bims-cagime 2024-09-01 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2024–09–01
23 papers selected by
Kıvanç Görgülü, Technical University of Munich

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.
The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
Tumour Microenvironment-Like Conditions Alter Pancreatic Cancer Cell Metabolism and Behaviour.
A nutrigeroscience approach: Dietary macronutrients and cellular senescence.
Cellular Energy Cycle Mediates an Advection-Like Forward Cell Flow to Support Collective Invasion.
Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate.
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer.
ImmunoCellCycle-ID: A high-precision immunofluorescence-based method for cell cycle identification.
Histone chaperone HIRA, promyelocytic leukemia protein, and p62/SQSTM1 coordinate to regulate inflammation during cell senescence.
19Fluorine-MRI Based Longitudinal Immuno-Microenvironment-Monitoring for Pancreatic Cancer.
METI: deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics.
Mitochondrial membrane lipids in the regulation of bioenergetic flux.
Immunometabolism of ferroptosis in the tumor microenvironment.
Senescent cells inhibit mouse myoblast differentiation via the SASP-lipid 15d-PGJ2 mediated modification and control of HRas.
What tool or method do you wish existed?
Function of CSNK2/CK2 selectively affects the endoplasmic reticulum and the Golgi apparatus in mtor-mediated autophagy induction.
Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.
Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration.
Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.
An RNAi screen for ribosome biogenesis genes required for Drosophila border cell collective migration.
Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat.
Influence of Simvastatin and Pravastatin on the Biophysical Properties of Model Lipid Bilayers and Plasma Membranes of Live Cells.

Dev Cell. 2024 Aug 22. pii: S1534-5807(24)00483-0. [Epub ahead of print]

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.

Alina L Li, Kensuke Sugiura, Noriyuki Nishiwaki, Kensuke Suzuki, Dorsay Sadeghian, Jun Zhao, Anirban Maitra, David Falvo, Rohit Chandwani, Jason R Pitarresi, Peter A Sims, Anil K Rustgi.

  Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.

Keywords:  FRA1; G-CSF; KRAS; PanIN; acinar-ductal metaplasia; pancreatic ductal adenocarcinoma; pancreatitis

DOI:  https://doi.org/10.1016/j.devcel.2024.07.021
Nat Metab. 2024 Aug;6(8): 1529-1548

The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.

Yijian Qiu, Olivia T Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S H Costa, Sara Violante, David L Spector, Justin R Cross, Michael J Lukey.

Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism.

DOI: https://doi.org/10.1038/s42255-024-01104-w
Am J Physiol Cell Physiol. 2024 Aug 26.

Tumour Microenvironment-Like Conditions Alter Pancreatic Cancer Cell Metabolism and Behaviour.

Georgina Louise Gardner, Jeffrey Alan Stuart.

  The tumour microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumours. Recently, 'physiological' cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1-8% O2). Nonetheless, further refinement of tumour-specific culture conditions may be needed. In this study, we describe the development of a Tumour Microenvironment Medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumour interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumour-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared to plasma-like conditions (Mouse Plasma Medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumour-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5%O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5%O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumour microenvironment-like conditions in standard cancer research.

Keywords:  Cell Culture; Metabolism; Oxygen; Physiological Media; Tumour Mircoenvironment

DOI:  https://doi.org/10.1152/ajpcell.00452.2024
Cell Metab. 2024 Aug 15. pii: S1550-4131(24)00327-9. [Epub ahead of print]

A nutrigeroscience approach: Dietary macronutrients and cellular senescence.

Mariah F Calubag, Paul D Robbins, Dudley W Lamming.

  Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.

Keywords:  branched-chain amino acids; cellular senescence; healthspan; macronutrients; nutrigeroscience; protein; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.cmet.2024.07.025
Adv Sci (Weinh). 2024 Aug;11(32): e2400719

Cellular Energy Cycle Mediates an Advection-Like Forward Cell Flow to Support Collective Invasion.

Jian Zhang, Jenna A Mosier, Yusheng Wu, Logan Waddle, Paul V Taufalele, Wenjun Wang, Heng Sun, Cynthia A Reinhart-King.

  Collective cell migration is a model for nonequilibrium biological dynamics, which is important for morphogenesis, pattern formation, and cancer metastasis. The current understanding of cellular collective dynamics is based primarily on cells moving within a 2D epithelial monolayer. However, solid tumors often invade surrounding tissues in the form of a stream-like 3D structure, and how biophysical cues are integrated at the cellular level to give rise to this collective streaming remains unclear. Here, it is shown that cell cycle-mediated bioenergetics drive a forward advective flow of cells and energy to the front to support 3D collective invasion. The cell division cycle mediates a corresponding energy cycle such that cellular adenosine triphosphate (ATP) energy peaks just before division. A reaction-advection-diffusion (RAD) type model coupled with experimental measurements further indicates that most cells enter an active division cycle at rear positions during 3D streaming. Once the cells progress to a later stage toward division, the high intracellular energy allows them to preferentially stream toward the tip and become leader cells. This energy-driven cellular flow may be a fundamental characteristic of 3D collective dynamics based on thermodynamic principles important for not only cancer invasion but also tissue morphogenesis.

Keywords:  bioenergetics; cancer metabolism; cell cycle; collective migration; go or grow; thermodynamics; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202400719
bioRxiv. 2024 Aug 17. pii: 2024.08.14.607813. [Epub ahead of print]

Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate.

Jesse S Handler, Zijie Li, Rachel K Dveirin, Weixiang Fang, Hani Goodarzi, Elana J Fertig, Reza Kalhor.

Identifying the key molecular pathways that enable metastasis by analyzing the eventual metastatic tumor is challenging because the state of the founder subclone likely changes following metastatic colonization. To address this challenge, we labeled primary mouse pancreatic ductal adenocarcinoma (PDAC) subclones with DNA barcodes to characterize their pre-metastatic state using ATAC-seq and RNA-seq and determine their relative in vivo metastatic potential prospectively. We identified a gene signature separating metastasis-high and metastasis-low subclones orthogonal to the normal-to-PDAC and classical-to-basal axes. The metastasis-high subclones feature activation of IL-1 pathway genes and high NF-κB and Zeb/Snail family activity and the metastasis-low subclones feature activation of neuroendocrine, motility, and Wnt pathway genes and high CDX2 and HOXA13 activity. In a functional screen, we validated novel mediators of PDAC metastasis in the IL-1 pathway, including the NF-κB targets Fos and Il23a, and beyond the IL-1 pathway including Myo1b and Tmem40. We scored human PDAC tumors for our signature of metastatic potential from mouse and found that metastases have higher scores than primary tumors. Moreover, primary tumors with higher scores are associated with worse prognosis. We also found that our metastatic potential signature is enriched in other human carcinomas, suggesting that it is conserved across epithelial malignancies. This work establishes a strategy for linking cancer cell state to future behavior, reveals novel functional regulators of PDAC metastasis, and establishes a method for scoring human carcinomas based on metastatic potential.

DOI: https://doi.org/10.1101/2024.08.14.607813
Nat Commun. 2024 Aug 27. 15(1): 7378

Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.

Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.

The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.

DOI: https://doi.org/10.1038/s41467-024-51363-0
Sci Transl Med. 2024 Aug 28. 16(762): eadj9366

Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer.

Loretah Chibaya, Kelly D DeMarco, Christina F Lusi, Griffin I Kane, Meghan L Brassil, Chaitanya N Parikh, Katherine C Murphy, Shreya R Chowdhury, Junhui Li, Boyang Ma, Tiana E Naylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R Pitarresi, Lihua Julie Zhu, Katherine A Fitzgerald, Prabhani U Atukorale, Marcus Ruscetti.

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and type I interferon-mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon-driven innate and adaptive immune response with durable antitumor efficacy against PDAC.

DOI: https://doi.org/10.1126/scitranslmed.adj9366
bioRxiv. 2024 Aug 15. pii: 2024.08.14.607961. [Epub ahead of print]

ImmunoCellCycle-ID: A high-precision immunofluorescence-based method for cell cycle identification.

Yu-Lin Chen, Yu-Chia Chen, Aussie Suzuki.

The cell cycle is a fundamental process essential for cell proliferation, differentiation, and development. It consists of four major phases: G1, S, G2, and M. These phases collectively drive the reproductive cycle and are meticulously regulated by various proteins that play critical roles in both the prevention and progression of cancer. Traditional methods for studying these functions, such as flow cytometry, require a substantial number of cells to ensure accuracy. In this study, we have developed a user-friendly, immunofluorescence-based method for identifying cell cycle stages, providing single-cell resolution and precise identification of G1, early S, late S, early G2, late G2, and each sub-stage of the M phase using fluorescence microscopy. This method provides high-precision cell cycle identification and can serve as an alternative to, or in combination with, traditional flow cytometry to dissect detailed substages of the cell cycle in a variety of cell lines.

DOI: https://doi.org/10.1101/2024.08.14.607961
Mol Cell. 2024 Aug 16. pii: S1097-2765(24)00660-9. [Epub ahead of print]

Histone chaperone HIRA, promyelocytic leukemia protein, and p62/SQSTM1 coordinate to regulate inflammation during cell senescence.

Nirmalya Dasgupta, Xue Lei, Christina Huan Shi, Rouven Arnold, Marcos G Teneche, Karl N Miller, Adarsh Rajesh, Andrew Davis, Valesca Anschau, Alexandre R Campos, Rebecca Gilson, Aaron Havas, Shanshan Yin, Zong Ming Chua, Tianhui Liu, Jessica Proulx, Michael Alcaraz, Mohammed Iqbal Rather, Josue Baeza, David C Schultz, Kevin Y Yip, Shelley L Berger, Peter D Adams.

  Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory senescence-associated secretory phenotype (SASP), is a cause of aging. In senescent cells, cytoplasmic chromatin fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. Promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRA's localization to PML NBs. Inactivation of HIRA does not directly block expression of nuclear factor κB (NF-κB) target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-κB pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in the regulation of SASP.

Keywords:  CCF; HIRA; NF-κB pathway; PML; PML NBs; SASP; cGAS-STING signaling; p62/SQSTM; senescence

DOI:  https://doi.org/10.1016/j.molcel.2024.08.006
J Magn Reson Imaging. 2024 Aug 27.

19Fluorine-MRI Based Longitudinal Immuno-Microenvironment-Monitoring for Pancreatic Cancer.

Wilfried Reichardt, Tabea Gewalt, Philipp Hafner, Steffen J Keller, Xun Chen, Asma Alrawashdeh, Yayu Li, Solène Besson, Stefan Fichtner-Feigl, Dominik von Elverfeldt, Huda Jumaa, Dietrich A Ruess.

   BACKGROUND: Pancreatic cancer has a poor prognosis. Targeting Kirsten Rat Sarcoma (KRAS) mutation and its related pathways may enhance immunotherapy efficacy. While in vivo monitoring of therapeutic response and immune cell migration remains challenging, Fluorine-19 MRI (19F MRI) may allow noninvasive longitudinal imaging of immune cells.
PURPOSE: Evaluating the potential of 19F MRI for monitoring changes in the tumor immune microenvironment, in response to combined SHP2/MEK inhibition.
STUDY TYPE: Pre-clinical animal study.
ANIMAL MODEL: Murine genetically engineered pancreatic cancer model (N = 20, both sexes).
FIELD STRENGTH/SEQUENCE: 9.4-T, two-dimensional multi-slice Rapid Acquisition with Relaxation Enhancement sequence. Intravenous injection of 19F-perfluorocarbon (PFC) nanoparticles.
ASSESSMENT: Upon tumor detection by conventional 1H MRI screening, 19F MRI was performed in mice 24 hours after PFC nanoparticle administration. Animals were randomly assigned to four treatment groups: allosteric Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor SHP099, the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor Trametinib, the combination of both, or a vehicle control (4 to 6 mice each group), administered every other day per oral gavage. 1H and 19F MRI was repeated 7 days and 14 days later. Pancreatic immune cell infiltrates were analyzed by flow cytometry and multiplex immunohistofluorescence (mIHF) upon sacrifice.
STATISTICAL TESTS: Independent t-tests and one-way analysis of variance.
RESULTS: 19F MRI revealed continuous decrease of PFC-signals in tumors from vehicle controls (100%, 80%, and 74% on days 0, 7, and 14, respectively), contrasting with stable or increasing signals under KRAS-pathway-directed treatment. MEK inhibition showed 100%, 152%, and 84% and dual SHP2/MEK1/2 inhibition demonstrated signals of 100%, 134%, and 100% on days 0, 7, 14, respectively. mIHF analyses indicated CD11b+ macrophages/monocytes as primary contributors to the observed 19F MRI signal differences.
DATA CONCLUSION: 19F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b+ macrophages/monocytes in pancreatic cancer.
EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Keywords:  19Fluorine‐MRI; KRAS; immuno‐microenvironment‐monitoring; pancreatic cancer

DOI:  https://doi.org/10.1002/jmri.29589
Nat Commun. 2024 Aug 25. 15(1): 7312

METI: deep profiling of tumor ecosystems by integrating cell morphology and spatial transcriptomics.

Jiahui Jiang, Yunhe Liu, Jiangjiang Qin, Jianfeng Chen, Jingjing Wu, Melissa P Pizzi, Rossana Lazcano, Kohei Yamashita, Zhiyuan Xu, Guangsheng Pei, Kyung Serk Cho, Yanshuo Chu, Ansam Sinjab, Fuduan Peng, Xinmiao Yan, Guangchun Han, Ruiping Wang, Enyu Dai, Yibo Dai, Bogdan A Czerniak, Andrew Futreal, Anirban Maitra, Alexander Lazar, Humam Kadara, Amir A Jazaeri, Xiangdong Cheng, Jaffer Ajani, Jianjun Gao, Jian Hu, Linghua Wang.

Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI's robust and consistent performance.

DOI: https://doi.org/10.1038/s41467-024-51708-9
Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]

Mitochondrial membrane lipids in the regulation of bioenergetic flux.

Stephen Thomas Decker, Katsuhiko Funai.

  Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.

Keywords:  bioenergetics; mitochondria; phospholipids

DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
Front Oncol. 2024 ;14 1441338

Immunometabolism of ferroptosis in the tumor microenvironment.

Gian Luca Lupica-Tondo, Emily N Arner, Denis A Mogilenko, Kelsey Voss.

  Ferroptosis is an iron-dependent form of cell death that results from excess lipid peroxidation in cellular membranes. Within the last decade, physiological and pathological roles for ferroptosis have been uncovered in autoimmune diseases, inflammatory conditions, infection, and cancer biology. Excitingly, cancer cell metabolism may be targeted to induce death by ferroptosis in cancers that are resistant to other forms of cell death. Ferroptosis sensitivity is regulated by oxidative stress, lipid metabolism, and iron metabolism, which are all influenced by the tumor microenvironment (TME). Whereas some cancer cell types have been shown to adapt to these stressors, it is not clear how immune cells regulate their sensitivities to ferroptosis. In this review, we discuss the mechanisms of ferroptosis sensitivity in different immune cell subsets, how ferroptosis influences which immune cells infiltrate the TME, and how these interactions can determine epithelial-to-mesenchymal transition (EMT) and metastasis. While much focus has been placed on inducing ferroptosis in cancer cells, these are important considerations for how ferroptosis-modulating strategies impact anti-tumor immunity. From this perspective, we also discuss some promising immunotherapies in the field of ferroptosis and the challenges associated with targeting ferroptosis in specific immune cell populations.

Keywords:  TME; ferroptosis; immunometabolism; iron; metastasis

DOI:  https://doi.org/10.3389/fonc.2024.1441338
Elife. 2024 Aug 28. pii: RP95229. [Epub ahead of print]13

Senescent cells inhibit mouse myoblast differentiation via the SASP-lipid 15d-PGJ2 mediated modification and control of HRas.

Swarang Sachin Pundlik, Alok Barik, Ashwin Venkateshvaran, Snehasudha Subhadarshini Sahoo, Mahapatra Anshuman Jaysingh, Raviswamy G H Math, Heera Lal, Maroof Athar Hashmi, Arvind Ramanathan.

  Senescent cells are characterized by multiple features such as increased expression of senescence-associated β-galactosidase activity (SA β-gal) and cell cycle inhibitors such as p21 or p16. They accumulate with tissue damage and dysregulate tissue homeostasis. In the context of skeletal muscle, it is known that agents used for chemotherapy such as Doxorubicin (Doxo) cause buildup of senescent cells, leading to the inhibition of tissue regeneration. Senescent cells influence the neighboring cells via numerous secreted factors which form the senescence-associated secreted phenotype (SASP). Lipids are emerging as a key component of SASP that can control tissue homeostasis. Arachidonic acid-derived lipids have been shown to accumulate within senescent cells, specifically 15d-PGJ2, which is an electrophilic lipid produced by the non-enzymatic dehydration of the prostaglandin PGD2. This study shows that 15d-PGJ2 is also released by Doxo-induced senescent cells as an SASP factor. Treatment of skeletal muscle myoblasts with the conditioned medium from these senescent cells inhibits myoblast fusion during differentiation. Inhibition of L-PTGDS, the enzyme that synthesizes PGD2, diminishes the release of 15d-PGJ2 by senescent cells and restores muscle differentiation. We further show that this lipid post-translationally modifies Cys184 of HRas in C2C12 mouse skeletal myoblasts, causing a reduction in the localization of HRas to the Golgi, increased HRas binding to Ras Binding Domain (RBD) of RAF Kinase (RAF-RBD), and activation of cellular Mitogen Activated Protein (MAP) kinase-Extracellular Signal Regulated Kinase (Erk) signaling (but not the Akt signaling). Mutating C184 of HRas prevents the ability of 15d-PGJ2 to inhibit the differentiation of muscle cells and control the activity of HRas. This work shows that 15d-PGJ2 released from senescent cells could be targeted to restore muscle homeostasis after chemotherapy.

Keywords:  HRas; SASP; biochemistry; chemical biology; mouse; muscle differentiation; oxylipins; senescence

DOI:  https://doi.org/10.7554/eLife.95229
Cell. 2024 Aug 22. pii: S0092-8674(24)00837-7. [Epub ahead of print]187(17): 4433-4438

What tool or method do you wish existed?

Yvonne Y Chen, Charles L Evavold, Matthias Mann, Emily R Davenport, Margaret McFall-Ngai, Magda Bienko, Hiroki R Ueda, Lin Tian, Nikki Tjahjono, Polina Anikeeva, Jun-Jie Gogo Liu, Tara L Deans, Xiaohua Shen.

We asked researchers from a range of disciplines across biology, engineering, and medicine to describe a current technological need. The goal is to provide a sample of the various technological gaps that exist and inspire future research projects.

DOI: https://doi.org/10.1016/j.cell.2024.07.043
Autophagy. 2024 Aug 23.

Function of CSNK2/CK2 selectively affects the endoplasmic reticulum and the Golgi apparatus in mtor-mediated autophagy induction.

Pablo Sanz-Martinez, Rayene Berkane, Alexandra Stolz.

  Selective macroautophagy/autophagy of the endoplasmic reticulum, known as reticulophagy/ER-phagy, is essential to maintain ER homeostasis. We recently showed that members of the autophagy receptor family RETREG/FAM134 are regulated by phosphorylation-dependent ubiquitination. In an unbiased screen we had identified several kinases downstream of MTOR with profound impact on reticulophagy flux, including ATR and CSNK2/CK2. Inhibition of CSNK2 by SGC-CK2-1 prevented regulatory ubiquitination of RETREG1/FAM134B and RETREG3/FAM134C upon autophagy activation as well as the formation of high-density RETREG1- and RETREG3-clusters. Here we report on additional resource data of global proteomics upon CSNK2 and ATR inhibition, respectively. Our data suggests that the function of CSNK2 is mainly limited to the ER/reticulophagy and Golgi/Golgiphagy, while ATR inhibition by VE-822 affects the vast majority of organelles/selective autophagy pathways.

Keywords:  Kinase signaling; LAMP1; RETREG; methuosis; selective autophagy; vacuolization

DOI:  https://doi.org/10.1080/15548627.2024.2395725
J Cell Biol. 2024 Nov 04. pii: e202308099. [Epub ahead of print]223(11):

Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.

Yewei Huang, Gan Luo, Kesong Peng, Yue Song, Yusha Wang, Hongtao Zhang, Jin Li, Xiangmin Qiu, Maomao Pu, Xinchang Liu, Chao Peng, Dante Neculai, Qiming Sun, Tianhua Zhou, Pintong Huang, Wei Liu.

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.

DOI: https://doi.org/10.1083/jcb.202308099
Cell. 2024 Aug 19. pii: S0092-8674(24)00835-3. [Epub ahead of print]

Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration.

Daniel R Hochbaum, Lauren Hulshof, Amanda Urke, Wengang Wang, Alexandra C Dubinsky, Hannah C Farnsworth, Richard Hakim, Sherry Lin, Giona Kleinberg, Keiramarie Robertson, Canaria Park, Alyssa Solberg, Yechan Yang, Caroline Baynard, Naeem M Nadaf, Celia C Beron, Allison E Girasole, Lynne Chantranupong, Marissa D Cortopassi, Shannon Prouty, Ludwig Geistlinger, Alexander S Banks, Thomas S Scanlan, Sandeep Robert Datta, Michael E Greenberg, Gabriella L Boulting, Evan Z Macosko, Bernardo L Sabatini.

  Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.

Keywords:  body-brain coordination; exploration; metabolism; neuroscience; synaptic plasticity; thyroid hormone; transcriptionally regulated behavior

DOI:  https://doi.org/10.1016/j.cell.2024.07.041
Oncologist. 2024 Aug 26. pii: oyae210. [Epub ahead of print]

Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.

Erkut H Borazanci, Nathan Bahary, Vincent Chung, Timothy K Huyck, Ebenezer A Kio, Elena Gabriela Chiorean, Roland T Skeel, Olatunji B Alese, Dana B Cardin, Christos Fountzilas, Wahid T Hanna, Alexis D Leal, Valerie Lee, Anne M Noonan, Philip A Philip, Zev A Wainberg, Hristina Pashova, Grace Mann, Paul E Oberstein.

   BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines.
PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed.
RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest.
CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

Keywords:  PDAC; metastatic pancreatic cancer; nab-paclitaxel; relacorilant

DOI:  https://doi.org/10.1093/oncolo/oyae210
MicroPubl Biol. 2024 ;2024

An RNAi screen for ribosome biogenesis genes required for Drosophila border cell collective migration.

Emily Burghardt, Jocelyn A McDonald.

Ribosome biogenesis is critical for the proper production of proteins in cells and has emerged as a regulator of cell invasion and migration in development and in cancer. The Drosophila border cells form a collective that invades and migrates through the surrounding tissue during oogenesis. We previously found that a significant number of ribosome biogenesis genes are differentially expressed from early to late migration stages. Here, we performed a small-scale RNAi screen of a subset of these ribosome genes. Knockdown of seven genes disrupted border cell migration, thus revealing a role for ribosome biogenesis genes in regulating collective cell migration.

DOI: https://doi.org/10.17912/micropub.biology.001292
Nature. 2024 Aug 28.

Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat.

Yitao Zhu, Lu Yao, Ana L Gallo-Ferraz, Bruna Bombassaro, Marcela R Simões, Ichitaro Abe, Jing Chen, Gitalee Sarker, Alessandro Ciccarelli, Linna Zhou, Carl Lee, Davi Sidarta-Oliveira, Noelia Martínez-Sánchez, Michael L Dustin, Cheng Zhan, Tamas L Horvath, Licio A Velloso, Shingo Kajimura, Ana I Domingos.

Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns1. Here we uncover the mechanism by which NPY in sympathetic neurons2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY+ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT4-6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.

DOI: https://doi.org/10.1038/s41586-024-07863-6
ACS Biomater Sci Eng. 2024 Aug 24.

Influence of Simvastatin and Pravastatin on the Biophysical Properties of Model Lipid Bilayers and Plasma Membranes of Live Cells.

Artu Ras Polita, Ru Ta Bagdonaitė, Arun Prabha Shivabalan, Gintaras Valinčius.

  Statins are among the most widely used drugs for the inhibition of cholesterol biosynthesis, prevention of cardiovascular diseases, and treatment of hypercholesterolemia. Additionally, statins also exhibit cholesterol-independent benefits in various diseases, including neuroprotective properties in Alzheimer's disease, anti-inflammatory effects in coronary artery disease, and antiproliferative activities in cancer, which likely result from the statins' interaction and alteration of lipid bilayers. However, the membrane-modulatory effects of statins and the mechanisms by which statins alter lipid bilayers remain poorly understood. In this work, we explore the membrane-modulating effects of statins on model lipid bilayers and live cells. Through the use of fluorescence lifetime imaging microscopy (FLIM) combined with viscosity-sensitive environmental probes, we demonstrate that hydrophobic, but not hydrophilic, statins are capable of changing the microviscosity and lipid order in model and live cell membranes. Furthermore, we show that hydrophobic simvastatin is capable of forming nanoscale cholesterol-rich domains and homogenizing the cholesterol concentrations in lipid bilayers. Our results provide a mechanistic framework for understanding the bimodal effects of simvastatin on the lipid order and the lateral organization of cholesterol in lipid bilayers. Finally, we demonstrate that simvastatin temporarily decreases the microviscosity of live cell plasma membranes, making them more permeable and increasing the level of intracellular chemotherapeutic drug accumulation.

Keywords:  BODIPY; FLIM; lipid order; model lipid bilayers; pravastatin; simvastatin; viscosity

DOI:  https://doi.org/10.1021/acsbiomaterials.4c00911