronic wounds. Senescent cells appear during the proliferation phase of the healing process where the SASP is involved in maintaining tissue homeostasis after damage. Interestingly, SASP composition and functionality was recently found to be temporally regulated, with distinct SASP profiles involved: a fibrogenic, followed by a fibrolytic SASP, which could have important implications for the role of senescent cells in wound healing. Given the number of factors at play a full understanding requires addressing the multiple levels of complexity, pertaining to the various cell behaviours, individually followed by investigating the interactions and influence each of these elements have on each other and the system as a whole. Here, a systems biology approach was adopted whereby a multi-scale model of wound healing that includes the dynamics of senescent cell behaviour and corresponding SASP composition within the wound microenvironment was developed. The model was built using the software CompuCell3D, which is based on a Cellular Potts modelling framework. We used an existing body of data on healthy wound healing to calibrate the model and validation was done on known disease conditions. The model provides understanding of the spatiotemporal dynamics of different senescent cell phenotypes and the roles they play within the wound healing process. The model also shows how an overall disruption of tissue-level coordination due to age-related changes results in different disease states including fibrosis and chronic wounds. Further specific data to increase model confidence could be used to explore senolytic treatments in wound disorders.

DOI: https://doi.org/10.1101/2024.07.04.602041
Aging Cell. 2024 Jul 16. e14258

The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.

Florencia Herbstein, Melanie Sapochnik, Alejandra Attorresi, Cora Pollak, Sergio Senin, David Gonilski-Pacin, Nicolas Ciancio Del Giudice, Manuel Fiz, Belén Elguero, Mariana Fuertes, Lara Müller, Marily Theodoropoulou, Lucas B Pontel, Eduardo Arzt.

  Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.

Keywords:  interleukin‐6; intracellular; pituitary; senescence; signaling; therapy‐induced senescence; tumors

DOI:  https://doi.org/10.1111/acel.14258
bioRxiv. 2024 Jul 02. pii: 2024.06.27.601015. [Epub ahead of print]

Mechanical evolution of metastatic cancer cells in three-dimensional microenvironment.

Karlin Hilai, Daniil Grubich, Marcus Akrawi, Hui Zhu, Razanne Zaghloul, Chenjun Shi, Man Do, Dongxiao Zhu, Jitao Zhang.

  Cellular biomechanics plays critical roles in cancer metastasis and tumor progression. Existing studies on cancer cell biomechanics are mostly conducted in flat 2D conditions, where cells' behavior can differ considerably from those in 3D physiological environments. Despite great advances in developing 3D in vitro models, probing cellular elasticity in 3D conditions remains a major challenge for existing technologies. In this work, we utilize optical Brillouin microscopy to longitudinally acquire mechanical images of growing cancerous spheroids over the period of eight days. The dense mechanical mapping from Brillouin microscopy enables us to extract spatially resolved and temporally evolving mechanical features that were previously inaccessible. Using an established machine learning algorithm, we demonstrate that incorporating these extracted mechanical features significantly improves the classification accuracy of cancer cells, from 74% to 95%. Building on this finding, we have developed a deep learning pipeline capable of accurately differentiating cancerous spheroids from normal ones solely using Brillouin images, suggesting the mechanical features of cancer cells could potentially serve as a new biomarker in cancer classification and detection.

Keywords:  3D microenvironment; Brillouin microscopy; biomechanics; breast cancer; cellular spheroid; metastasis

DOI:  https://doi.org/10.1101/2024.06.27.601015
J Cachexia Sarcopenia Muscle. 2024 Jul 15.

Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation.

Georgia Lenihan-Geels, Francisco Garcia Carrizo, Marina Leer, Sabrina Gohlke, Moritz Oster, Sophie Pöhle-Kronawitter, Christiane Ott, Alexandra Chadt, Isabel N Reinisch, Markus Galhuber, Chen Li, Wenke Jonas, Markus Jähnert, Susanne Klaus, Hadi Al-Hasani, Tilman Grune, Annette Schürmann, Tobias Madl, Andreas Prokesch, Michael Schupp, Tim J Schulz.

   BACKGROUND: The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.
METHODS: A mouse model with inducible deletion of the p53-encoding gene, Trp53, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.
RESULTS: Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (-62,0%; P < 0.0001 and -52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2-3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (-13.8%; P = 0.049 and -22.2%; P = 0.0384, respectively).
CONCLUSIONS: These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting-like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short-term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.

Keywords:  Energy conservation; Metabolic efficiency; Metabolic homeostasis; Metabolism; Skeletal muscle; p53

DOI:  https://doi.org/10.1002/jcsm.13529
Nat Cell Biol. 2024 Jul 19.

An E3 ligase and autophagy adaptor regulates tau proteostasis through nested phase separation.

DOI: https://doi.org/10.1038/s41556-024-01466-z
Tob Induc Dis. 2024 ;22

Effect of smoking cessation on the likelihood of pancreatitis and pancreatic cancer.

Xiao Han, Zouhua Xu, Dongmei Ma, Zhi Ling, Xiaowu Dong, Xuebing Yan, Yong Chen, Guotao Lu, Xudong Yin, Hongwei Xu.

   INTRODUCTION: Tobacco smoking is a major risk factor for various diseases worldwide, including pancreatic exocrine diseases such as pancreatitis and pancreatic cancer (PC). Currently, few studies have examined the impact of smoking cessation on the likelihood of common pancreatic exocrine diseases. This study sought to determine whether smoking cessation would reduce pancreatitis and PC morbidity.
METHODS: This cohort study used data from the UK Biobank (UKB) to examine the association between smoking status and the likelihood of pancreatitis and PC among 492855 participants. The subjects were divided into never smokers, ex-smokers, and current smokers. Using a multivariate-adjusted binary logistic regression model, we analyzed the relationship between different smoking conditions and the likelihood of pancreatitis and PC. Further, we studied the impact of smoking cessation on pancreatitis and PC compared with current smoking.
RESULTS: After adjusting for potential confounders, current smokers had higher odds for acute pancreatitis (AP) (AOR=1.38; 95% CI: 1.18-1.61), chronic pancreatitis (CP) (AOR=3.29; 95% CI: 2.35-4.62) and PC (AOR=1.72; 95% CI: 1.42-2.09). People who quit smoking had comparable odds for the diseases as those who never smoked. Compared with current smokers, ex-smokers had reduced odds for AP (AOR=0.76; 95% CI: 0.64-0.89), CP (AOR=0.31; 95% CI: 0.21-0.46), and PC (AOR=0.62; 95% CI: 0.50-0.76). Subgroup analysis revealed reduced odds for these pancreatic diseases in males and females.
CONCLUSIONS: Smokers have an increased odds for pancreatitis and pancreatic cancer. Moreover, smoking cessation can significantly reduce the odds for acute pancreatitis, chronic pancreatitis and pancreatic cancer.

Keywords:  pancreatic cancer; pancreatitis; smoking; smoking cessation

DOI:  https://doi.org/10.18332/tid/190635
Oncogene. 2024 Jul 17.

GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase.

Yutong Chen, Weiyu Zhang, Yan Zeng, Pengfei Yang, Yaning Li, Xinyue Liang, Kecheng Liu, Hai Lin, Yalan Dai, Jiancong Zhou, Bingqi Hou, Zhenting Ma, Yujing Lin, Wenzheng Pang, Linjuan Zeng.

Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.

DOI: https://doi.org/10.1038/s41388-024-03102-4
Nat Methods. 2024 Jul 18.

CryoDRGN-ET: deep reconstructing generative networks for visualizing dynamic biomolecules inside cells.

Ramya Rangan, Ryan Feathers, Sagar Khavnekar, Adam Lerer, Jake D Johnston, Ron Kelley, Martin Obr, Abhay Kotecha, Ellen D Zhong.

Advances in cryo-electron tomography (cryo-ET) have produced new opportunities to visualize the structures of dynamic macromolecules in native cellular environments. While cryo-ET can reveal structures at molecular resolution, image processing algorithms remain a bottleneck in resolving the heterogeneity of biomolecular structures in situ. Here, we introduce cryoDRGN-ET for heterogeneous reconstruction of cryo-ET subtomograms. CryoDRGN-ET learns a deep generative model of three-dimensional density maps directly from subtomogram tilt-series images and can capture states diverse in both composition and conformation. We validate this approach by recovering the known translational states in Mycoplasma pneumoniae ribosomes in situ. We then perform cryo-ET on cryogenic focused ion beam-milled Saccharomyces cerevisiae cells. CryoDRGN-ET reveals the structural landscape of S. cerevisiae ribosomes during translation and captures continuous motions of fatty acid synthase complexes inside cells. This method is openly available in the cryoDRGN software.

DOI: https://doi.org/10.1038/s41592-024-02340-4
bioRxiv. 2024 Jul 08. pii: 2024.07.08.600855. [Epub ahead of print]

The WAVE complex forms linear arrays at negative membrane curvature to instruct lamellipodia formation.

Muziyue Wu, Paul Marchando, Kirstin Meyer, Ziqi Tang, Derek N Woolfson, Orion D Weiner.

Cells generate a wide range of actin-based membrane protrusions for various cell behaviors. These protrusions are organized by different actin nucleation promoting factors. For example, N-WASP controls finger-like filopodia, whereas the WAVE complex controls sheet-like lamellipodia. These different membrane morphologies likely reflect different patterns of nucleator self-organization. N-WASP phase separation has been successfully studied through biochemical reconstitutions, but how the WAVE complex self-organizes to instruct lamellipodia is unknown. Because WAVE complex self-organization has proven refractory to cell-free studies, we leverage in vivo biochemical approaches to investigate WAVE complex organization within its native cellular context. With single molecule tracking and molecular counting, we show that the WAVE complex forms highly regular multi-layered linear arrays at the plasma membrane that are rem-iniscent of a microtubule-like organization. Similar to the organization of microtubule protofilaments in a curved array, membrane curvature is both necessary and sufficient for formation of these WAVE complex linear arrays, though actin polymerization is not. This dependency on negative membrane curvature could explain both the templating of lamellipodia and their emergent behaviors, including barrier avoidance. Our data uncover the key biophysical properties of mesoscale WAVE complex patterning and highlight an integral relationship between NPF self-organization and cell morphogenesis.

DOI: https://doi.org/10.1101/2024.07.08.600855
Trends Mol Med. 2024 Jul 13. pii: S1471-4914(24)00188-6. [Epub ahead of print]

Striking senescence with sodium transporter inhibition.

Bettina Schock, Steven O'Reilly.

  Senescence is associated with multiple morbidities and therapeutic targeting of these cells is a key aim. In a recent study, Katsuumi et al. found that targeting sodium-glucose co-transporter 2 (SGLT2) promoted immune clearance of senescent cells via programmed cell death-1 ligand (PD-L1) suppression, thus promoting immunosurveillance. This could have profound implications for many age-related diseases, including cancer and frailty.

Keywords:  AMPK; age-related diseases; immunosurveillance; senescence; senolysis

DOI:  https://doi.org/10.1016/j.molmed.2024.07.002
ACS Chem Biol. 2024 Jul 18.

Imaging Interorganelle Phospholipid Transport by Extended Synaptotagmins Using Bioorthogonally Tagged Lipids.

Lin Luan, Dongjun Liang, Din-Chi Chiu, Reika Tei, Jeremy M Baskin.

The proper distribution of lipids within organelle membranes requires rapid interorganelle lipid transport, much of which occurs at membrane contact sites and is mediated by lipid transfer proteins (LTPs). Our current understanding of LTP mechanism and function is based largely on structural studies and in vitro reconstitution. Existing cellular assays for LTP function use indirect readouts, and it remains an open question as to whether substrate specificity and transport kinetics established in vitro are similar in cellular settings. Here, we harness bioorthogonal chemistry to develop tools for direct visualization of interorganelle transport of phospholipids between the plasma membrane (PM) and the endoplasmic reticulum (ER). Unnatural fluorescent phospholipid analogs generated by the transphosphatidylation activity of phospholipase D (PLD) at the PM are rapidly transported to the ER dependent in part upon extended synaptotagmins (E-Syts), a family of LTPs at ER-PM contact sites. Ectopic expression of an artificial E-Syt-based tether at ER-mitochondria contact sites results in fluorescent phospholipid accumulation in mitochondria. Finally, in vitro reconstitution assays demonstrate that the fluorescent lipids are bona fide E-Syt substrates. Thus, fluorescent lipids generated in situ via PLD activity and bioorthogonal chemical tagging can enable direct visualization of the activity of LTPs that mediate bulk phospholipid transport at ER-PM contact sites.

DOI: https://doi.org/10.1021/acschembio.4c00345
bioRxiv. 2024 Jul 13. pii: 2023.10.29.564655. [Epub ahead of print]

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds.

Roberto Alonso-Matilla, Paolo P Provenzano, David J Odde.

Despite recent experimental progress in characterizing cell migration mechanics, our understanding of the mechanisms governing rapid cell movement remains limited. To effectively limit tumor growth, antitumoral T cells need to rapidly migrate to find and kill cancer cells. To investigate the upper limits of cell speed, we developed a new hybrid stochastic-mean field model of bleb-based cell motility. We first examined the potential for adhesion-free bleb-based migration and show that cells migrate inefficiently in the absence of adhesion-based forces, i.e., cell swimming. While no cortical contractility oscillations are needed for cells to swim in viscoelastic media, high-to-low cortical contractility oscillations are necessary for cell swimming in viscous media. This involves a high cortical contractility phase with multiple bleb nucleation events, followed by an intracellular pressure buildup recovery phase at low cortical tensions, resulting in modest net cell motion. However, our model suggests that cells can employ a hybrid bleb- and adhesion-based migration mechanism for rapid cell motility and identifies conditions for optimality. The model provides a momentum-conserving mechanism underlying rapid single-cell migration and identifies factors as design criteria for engineering T cell therapies to improve movement in mechanically complex environments.

DOI: https://doi.org/10.1101/2023.10.29.564655
J Surg Oncol. 2024 Jul 17.

Survival benefit associated with screening of patients at elevated risk for pancreatic cancer.

William J Kane, Kathleen R Haden, Elizabeth N Martin, Vanessa M Shami, Andrew Y Wang, Daniel S Strand, Sara J Adair, Sarbajeet Nagdas, Allan Tsung, Victor M Zaydfudim, Reid B Adams, Todd W Bauer.

  BACKGROUND & OBJECTIVES: Screening for pancreatic cancer is recommended for individuals with a strong family history, certain genetic syndromes, or a neoplastic cyst of the pancreas. However, limited data supports a survival benefit attributable to screening these higher-risk individuals.
METHODS: All patients enrolled in screening at a High-Risk Pancreatic Cancer Clinic (HRC) from July 2013 to June 2020 were identified from a prospectively maintained institutional database and compared to patients evaluated at a Surgical Oncology Clinic (SOC) at the same institution during the same period. Clinical outcomes of patients selected for surgical resection, particularly clinicopathologic stage and overall survival, were compared.
RESULTS: Among 826 HRC patients followed for a median (IQR) of 2.3 (0.8-4.2) years, 128 were selected for surgical resection and compared to 402 SOC patients selected for resection. Overall survival was significantly longer among HRC patients (median survival: not reached vs. 2.6 years, p < 0.001). Among 31 HRC and 217 SOC patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC), the majority of HRC patients were diagnosed with stage 0 disease (carcinoma in situ), while the majority of SOC patients were diagnosed with stage II disease (p < 0.001). Overall survival after resection of invasive PDAC was also significantly longer among HRC patients compared to SOC patients (median survival 5.5 vs. 1.6 years, p = 0.002).
CONCLUSION: Patients at increased risk for PDAC and followed with guideline-based screening exhibited downstaging of disease and improved survival from PDAC in comparison to patients who were not screened.

Keywords:  cancer screening; pancreatectomy; pancreatic adenocarcinoma; pancreatic cancer; pancreatoduodenectomy; surgical oncology

DOI:  https://doi.org/10.1002/jso.27784
Sci Am. 2024 Jun 01. 330(6): 71

The Human Body Is Made of Bags: We are like levers and computers, but above all, humans are bags of biology.

Bethany Brookshire.

DOI: https://doi.org/10.1038/scientificamerican062024-8QJXgJPLpTamZNZ85L3oe
Autophagy. 2024 Jul 15. 1-12

Key considerations for investigating and interpreting autophagy in skeletal muscle.

Fasih A Rahman, Brittany L Baechler, Joe Quadrilatero.

  Skeletal muscle plays a crucial role in generating force to facilitate movement. Skeletal muscle is a heterogenous tissue composed of diverse fibers with distinct contractile and metabolic profiles. The intricate classification of skeletal muscle fibers exists on a continuum ranging from type I (slow-twitch, oxidative) to type II (fast-twitch, glycolytic). The heterogenous distribution and characteristics of fibers within and between skeletal muscles profoundly influences cellular signaling; however, this has not been broadly discussed as it relates to macroautophagy/autophagy. The growing interest in skeletal muscle autophagy research underscores the necessity of comprehending the interplay between autophagic responses among skeletal muscles and fibers with different contractile properties, metabolic profiles, and other related signaling processes. We recommend approaching the interpretation of autophagy findings with careful consideration for two key reasons: 1) the distinct behaviors and responses of different skeletal muscles or fibers to various perturbations, and 2) the potential impact of alterations in skeletal muscle fiber type or metabolic profile on observed autophagic outcomes. This review provides an overview of the autophagic profile and response in skeletal muscles/fibers of different types and metabolic profiles. Further, this review discusses autophagic findings in various conditions and diseases that may differentially affect skeletal muscle. Finally, we provide key points of consideration to better enable researchers to fine-tune the design and interpretation of skeletal muscle autophagy experiments.Abbreviation: AKT1: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG4: autophagy related 4 cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CS: citrate synthase; DIA: diaphragm; EDL: extensor digitorum longus; FOXO3/FOXO3A: forkhead box O3; GAS; gastrocnemius; GP: gastrocnemius-plantaris complex; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MYH: myosin heavy chain; PINK1: PTEN induced kinase 1; PLANT: plantaris; PRKN: parkin RBR E3 ubiquitin protein ligase; QUAD: quadriceps; RA: rectus abdominis; RG: red gastrocnemius; RQ: red quadriceps; SOL: soleus; SQSTM1: sequestosome 1; TA: tibialis anterior; WG: white gastrocnemius; WQ: white quadriceps; WVL: white vastus lateralis; VL: vastus lateralis; ULK1: unc-51 like autophagy activating kinase 1.

Keywords:  Contraction; fiber type; metabolic; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2024.2373676
Cold Spring Harb Perspect Med. 2024 Jul 15. pii: a041551. [Epub ahead of print]

Imaging Tumor Metabolism.

Thomas Ruan, Kayvan R Keshari.

Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.

DOI: https://doi.org/10.1101/cshperspect.a041551
Sci Adv. 2024 Jul 19. 10(29): eadl6366

A fibronectin gradient remodels mixed-phase mesoderm.

Min Zhu, Bin Gu, Evan C Thomas, Yunyun Huang, Yun-Kyo Kim, Hirotaka Tao, Theodora M Yung, Xin Chen, Kaiwen Zhang, Elizabeth K Woolaver, Mikaela R Nevin, Xi Huang, Rudolph Winklbauer, Janet Rossant, Yu Sun, Sevan Hopyan.

Physical processes ultimately shape tissue during development. Two emerging proposals are that cells migrate toward stiffer tissue (durotaxis) and that the extent of cell rearrangements reflects tissue phase, but it is unclear whether and how these concepts are related. Here, we identify fibronectin-dependent tissue stiffness as a control variable that underlies and unifies these phenomena in vivo. In murine limb bud mesoderm, cells are either caged, move directionally, or intercalate as a function of their location along a stiffness gradient. A modified Landau phase equation that incorporates tissue stiffness accurately predicts cell diffusivity upon loss or gain of fibronectin. Fibronectin is regulated by WNT5A-YAP feedback that controls cell movements, tissue shape, and skeletal pattern. The results identify a key determinant of phase transition and show how fibronectin-dependent directional cell movement emerges in a mixed-phase environment in vivo.

DOI: https://doi.org/10.1126/sciadv.adl6366
bioRxiv. 2024 Jul 04. pii: 2024.07.02.601733. [Epub ahead of print]

FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis.

Matthew Yorek, Xingshan Jiang, Shanshan Liu, Jiaqing Hao, Jianyu Yu, Anthony Avellino, Zhanxu Liu, Melissa Curry, Henry Keen, Jianqiang Shao, Anand Kanagasabapathy, Maiying Kong, Yiqin Xiong, Edward R Sauter, Sonia L Sugg, Bing Li.

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo . Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.
Graphic Abstract:
Highlights: Unlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages.Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophagesDeficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophagesFABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis.

DOI: https://doi.org/10.1101/2024.07.02.601733
J Exp Clin Cancer Res. 2024 Jul 18. 43(1): 198

The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers.

Carla Mottini, Francesca Romana Auciello, Isabella Manni, Christian Pilarsky, Damiano Caputo, Giulio Caracciolo, Alessandro Rossetta, Elena Di Gennaro, Alfredo Budillon, Giovanni Blandino, Maria Serena Roca, Giulia Piaggio.

  Pancreatic cancer (PC) is a clinically challenging tumor to combat due to its advanced stage at diagnosis as well as its resistance to currently available therapies. The absence of early symptoms and known detectable biomarkers renders this disease incredibly difficult to detect/manage. Recent advances in the understanding of PC biology have highlighted the importance of cancer-immune cell interactions, not only in the tumor micro-environment but also in distant systemic sites, like the bone marrow, spleen and circulating immune cells, the so-called macro-environment. The response of the macro-environment is emerging as a determining factor in tumor development by contributing to the formation of an increasingly immunogenic micro-environment promoting tumor homeostasis and progression. We will summarize the key events associated with the feedback loop between the tumor immune micro-environment (TIME) and the tumor immune macroenvironment (TIMaE) in pancreatic precancerous lesions along with how it regulates disease development and progression. In addition, liquid biopsy biomarkers capable of diagnosing PC at an early stage of onset will also be discussed. A clearer understanding of the early crosstalk between micro-environment and macro-environment could contribute to identifying new molecular therapeutic targets and biomarkers, consequently improving early PC diagnosis and treatment.

Keywords:  Circulating biomarkers; Immune landscape; Macro-environment; Micro-environment; Pancreatic cancer

DOI:  https://doi.org/10.1186/s13046-024-03117-5
bioRxiv. 2024 Jul 06. pii: 2024.04.03.588011. [Epub ahead of print]

qMAP enabled microanatomical mapping of human skin aging.

Kyu Sang Han, Inbal B Sander, Jacqueline Kumer, Eric Resnick, Clare Booth, Guoqing Cheng, Yebin Im, Bartholomew Starich, Ashley L Kiemen, Jude M Phillip, Sashank Reddy, Corrine E Joshu, Joel C Sunshine, Jeremy D Walston, Denis Wirtz, Pei-Hsun Wu.

Aging is a major driver of diseases in humans. Identifying features associated with aging is essential for designing robust intervention strategies and discovering novel biomarkers of aging. Extensive studies at both the molecular and organ/whole-body physiological scales have helped determined features associated with aging. However, the lack of meso-scale studies, particularly at the tissue level, limits the ability to translate findings made at molecular scale to impaired tissue functions associated with aging. In this work, we established a tissue image analysis workflow - quantitative micro-anatomical phenotyping (qMAP) - that leverages deep learning and machine vision to fully label tissue and cellular compartments in tissue sections. The fully mapped tissue images address the challenges of finding an interpretable feature set to quantitatively profile age-related microanatomic changes. We optimized qMAP for skin tissues and applied it to a cohort of 99 donors aged 14 to 92. We extracted 914 microanatomic features and found that a broad spectrum of these features, represented by 10 cores processes, are strongly associated with aging. Our analysis shows that microanatomical features of the skin can predict aging with a mean absolute error (MAE) of 7.7 years, comparable to state-of-the-art epigenetic clocks. Our study demonstrates that tissue-level architectural changes are strongly associated with aging and represent a novel category of aging biomarkers that complement molecular markers. Our results highlight the complex and underexplored multi-scale relationship between molecular and tissue microanatomic scales.

DOI: https://doi.org/10.1101/2024.04.03.588011
Mol Imaging Biol. 2024 Jul 17.

Cryo-Fluorescence Tomography as a Tool for Visualizing Whole-Body Inflammation Using Perfluorocarbon Nanoemulsion Tracers.

Benjamin I Leach, Deanne Lister, Stephen R Adams, Julie Bykowski, Amy B Schwartz, Patrick McConville, Hemi Dimant, Eric T Ahrens.

   PURPOSE: We explore the use of intravenously delivered fluorescent perfluorocarbon (PFC) nanoemulsion tracers and multi-spectral cryo-fluorescence tomography (CFT) for whole-body tracer imaging in murine inflammation models. CFT is an emerging technique that provides high-resolution, three-dimensional mapping of probe localization in intact animals and tissue samples, enabling unbiased validation of probe biodistribution and minimizes reliance on laborious histological methods employing discrete tissue panels, where disseminated populations of PFC-labeled cells may be overlooked. This methodology can be used to streamline the development of new generations of non-invasive, cellular-molecular imaging probes for in vivo imaging.
PROCEDURES: Mixtures of nanoemulsions with different fluorescent emission wavelengths were administered intravenously to naïve mice and models of acute inflammation, colitis, and solid tumor. Mice were euthanized 24 h post-injection, frozen en bloc, and imaged at high resolution (~ 50 µm voxels) using CFT at multiple wavelengths.
RESULTS: PFC nanoemulsions were visualized using CFT within tissues of the reticuloendothelial system and inflammatory lesions, consistent with immune cell (macrophage) labeling, as previously reported in in vivo magnetic resonance and nuclear imaging studies. The CFT signals show pronounced differences among fluorescence wavelengths and tissues, presumably due to autofluorescence, differential fluorescence quenching, and scattering of incident and emitted light.
CONCLUSIONS: CFT is an effective and complementary methodology to in vivo imaging for validating PFC nanoemulsion biodistribution at high spatial localization, bridging the resolution gap between in vivo imaging and histology.

Keywords:  Cancer; Cryo-fluorescence tomography; Fluorine-19; Inflammation; MRI; Macrophage; Mouse; Nanoemulsion; PET; Perfluorocarbon

DOI:  https://doi.org/10.1007/s11307-024-01926-w