bims-cagime 2024-12-15 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2024–12–15
27 papers selected by
Kıvanç Görgülü, Technical University of Munich

Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma.
Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria.
Disagreement on foundational principles of biological aging.
Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.
Quantitative MRI Measurements Capture Pancreatic Cancer and Stroma Reactions to New KRAS Inhibitor.
How to build the virtual cell with artificial intelligence: Priorities and opportunities.
How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot.
Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.
Highly multiplexed imaging in the omics era: understanding tissue structures in health and disease.
Cu in cancer metabolism.
Amoeboid cells undergo durotaxis with soft end polarized NMIIA.
A FRET Autophagy Imaging Platform by Macrocyclic Amphiphile.
Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.
Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors.
Effects of Ca2+ on the Structure and Dynamics of PIP3 in Model Membranes Containing PC and PS.
Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas.
π-HuB: the proteomic navigator of the human body.
Oligometastatic pancreatic cancer - prognostic factors for oncosurgical individualized therapy.
Budding of Asymmetric Lipid Bilayers: Effects of Cholesterol, Anionic Lipid, and Electric Field.
A lipid made by tumour cells reprograms immune cells.
pERK transition-induced directional mode switching promotes epithelial tumor cell migration.
Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma.
Nanoarchitectonics and Simulation on the Molecular-Level Interactions between p-Sulfonic Acid Calix[4]arene and Langmuir Monolayers Representing Healthy and Cancerous Cell Membranes.
Ferroptosis: when metabolism meets cell death.
A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.
An integrative multi-omics analysis reveals a multi-analyte signature of pancreatic ductal adenocarcinoma in serum.
Sacrificial capillary pumps to engineer multiscalar biological forms.

Nat Biomed Eng. 2024 Dec 10.

Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma.

Aristeidis Papargyriou, Mulham Najajreh, David P Cook, Carlo H Maurer, Stefanie Bärthel, Hendrik A Messal, Sakthi K Ravichandran, Till Richter, Moritz Knolle, Thomas Metzler, Akul R Shastri, Rupert Öllinger, Jacob Jasper, Laura Schmidleitner, Surui Wang, Christian Schneeweis, Hellen Ishikawa-Ankerhold, Thomas Engleitner, Laura Mataite, Mariia Semina, Hussein Trabulssi, Sebastian Lange, Aashreya Ravichandra, Maximilian Schuster, Sebastian Mueller, Katja Peschke, Arlett Schäfer, Sophie Dobiasch, Stephanie E Combs, Roland M Schmid, Andreas R Bausch, Rickmer Braren, Irina Heid, Christina H Scheel, Günter Schneider, Anja Zeigerer, Malte D Luecken, Katja Steiger, Georgios Kaissis, Jacco van Rheenen, Fabian J Theis, Dieter Saur, Roland Rad, Maximilian Reichert.

In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance and mortality rates. However, such morphological and phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the phenotypic landscape seen in murine and human PDAC, that the pronounced molecular and morphological intratumoural and intertumoural heterogeneity of organoids is governed by defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), and that different organoid phenotypes represent distinct tumour-cell states with unique biological features in vivo. We also show that phenotype-specific therapeutic vulnerabilities and modes of treatment-induced phenotype reprogramming can be captured in phenotypic heterogeneity maps. Our methodology and analyses of tumour-cell heterogeneity in PDAC may guide the development of phenotype-targeted treatment strategies.

DOI: https://doi.org/10.1038/s41551-024-01273-9
Cell Death Dis. 2024 Dec 06. 15(12): 884

Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria.

Yusuke Hirata, Yuto Yamada, Soma Taguchi, Ryota Kojima, Haruka Masumoto, Shinnosuke Kimura, Takuya Niijima, Takashi Toyama, Ryoji Kise, Emiko Sato, Yasunori Uchida, Junya Ito, Kiyotaka Nakagawa, Tomohiko Taguchi, Asuka Inoue, Yoshiro Saito, Takuya Noguchi, Atsushi Matsuzawa.

Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.

DOI: https://doi.org/10.1038/s41419-024-07237-w
PNAS Nexus. 2024 Dec;3(12): pgae499

Disagreement on foundational principles of biological aging.

Vadim N Gladyshev, Benjamin Anderson, Hanna Barlit, Benjamin Barré, Samuel Beck, Bahareh Behrouz, Daniel W Belsky, Amandine Chaix, Manish Chamoli, Brian H Chen, Kaiyang Cheng, Jane Chuprin, Gary A Churchill, Andrea Cipriano, Alex Colville, Joris Deelen, Yuri Deigin, KeHuan K Edmonds, Bradley W English, Ruogu Fang, Michael Florea, Iosif M Gershteyn, Diljeet Gill, Laura H Goetz, Vera Gorbunova, Patrick T Griffin, Steve Horvath, Martin Borch Jensen, Xin Jin, Sara Jovanovska, Kathrin M Kajderowicz, Tomoko Kasahara, Csaba Kerepesi, Subhash Kulkarni, Vyacheslav M Labunskyy, Morgan E Levine, Sergiy Libert, J Yuyang Lu, Yuancheng Ryan Lu, Riccardo E Marioni, Brianah M McCoy, Wayne Mitchell, Mahdi Moqri, Farzaneh Nasirian, Peter Niimi, Hamilton Se-Hwee Oh, Brian Okundaye, Andrey A Parkhitko, Leonid Peshkin, Mia Petljak, Jesse R Poganik, Glen Pridham, Daniel E L Promislow, Weronika Prusisz, Margaux Quiniou, Ken Raj, Daniel Richard, Jose Luis Ricon, Jarod Rutledge, Morten Scheibye-Knudsen, Nicholas J Schork, Andrei Seluanov, Michael Shadpour, Anastasia V Shindyapina, Steven R Shuken, Sruthi Sivakumar, Thomas Stoeger, Ayumu Sugiura, Nadia R Sutton, Alexander Suvorov, Andrei E Tarkhov, Emma C Teeling, Alexandre Trapp, Alexander Tyshkovskiy, Maximilian Unfried, Cavin K Ward-Caviness, Sun Hee Yim, Kejun Ying, Jeffrey Yunes, Bohan Zhang, Alex Zhavoronkov.

To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.

DOI: https://doi.org/10.1093/pnasnexus/pgae499
bioRxiv. 2024 Nov 26. pii: 2024.09.27.615385. [Epub ahead of print]

Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.

Deena B Snoke, Jos L van der Velden, Emma R Bellafleur, Jacob S Dearborn, Sean M Lenahan, Skyler C J Heininger, Jennifer L Ather, Hailey Sarausky, Daniel Stephenson, Julie A Reisz, Angelo D'Alessandro, Devdoot Majumdar, Thomas P Ahern, Kim L Sandler, Bennett A Landman, Yvonne M W Janssen-Heininger, Matthew E Poynter, David J Seward, Michael J Toth.

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific Kras G12D/+ ( G12D ) mice. G12D mice develop CC over a protracted time course and phenocopy tissue, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. CC in G12D mice is characterized by early loss of adipose tissue, a phenotype confirmed in a large cohort of patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.

DOI: https://doi.org/10.1101/2024.09.27.615385
bioRxiv. 2024 Nov 25. pii: 2024.11.22.624844. [Epub ahead of print]

Quantitative MRI Measurements Capture Pancreatic Cancer and Stroma Reactions to New KRAS Inhibitor.

Mamta Gupta, Hoon Choi, Samantha B Kemp, Emma E Furth, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Mark Rosen, Fang Liu, Quy Cao, Ben Z Stanger, Rong Zhou.

In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a breakthrough for PDAC treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable for management of patients undergoing KRASi therapy. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size (standard care assessment) change induced by KRASi treatment. We tested this hypothesis in multiple preclinical PDAC models receiving MRTX1133, an investigational new drug specific for KRAS G12D mutation. Quantitative imaging markers corroborated by immunohistochemistry (IHC) revealed significant and profound changes related to cell death accompanied by changes in tumor cellularity, capillary perfusion /permeability and stromal matrix as early as 48h and day-7 after initiation of KRASi treatment, and greatly prolonged median survival over controls in a genetic engineered mouse model of PDAC (KPC). The MRI markers also captured distinct responses to KRASi therapy from PDAC tumors carrying KRAS G12C versus KRAS G12D mutation. In tumors developed resistance to MRTX1133, the imaging markers exhibited a reversal from those of responding tumors. Our findings have established that multiparametric MRI provide biological insights including cell death, reduced cellularity and tumor microenvironment changes induced by KRASi treatment and set the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.
Translational relevance: Emerging small molecule KRAS inhibitors (KRASi) represent a new class of therapy for PDAC. Clinical tools that can provide biological insights beyond tumor size change are desirable for management of patients under KRASi therapy. DWI and DCE are frequently applied MRI methods for assessing cancer treatment responses in clinical trials. Using multiple PDAC models, we examined whether DWI, DCE and MTR can enhance the standard care assessment (tumor size) to MRTX1133, a KARSi with investigational new drug (IND) status. Our data demonstrate the abilities of DWI, DCE and MTR derived imaging markers to detect the early (48h) cell death, pronounced stromal changes and development of resistance to KRASi. This study has high translational relevance by testing clinically ready MRI methods, an IND and a genetic engineered mouse model that recapitulates saline features of human PDAC.

DOI: https://doi.org/10.1101/2024.11.22.624844
Cell. 2024 Dec 12. pii: S0092-8674(24)01332-1. [Epub ahead of print]187(25): 7045-7063

How to build the virtual cell with artificial intelligence: Priorities and opportunities.

Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B Burkhardt, Andrea Califano, Jonah Cool, Abby F Dernburg, Kirsty Ewing, Emily B Fox, Matthias Haury, Amy E Herr, Eric Horvitz, Patrick D Hsu, Viren Jain, Gregory R Johnson, Thomas Kalil, David R Kelley, Shana O Kelley, Anna Kreshuk, Tim Mitchison, Stephani Otte, Jay Shendure, Nicholas J Sofroniew, Fabian Theis, Christina V Theodoris, Srigokul Upadhyayula, Marc Valer, Bo Wang, Eric Xing, Serena Yeung-Levy, Marinka Zitnik, Theofanis Karaletsos, Aviv Regev, Emma Lundberg, Jure Leskovec, Stephen R Quake.

  Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.

Keywords:  AI; ML; cell biology; virtual cell

DOI:  https://doi.org/10.1016/j.cell.2024.11.015
Cell. 2024 Dec 03. pii: S0092-8674(24)01337-0. [Epub ahead of print]

How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot.

Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai.

  Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.

Keywords:  NINJ1; NINJ2; inflammatory cell death; lytic cell death; membrane solubilization; necroptosis; ninjurin-1; ninjurin-2; plasma membrane rupture; pyroptosis

DOI:  https://doi.org/10.1016/j.cell.2024.11.021
Autophagy. 2024 Dec 11.

Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death.

Karla Alvarez-Valadez, Allan Sauvat, Julien Diharce, Marion Leduc, Gautier Stoll, Lionel Guittat, Flavia Lambertucci, Juliette Paillet, Omar Motino, Lucille Ferret, Alexandra Muller, Sabrina Forveille, Maria Chiara Maiuri, Oliver Kepp, Alexandre G de Brevern, Harald Wodrich, Jonathan G Pol, Guido Kroemer, Mojgan Djavaheri-Mergny.

  Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.

Keywords:  Autophagy; NPC intracellular cholesterol transporter 1 and 2; TFEB; cancer; lipid transport; lysosomal membrane permeabilization

DOI:  https://doi.org/10.1080/15548627.2024.2440842
Nat Methods. 2024 Dec;21(12): 2209-2211

Highly multiplexed imaging in the omics era: understanding tissue structures in health and disease.

Bernd Bodenmiller.

DOI: https://doi.org/10.1038/s41592-024-02538-6
Nat Cell Biol. 2024 Dec;26(12): 2013

Cu in cancer metabolism.

Zhe Wang.

DOI: https://doi.org/10.1038/s41556-024-01578-6
Elife. 2024 Dec 13. pii: RP96821. [Epub ahead of print]13

Amoeboid cells undergo durotaxis with soft end polarized NMIIA.

Chenlu Kang, Pengcheng Chen, Xin Yi, Dong Li, Yiping Hu, Yihong Yang, Huaqing Cai, Bo Li, Congying Wu.

  Cell migration towards stiff substrates has been coined as durotaxis and implicated in development, wound healing, and cancer, where complex interplays between immune and non-immune cells are present. Compared to the emerging mechanisms underlying the strongly adhesive mesenchymal durotaxis, little is known about whether immune cells - migrating in amoeboid mode - could follow mechanical cues. Here, we develop an imaging-based confined migration device with a stiffness gradient. By tracking live cell trajectory and analyzing the directionality of T cells and neutrophils, we observe that amoeboid cells can durotax. We further delineate the underlying mechanism to involve non-muscle myosin IIA (NMIIA) polarization towards the soft-matrix-side but may not require differential actin flow up- or down-stiffness gradient. Using the protista Dictyostelium, we demonstrate the evolutionary conservation of amoeboid durotaxis. Finally, these experimental phenomena are theoretically captured by an active gel model capable of mechanosensing. Collectively, these results may shed new lights on immune surveillance and recently identified confined migration of cancer cells, within the mechanically inhomogeneous tumor microenvironment or the inflamed fibrotic tissues.

Keywords:  T cell; cell biology; cell migration; cytoskeleton; dictyostelium; durotaxis; mechanobiology; neutrophil

DOI:  https://doi.org/10.7554/eLife.96821
Angew Chem Int Ed Engl. 2024 Dec 12. e202420793

A FRET Autophagy Imaging Platform by Macrocyclic Amphiphile.

Ze-Tao Jiang, Jie Chen, Fang-Yuan Chen, Yuan-Qiu Cheng, Shun-Yu Yao, Rong Ma, Wen-Bo Li, Hongzhong Chen, Dong-Sheng Guo.

  Autophagy is a ubiquitous process of organelle interaction in eukaryotic cells, in which various organelles or proteins are recycled and operated through the autophagy pathway to ensure nutrient and energy homeostasis. Although numerous fluorescent probes have been developed to image autophagy, these environment-responsive probes suffer from inherent deficiencies such as inaccuracy and limited versatility. Here, we present a modular macrocyclic amphiphile Förster Resonance Energy Transfer (FRET) platform (SC6A12C/NCM, SN), constructed through the amphiphilic assembly of sulfonatocalix[6]arene (SC6A12C) with N-cetylmorpholine (NCM) for lysosome targeting. The hydrophobic fluorophore BPEA (FRET donor) was entrapped within the inner hydrophobic phase and showed strong fluorescence emission. Attributed to the broad-spectrum encapsulation of SC6A12C, three commercially available organelle probes (Mito-Tracker Red, ER Tracker Red, and RhoNox-1) were selected as SC6A12C guests (FRET acceptors). During autophagy process, the formation of intracellular host-guest complexes leads to strong FRET signal, allowing us to visualize the fusion of mitochondria, endoplasmic reticulum, and Golgi apparatus with lysosomes, respectively. This study provides a versatile and accessible platform for imaging organelle autophagy.

Keywords:  FRET; autophagy imaging; calixarenes; macrocyclic amphiphiles; molecular recognition

DOI:  https://doi.org/10.1002/anie.202420793
Nature. 2024 Dec 11.

Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.

Ignacio Melero, Maria de Miguel Luken, Guillermo de Velasco, Elena Garralda, Juan Martín-Liberal, Markus Joerger, Guzman Alonso, Maria-Elisabeth Goebeler, Martin Schuler, David König, Reinhard Dummer, Maria Reig, Maria-Esperanza Rodriguez Ruiz, Emiliano Calvo, Jorge Esteban-Villarrubia, Arjun Oberoi, Paula Sabat, Juan José Soto-Castillo, Kira-Lee Koster, Omar Saavedra, Cyrus Sayehli, Tanja Gromke, Heinz Läubli, Egle Ramelyte, Marta Fortuny, Ana Landa-Magdalena, Irene Moreno, Javier Torres-Jiménez, Alberto Hernando-Calvo, Dagmar Hess, Fabricio Racca, Heike Richly, Andreas M Schmitt, Corinne Eggenschwiler, Marco Sanduzzi-Zamparelli, Anna Vilalta-Lacarra, Jörg Trojan, Christine Koch, Peter R Galle, Friedrich Foerster, Zlatko Trajanoski, Hubert Hackl, Falk Gogolla, Florestan J Koll, Peter Wild, Felix Kyoung Hwan Chun, Henning Reis, Peter Lloyd, Matthias Machacek, Thomas F Gajewski, Wolf H Fridman, Alexander M M Eggermont, Ralf Bargou, Sandra Schöniger, Josef Rüschoff, Anastasiia Tereshchenko, Carina Zink, Antonio da Silva, Felix S Lichtenegger, Julia Akdemir, Manfred Rüdiger, Phil L'Huillier, Aradhana Dutta, Markus Haake, Alexandra Auckenthaler, Ana Gjorgjioska, Bernhard Rössler, Frank Hermann, Mara Liebig, Daniela Reichhardt, Christine Schuberth-Wagner, Jörg Wischhusen, Petra Fettes, Marlene Auer, Kathrin Klar, Eugen Leo.

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment1. Yet, response rates are still limited, and tumour progression commonly occurs2. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition3. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

DOI: https://doi.org/10.1038/s41586-024-08305-z
EMBO Rep. 2024 Dec 11.

Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors.

Yuhao Shi, Amber McKenery, Melissa Dolan, Michalis Mastri, James W Hill, Adam Dommer, Sebastien Benzekry, Mark Long, Scott I Abrams, Igor Puzanov, John M L Ebos.

  Therapeutic inhibition of programmed cell death ligand (PD-L1) is linked to alterations in interferon (IFN) signaling. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined IFN-related secretory changes in tumor cells following resistance to PD-L1 inhibition. Here we report an anti-PD-L1 treatment-induced secretome (PTIS) in tumor models of acquired resistance that is regulated by type I IFNs. These secretory changes can suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing that tumor-intrinsic treatment adaptations can exert broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth can slow or stop when PTIS components are disrupted individually, or when type I IFN signaling machinery is blocked. Interestingly, genetic and therapeutic disruption of PD-L1 in vitro can only partially recapitulate the PTIS phenotype highlighting the importance of developing in vivo-based resistance models to more faithfully mimic clinically-relevant treatment failure. Together, this study shows acquired resistance to immune-checkpoint inhibitors 'rewires' tumor secretory programs controlled by type I IFNs that, in turn, can protect from immune cell attack.

Keywords:  IFN; Immune-checkpoint; PD-L1; Resistance; Secretome

DOI:  https://doi.org/10.1038/s44319-024-00333-0
Biochemistry. 2024 Dec 10.

Effects of Ca2+ on the Structure and Dynamics of PIP3 in Model Membranes Containing PC and PS.

Ashley D Bernstein, Gertrude A Asante Ampadu, Yanxing Yang, Gobin Raj Acharya, Thomas M Osborn Popp, Andrew J Nieuwkoop.

Phosphatidylinositol phosphates (PIPs) are a family of seven different eukaryotic membrane lipids that have a large role in cell viability, despite their minor concentration in eukaryotic cellular membranes. PIPs tightly regulate cellular processes, such as cellular growth, metabolism, immunity, and development through direct interactions with partner proteins. Understanding the biophysical properties of PIPs in the complex membrane environment is important to understand how PIPs selectively regulate a partner protein. Here, we investigate the structure and dynamics of PIP3 in lipid bilayers that are simplified models of the natural membrane environment. We probe the effects of the anionic lipid phosphatidylserine (PS) and the divalent cation Ca2+ by using full-length lipids in well-formed bilayers. We used solution and solid-state NMR on naturally abundant 1H, 31P, and 13C atoms combined with molecular dynamics (MD) simulations to characterize the structure and dynamics of PIPs. 1H and 31P 1D spectra show good resolution at temperatures above the phase transition with isolated peaks in the headgroup, interfacial, and bilayer regions. Site-specific assignment of the chemical shifts of these reporters enables the measurement of the effects of Ca2+ and PS at the single atom level. In particular, the resolved 31P signals of the PIP3 headgroup allow for extremely well-localized information about PIP3 phosphate dynamics, which the MD simulations can further explain. A quantitative assessment of cross-polarization kinetics provides additional dynamics measurements for the PIP3 headgroups.

DOI: https://doi.org/10.1021/acs.biochem.4c00513
Ann Surg Oncol. 2024 Dec 10.

Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas.

Ellis L Eikenboom, Naaz Nasar, Kenneth Seier, Mithat Gönen, Manon C W Spaander, Eileen M O'Reilly, William R Jarnagin, Jeffrey Drebin, Michael I D'Angelica, T Peter Kingham, Vinod P Balachandran, Kevin C Soares, Anja Wagner, Alice C Wei.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare.
METHODS: This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts.
RESULTS: Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%]).
CONCLUSION: Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy.

Keywords:  Lynch syndrome; Microsatellite instability; Mismatch repair deficient; Overall survival; Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1245/s10434-024-16621-x
Nature. 2024 Dec;636(8042): 322-331

π-HuB: the proteomic navigator of the human body.

π-HuB Consortium

The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body at unprecedented resolution and scale. Here we introduce a big-science endeavour called π-HuB (proteomic navigator of the human body). The aim of the π-HuB project is to (1) generate and harness multimodality proteomic datasets to enhance our understanding of human biology; (2) facilitate disease risk assessment and diagnosis; (3) uncover new drug targets; (4) optimize appropriate therapeutic strategies; and (5) enable intelligent healthcare, thereby ushering in a new era of proteomics-driven phronesis medicine. This ambitious mission will be implemented by an international collaborative force of multidisciplinary research teams worldwide across academic, industrial and government sectors.

DOI: https://doi.org/10.1038/s41586-024-08280-5
Rozhl Chir. 2024 ;103(11): 421-428

Oligometastatic pancreatic cancer - prognostic factors for oncosurgical individualized therapy.

B Mohelníková Duchoňová, H Švébišová, A Langer, P Skalický, J Tesaříková, M Gregořík, M Loveček.

  Currently, no international consensus includes surgery as part of the standard of metastatic pancreatic ductal adenocarcinoma care. There is weak evidence to support the general introduction of surgical resection in the metastatic pancreatic ductal adenocarcinoma treatment. However, in the rare cases of oligometastatic spread there is increasing evidence that surgical intervention can lead to favourable outcomes. Individualisation of the care and tailored therapy refers not only to targeted treatment but also to the whole complex cancer care, including the indication for surgery. This review summarizes the current status of combined oncosurgical therapy in the multidisciplinary management of oligometastatic pancreatic cancer, together with our own experience, and discusses future perspectives, particularly regarding prognostic and predictive factors that could better predict this group.

Keywords:  Pancreatic cancer; metastasectomy; metastasis; neoadjuvant chemotherapy; neoplasm metastasis; pancreatic cancer

DOI:  https://doi.org/10.48095/ccrvch2024421
J Phys Chem B. 2024 Dec 13.

Budding of Asymmetric Lipid Bilayers: Effects of Cholesterol, Anionic Lipid, and Electric Field.

Jin Zhu, Yu Cao, Xiaoxue Qin, Qing Liang.

Membrane budding is vital for various cellular processes such as synaptic activity regulation, vesicle transport and release, and endocytosis/exocytosis. Although protein-mediated membrane budding has been extensively investigated, the effects of the lipid asymmetry of the two leaflets and the asymmetrically electrical environments of the cellular membrane on membrane budding remain elusive. In this work, using coarse-grained molecular dynamics simulations, we systematically investigate the impacts of lipid bilayer asymmetry and external electric fields mimicking the asymmetric membrane potential on the membrane budding. The results show that the differential stress induced by the asymmetric distribution of lipids in the two leaflets is a crucial factor for the membrane budding. The unidirectional flip of cholesterol induced by the membrane curvature and the asymmetric ion adsorption induced by the anionic lipids promote the budding process. Furthermore, the external electric field applied perpendicularly to the bilayer plane increases the transmembrane potential and produces an additional differential stress across the leaflets by imposing an asymmetric torque on the lipid headgroups in the two leaflets, facilitating the membrane budding. These findings offer insights into how the structural and the environmental asymmetry in natural cellular membranes influence membrane budding in cellular processes.

DOI: https://doi.org/10.1021/acs.jpcb.4c07782
Nature. 2024 Dec 11.

A lipid made by tumour cells reprograms immune cells.

Anthony C Buzzai, Thomas Tüting.



Keywords:  Cancer; Immunology; Medical research

DOI:  https://doi.org/10.1038/d41586-024-03855-8
Proc Natl Acad Sci U S A. 2024 Dec 17. 121(51): e2318871121

pERK transition-induced directional mode switching promotes epithelial tumor cell migration.

Huijing Yu, Guanli Xiao, Mingyao Gu, Liting Zhang, Ming Xia, Shimin Mo, Yuying Zhao, Chaoliang Wei.

  Increasing evidence suggests that tumor cells exhibit extreme plasticity in migration modes in order to adapt to microenvironments. However, the underlying mechanism for governing the migration mode switching is still unclear. Here, we revealed that epithelial tumor cells could develop a stable directional mode driven by hyperactivated ERK activity. This highly activated and dynamically changing ERK activity, called pERK transition, is crucial for inducing the switch from pauses state to directional movement and is also necessary for maintaining epithelial tumor cells in the directional mode. PERK transition integrated pERK surf, the dynamic and localized ERK activity at the leading edge. The sequential activation of RhoA and Rac1 by pERK transition played critical roles in generation of pERK surf activity through a movement feedback mechanism. PERK transition activity converted the orderly collective migration into the disordered dispersal movement, enhanced the invasiveness of epithelial tumor cells, and promoted their metastasis in immune-deficient mice. These findings revealed that the exquisite spatiotemporal organization of ERK activity orchestrates migration and invasion of tumor cells and provide evidence for the mechanism underlying migration mode switching in epithelial tumor cells.

Keywords:  migration mode switching; migration plasticity; pERK surf; pERK transition; rampage mode

DOI:  https://doi.org/10.1073/pnas.2318871121
Cancer Commun (Lond). 2024 Dec 08.

Reciprocal tumor-platelet interaction through the EPHB1-EFNB1 axis in the liver metastatic niche promotes metastatic tumor outgrowth in pancreatic ductal adenocarcinoma.

Lin-Li Yao, Wei-Ting Qin, Li-Peng Hu, Tie-Zhu Shi, Jian Yu Yang, Qing Li, Hui-Zhen Nie, Jun Li, Xu Wang, Lei Zhu, De-Jun Liu, Yan-Li Zhang, Shu-Heng Jiang, Zhi-Gang Zhang, Xiao-Mei Yang, Dong-Xue Li, Xue-Li Zhang.

   BACKGROUND: The interaction between the metastatic microenvironment and tumor cells plays an important role in metastatic tumor formation. Platelets play pivotal roles in hematogenous cancer metastasis through tumor cell-platelet interaction in blood vessels. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy distinguished by its notable tendency to metastasize to the liver. However, the role of platelet in the liver metastatic niche of PDAC remains elusive. This study aimed to elucidate the role of platelets and their interactions with tumor cells in the liver metastatic niche of PDAC.
METHODS: An mCherry niche-labeling system was established to identify cells in the liver metastatic niche of PDAC. Platelet depletion in a liver metastasis mouse model was used to observe the function of platelets in PDAC liver metastasis. Gain-of-function and loss-of-function of erythropoietin-producing hepatocellular receptor B1 (Ephb1), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (Tph1)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.
RESULTS: The mCherry metastatic niche-labeling system revealed the presence of activated platelets in the liver metastatic niche of PDAC patients. Platelet depletion decreased liver metastatic tumor growth in mice. Mechanistically, tumor cell-expressed EPHB1 and platelet-expressed Ephrin B1 (EFNB1) mediated contact-dependent activation of platelets via reverse signaling-mediated AKT signaling activation, and in turn, activated platelet-released 5-HT, further enhancing tumor growth.
CONCLUSION: We revealed the crosstalk between platelets and tumor cells in the liver metastatic niche of PDAC. Reciprocal tumor-platelet interaction mediated by the EPHB1-EFNB1 reverse signaling promoted metastatic PDAC outgrowth via 5-HT in the liver. Interfering the tumor-platelet interaction by targeting the EPHB1-EFNB1 axis may represent a promising therapeutic intervention for PDAC liver metastasis.

Keywords:  5‐HT; Axon guidance molecule; Liver metastatic niche; Reverse signaling; Tumor‐platelet interaction

DOI:  https://doi.org/10.1002/cac2.12637
Langmuir. 2024 Dec 11.

Nanoarchitectonics and Simulation on the Molecular-Level Interactions between p-Sulfonic Acid Calix[4]arene and Langmuir Monolayers Representing Healthy and Cancerous Cell Membranes.

Ellen C Wrobel, Lucas Stori de Lara, Ângelo de Fátima, Osvaldo N Oliveira.

The design of chemotherapeutic drug carriers requires precise information on their interaction with the plasma membrane since the carriers should be internalized by cells without disrupting or compromising the overall integrity of the membrane. In this study, we employ Langmuir monolayers mimicking the outer leaflet of plasma membranes of healthy and cancerous cells to determine the molecular-level interactions with a water-soluble calixarene derivative, p-sulfonic acid calix[4]arene (SCX4), which is promising as drug carrier. The cancer membrane models comprised either 40% 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 30% cholesterol (Chol), 20% 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and 10% 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS). The healthy membrane models were composed of 60% DPPC or DOPC, 30% Chol, and 10% DPPE. SCX4 expanded the surface pressure isotherms and decreased compressional moduli in all membrane models, altering their morphologies as seen in Brewster angle microscopy images. A combination of polarization-modulated infrared reflection absorption spectroscopy and molecular dynamics simulations revealed that SCX4 interacts preferentially with lipid headgroups in cancer membrane models through electrostatic interactions with the amine groups of DPPS and DPPE. In healthy membrane models, SCX4 interacts mostly with cholesterol through van der Waals forces. Using a multidimensional projection technique to compare data from the distinct membrane models, we observed that SCX4 effects depend on membrane composition with no preference for cancer or healthy membrane models, which is consistent with its biocompatibility. Furthermore, the interactions and close location of SCX4 to the headgroups indicate that it does not compromise membrane integrity, confirming that SCX4 may be a suitable drug carrier.

DOI: https://doi.org/10.1021/acs.langmuir.4c03948
Physiol Rev. 2024 Dec 11.

Ferroptosis: when metabolism meets cell death.

Jiashuo Zheng 郑嘉烁, Marcus Conrad.

  We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and pro-ferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

Keywords:  cancer therapy; cell metabolism; ferroptosis; pathology; physiology

DOI:  https://doi.org/10.1152/physrev.00031.2024
Cell. 2024 Dec 07. pii: S0092-8674(24)01326-6. [Epub ahead of print]

A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.

Wenbin Mei, Schayan Faraj Tabrizi, Christopher Godina, Anthea F Lovisa, Karolin Isaksson, Helena Jernström, Sohail F Tavazoie.

  Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis.

Keywords:  LRP1; PCSK9; USP18; XAF1; breast cancer; genetic; knockin; metastasis; prognostic; therapy

DOI:  https://doi.org/10.1016/j.cell.2024.11.009
J Gastroenterol. 2024 Dec 12.

An integrative multi-omics analysis reveals a multi-analyte signature of pancreatic ductal adenocarcinoma in serum.

Rex Devasahayam Arokia Balaya, Partho Sen, Caroline W Grant, Roman Zenka, Marimuthu Sappani, Jeyaseelan Lakshmanan, Arjun P Athreya, Richard K Kandasamy, Akhilesh Pandey, Seul Kee Byeon.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a formidable health challenge due to its detection at a late stage and a lack of reliable biomarkers for early detection. Although levels of carbohydrate antigen 19-9 are often used in conjunction with imaging-based tests to aid in the diagnosis of PDAC, there is still a need for more sensitive and specific biomarkers for early detection of PDAC.
METHODS: We obtained serum samples from 88 subjects (patients with PDAC (n = 58) and controls (n = 30)). We carried out a multi-omics analysis to measure cytokines and related proteins using proximity extension technology and lipidomics and metabolomics using tandem mass spectrometry. Statistical analysis was carried out to find molecular alterations in patients with PDAC and a machine learning model was used to derive a molecular signature of PDAC.
RESULTS: We quantified 1,462 circulatory proteins along with 873 lipids and 1,001 metabolites. A total of 505 proteins, 186 metabolites and 33 lipids including bone marrow stromal antigen 2 (BST2), keratin 18 (KRT18), and cholesteryl ester(20:5) were found to be significantly altered in patients. We identified different levels of sphingosine, sphinganine, urobilinogen and lactose indicating that glycosphingolipid and galactose metabolisms were significantly altered in patients compared to controls. In addition, elevated levels of diacylglycerols and decreased cholesteryl esters were observed in patients. Using a machine learning model, we identified a signature of 38 biomarkers for PDAC, composed of 21 proteins, 4 lipids, and 13 metabolites.
CONCLUSIONS: Overall, this study identified several proteins, metabolites and lipids involved in various pathways including cholesterol and lipid metabolism to be changing in patients. In addition, we discovered a multi-analyte signature that could be further tested for detection of PDAC.

Keywords:  Biomarkers; Multi-omics analysis; Pancreatic cancer; Pathogenesis; Serum

DOI:  https://doi.org/10.1007/s00535-024-02197-6
Nature. 2024 Dec;636(8042): 361-367

Sacrificial capillary pumps to engineer multiscalar biological forms.

Subramanian Sundaram, Joshua H Lee, Isabel M Bjørge, Christos Michas, Sudong Kim, Alex Lammers, João F Mano, Jeroen Eyckmans, Alice E White, Christopher S Chen.

Natural tissues are composed of diverse cells and extracellular materials whose arrangements across several length scales-from subcellular lengths1 (micrometre) to the organ scale2 (centimetre)-regulate biological functions. Tissue-fabrication methods have progressed to large constructs, for example, through stereolithography3 and nozzle-based bioprinting4,5, and subcellular resolution through subtractive photoablation6-8. However, additive bioprinting struggles with sub-nozzle/voxel features9 and photoablation is restricted to small volumes by prohibitive heat generation and time10. Building across several length scales with temperature-sensitive, water-based soft biological matter has emerged as a critical challenge, leaving large classes of biological motifs-such as multiscalar vascular trees with varying calibres-inaccessible with present technologies11,12. Here we use gallium-based engineered sacrificial capillary pumps for evacuation (ESCAPE) during moulding to generate multiscalar structures in soft natural hydrogels, achieving both cellular-scale (<10 µm) and millimetre-scale features. Decoupling the biomaterial of interest from the process of constructing the geometry allows non-biocompatible tools to create the initial geometry. As an exemplar, we fabricated branched, cell-laden vascular trees in collagen, spanning approximately 300-µm arterioles down to the microvasculature (roughly ten times smaller). The same approach can micropattern the inner surface of vascular walls with topographical cues to orient cells in 3D and engineer fine structures such as vascular malformations. ESCAPE moulding enables the fabrication of multiscalar forms in soft biomaterials, paving the way for a wide range of tissue architectures that were previously inaccessible in vitro.

DOI: https://doi.org/10.1038/s41586-024-08175-5