bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–01–22
24 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Fasting and fasting mimicking diets in cancer prevention and therapy.
  2. Analysis of Energy-Driven Leader-Follower Hierarchy During Collective Cancer Cell Invasion.
  3. Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation.
  4. Bodywide ecological interventions on cancer.
  5. Acetyl-CoA metabolism in cancer.
  6. Oncologic Resection of Pancreatic Cancer with Isolated Liver Metastasis: Favorable Outcomes in Select Patients.
  7. Invadopodia Methods: Detection of Invadopodia Formation and Activity in Cancer Cells Using Reconstituted 2D and 3D Collagen-Based Matrices.
  8. Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma.
  9. Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.
  10. Robustness and Universality in Organelle Size Control.
  11. Genome-scale CRISPR screening in a single mouse liver.
  12. Analysis of Collective Migration Patterns Within Tumors.
  13. Approaches to Determine Nuclear Shape in Cells During Migration Through Collagen Matrices.
  14. Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
  15. Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer.
  16. Membrane reshaping by protein condensates.
  17. The excitable fluid mosaic.
  18. Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis.
  19. A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407).
  20. Role of epigenetics in pancreatic ductal adenocarcinoma.
  21. EMP1+ tumor cells drive metastatic relapse.
  22. Coordinated cancer chaos.
  23. Proteogenomic analysis of human pancreatic ductal adenocarcinoma.
  24. Profiling the Mammalian Lipidome by Quantitative Shotgun Lipidomics.
  1. Trends Cancer. 2023 Jan 14. pii: S2405-8033(22)00268-0. [Epub ahead of print]
    Fasting and fasting mimicking diets in cancer prevention and therapy.
    Olga Blaževitš, Maira Di Tano, Valter D Longo.
      Fasting mimicking diets (FMDs) are emerging as effective dietary interventions with the potential to improve healthspan and decrease the incidence of cancer and other age-related diseases. Unlike chronic dietary restrictions or water-only fasting, FMDs represent safer and less challenging options for cancer patients. FMD cycles increase protection in healthy cells while sensitizing cancer cells to various therapies, partly by generating complex environments that promote differential stress resistance (DSR) and differential stress sensitization (DSS), respectively. More recent data indicate that FMD cycles enhance the efficacy of a range of drugs targeting different cancers in mice by stimulating antitumor immunity. Here, we report on the effects of FMD cycles on cancer prevention and treatment and the mechanisms implicated in these effects.
    Keywords:  cancer treatment; differential stress resistance (DSR); differential stress sensitization (DSS); fasting mimicking diet
    DOI:  https://doi.org/10.1016/j.trecan.2022.12.006
  2. Methods Mol Biol. 2023 ;2608 247-262
    Analysis of Energy-Driven Leader-Follower Hierarchy During Collective Cancer Cell Invasion.
    Jian Zhang, Cynthia A Reinhart-King.
      Many solid tumors can invade the surrounding three-dimensional (3D) tissue in a collective manner, and increasing evidence suggests that collective migration makes cancer cell clusters more invasive and metastatic than individual cells. A cohesive cohort of cancer cells can have many advantages over individual cells, including more efficient bioenergetics that have been recently identified. Minimization of bioenergetic costs during collective cell migration drives leader-follower dynamics and contributes to enhanced cancer invasion. Hence, it is critical to understand the migratory and bioenergetic dynamics of cancer collective invasion. While analysis of structures and dynamics in a 3D space has been a challenging task, here we describe a widely applicable method to analyze the energy-driven leader-follower hierarchy during cancer collective invasion. An in vitro tumor spheroid model is employed to reproduce the in vivo collective behaviors of cancer cells while allowing high spatiotemporal resolution imaging, where the leader-follower dynamics can be analyzed by tracking nuclear positions. As glucose is one of the main energy sources that fuel cancer cell migration, the quantification of glucose uptake along the invading strands provides an estimate of the energy demand associated with collective invasion. Finally, we describe a method to quantify the dynamics of intracellular energy level using the PercevalHR ATP:ADP ratio biosensor.
    Keywords:  3D migration; Bioenergetics; Cancer invasion; Collective migration; Energy metabolism; Glucose uptake; Leader cell; Tumor spheroid
    DOI:  https://doi.org/10.1007/978-1-0716-2887-4_15
  3. Nat Cell Biol. 2023 Jan 16.
    Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation.
    Chengsheng Wu, Taha Rakhshandehroo, Hiromi I Wettersten, Alejandro Campos, Tami von Schalscha, Shashi Jain, Ziqi Yu, Jiali Tan, Evangeline Mose, Betzaira G Childers, Andrew M Lowy, Sara M Weis, David A Cheresh.
      Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5β1 or αVβ3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.
    DOI:  https://doi.org/10.1038/s41556-022-01055-y
  4. Nat Med. 2023 Jan 19.
    Bodywide ecological interventions on cancer.
    Guido Kroemer, Jennifer L McQuade, Miriam Merad, Fabrice André, Laurence Zitvogel.
      Historically, cancer research and therapy have focused on malignant cells and their tumor microenvironment. However, the vascular, lymphatic and nervous systems establish long-range communication between the tumor and the host. This communication is mediated by metabolites generated by the host or the gut microbiota, as well by systemic neuroendocrine, pro-inflammatory and immune circuitries-all of which dictate the trajectory of malignant disease through molecularly defined biological mechanisms. Moreover, aging, co-morbidities and co-medications have a major impact on the development, progression and therapeutic response of patients with cancer. In this Perspective, we advocate for a whole-body 'ecological' exploration of malignant disease. We surmise that accumulating knowledge on the intricate relationship between the host and the tumor will shape rational strategies for systemic, bodywide interventions that will eventually improve tumor control, as well as quality of life, in patients with cancer.
    DOI:  https://doi.org/10.1038/s41591-022-02193-4
  5. Nat Rev Cancer. 2023 Jan 19.
    Acetyl-CoA metabolism in cancer.
    David A Guertin, Kathryn E Wellen.
      Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.
    DOI:  https://doi.org/10.1038/s41568-022-00543-5
  6. J Hepatobiliary Pancreat Sci. 2023 Jan 18.
    Oncologic Resection of Pancreatic Cancer with Isolated Liver Metastasis: Favorable Outcomes in Select Patients.
    Minako Nagai, Michael J Wright, Ding Ding, Elizabeth D Thompson, Ammar A Javed, Matthew J Weiss, Ralph H Hruban, Jun Yu, Richard A Burkhart, Jin He, John L Cameron, Christopher L Wolfgang, William R Burns.
       BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery.
    METHODS: Using an institutional database, PDAC patients undergoing liver resection for isolated metastasis were identified. Their overall survival (OS), treatment factors and clinicopathological variables associated with survival were also evaluated.
    RESULTS: Forty-seven patients underwent curative-intent surgery for metastatic PDAC to the liver between 2000-2019. Median OS was 21.9 months from diagnosis. Fourteen patients underwent unplanned resection of radiographically-occult liver metastasis during pancreatectomy with median OS of 8.7 months. On the other hand, 29 patients received systemic chemotherapy followed by planned resection; this cohort had the most favorable prognosis following aggressive surgery with median OS was 38.1 months from diagnosis and 24.1 months from surgery. Preoperative chemotherapy (HR=7.1; P=.002) and moderate-/well-differentiation of the primary tumor (HR=3.7; P=.003) were associated with prolonged survival in multivariate analysis, whereas lymph node metastases, response to preoperative therapy, number of liver metastasis, and extent of liver surgery were not.
    CONCLUSIONS: In select patients with PDAC and isolated liver metastasis, curative-intent surgery can result in meaningful survival. This aggressive approach seems most beneficial in patients following induction chemotherapy.
    Keywords:  Oligometastatic pancreatic cancer; chemotherapy; isolated liver metastasis; resection
    DOI:  https://doi.org/10.1002/jhbp.1303
  7. Methods Mol Biol. 2023 ;2608 225-246
    Invadopodia Methods: Detection of Invadopodia Formation and Activity in Cancer Cells Using Reconstituted 2D and 3D Collagen-Based Matrices.
    David Remy, Anne-Sophie Macé, Philippe Chavrier, Pedro Monteiro.
      Tumor dissemination involves cancer cell migration through the extracellular matrix (ECM). ECM is mainly composed of collagen fibers that oppose cell invasion. To overcome hindrance in the matrix, cancer cells deploy a protease-dependent program in order to remodel the matrix fibers. Matrix remodeling requires the formation of actin-based matrix/plasma membrane contact sites called invadopodia, responsible for collagen cleavage through the accumulation and activity of the transmembrane type-I matrix metalloproteinase (MT1-MMP). In this article, we describe experimental procedures designed to assay for invadopodia formation and for invadopodia activity using 2D and 3D models based on gelatin (denatured collagen) and fibrillar type-I collagen matrices.
    Keywords:  Collagen; Confocal spinning disk microscopy; Gelatin; Indirect immunofluorescence; Invadopodia; Matrix degradation
    DOI:  https://doi.org/10.1007/978-1-0716-2887-4_14
  8. Nat Commun. 2023 Jan 18. 14(1): 292
    Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma.
    L Paige Ferguson, Jovylyn Gatchalian, Matthew L McDermott, Mari Nakamura, Kendall Chambers, Nirakar Rajbhandari, Nikki K Lytle, Sara Brin Rosenthal, Michael Hamilton, Sonia Albini, Martin Wartenberg, Inti Zlobec, José A Galván, Eva Karamitopoulou, Vera Vavinskaya, Alexis Wascher, Andrew M Lowy, Christian M Schürch, Pier Lorenzo Puri, Benoit G Bruneau, Diana C Hargreaves, Tannishtha Reya.
      Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.
    DOI:  https://doi.org/10.1038/s41467-023-35796-7
  9. Nat Cancer. 2023 Jan 16.
    Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.
    Jingya Qiu, Bihui Xu, Darwin Ye, Diqiu Ren, Shangshang Wang, Joseph L Benci, Yuanming Xu, Hemant Ishwaran, Jean-Christophe Beltra, E John Wherry, Junwei Shi, Andy J Minn.
      Prolonged interferon (IFN) signaling in cancer cells can promote resistance to immune checkpoint blockade (ICB). How cancer cells retain effects of prolonged IFN stimulation to coordinate resistance is unclear. We show that, across human and/or mouse tumors, immune dysfunction is associated with cancer cells acquiring epigenetic features of inflammatory memory. Here, inflammatory memory domains, many of which are initiated by chronic IFN-γ, are maintained by signal transducer and activator of transcription (STAT)1 and IFN regulatory factor (IRF)3 and link histone 3 lysine 4 monomethylation (H3K4me1)-marked chromatin accessibility to increased expression of a subset of IFN-stimulated genes (ISGs). These ISGs include the RNA sensor OAS1 that amplifies type I IFN (IFN-I) and immune inhibitory genes. Abrogating cancer cell IFN-I signaling restores anti-programmed cell death protein 1 (PD1) response by increasing IFN-γ in immune cells, promoting dendritic cell and CD8+ T cell interactions, and expanding T cells toward effector-like states rather than exhausted states. Thus, cancer cells acquire inflammatory memory to augment a subset of ISGs that promote and predict IFN-driven immune dysfunction.
    DOI:  https://doi.org/10.1038/s43018-022-00490-y
  10. Phys Rev Lett. 2023 Jan 06. 130(1): 018401
    Robustness and Universality in Organelle Size Control.
    Kiandokht Panjtan Amiri, Asa Kalish, Shankar Mukherji.
      One of the grand challenges in cellular biophysics is understanding the precision with which cells assemble and maintain subcellular structures. Organelle sizes, for example, must be flexible enough to allow cells to grow or shrink them as environments demand yet be maintained within homeostatic limits. Despite identification of molecular factors that regulate organelle sizes we lack insight into the quantitative principles underlying organelle size control. Here we show experimentally that cells can robustly control average fluctuations in organelle size. By demonstrating that organelle sizes obey a universal scaling relationship we predict theoretically, our framework suggests that organelles grow in random bursts from a limiting pool of building blocks. Burstlike growth provides a general biophysical mechanism by which cells can maintain on average reliable yet plastic organelle sizes.
    DOI:  https://doi.org/10.1103/PhysRevLett.130.018401
  11. Cell Genom. 2022 Dec 14. pii: 100217. [Epub ahead of print]2(12):
    Genome-scale CRISPR screening in a single mouse liver.
    Heather R Keys, Kristin A Knouse.
      A complete understanding of the genetic determinants underlying mammalian physiology and disease is limited by the capacity for high-throughput genetic dissection in the living organism. Genome-wide CRISPR screening is a powerful method for uncovering the genetic regulation of cellular processes, but the need to stably deliver single guide RNAs to millions of cells has largely restricted its implementation to ex vivo systems. There thus remains a need for accessible high-throughput functional genomics in vivo. Here, we establish genome-wide screening in the liver of a single mouse and use this approach to uncover regulation of hepatocyte fitness. We uncover pathways not identified in cell culture screens, underscoring the power of genetic dissection in the organism. The approach we developed is accessible, scalable, and adaptable to diverse phenotypes and applications. We have hereby established a foundation for high-throughput functional genomics in a living mammal, enabling comprehensive investigation of physiology and disease.
    DOI:  https://doi.org/10.1016/j.xgen.2022.100217
  12. Methods Mol Biol. 2023 ;2608 305-323
    Analysis of Collective Migration Patterns Within Tumors.
    Ralitza Staneva, Andrew G Clark.
      Metastasis is a hallmark of cancer and the leading cause of mortality among cancer patients. Cancer, in its most deadly form, is thus not only a disease of uncontrolled cell growth but also a disease of uncontrolled cell migration. The study of tumor cell migration requires both experimental systems that are representative of the complex tumor environment as well as quantitative tools to analyze migration patterns. In this chapter, we focus on experimental and analytical methods to capture and analyze cell migration in live explants from mouse intestinal tumors. We first describe a protocol to extract and perform ex vivo live imaging on intestinal tumors in mice. We then provide a step-by-step image analysis workflow using freely available software and custom analysis scripts for extracting several parameters related to collective cell migration and cell and tissue organization.
    Keywords:  Cancer; Collective cell migration; Quantitative biology
    DOI:  https://doi.org/10.1007/978-1-0716-2887-4_18
  13. Methods Mol Biol. 2023 ;2608 97-114
    Approaches to Determine Nuclear Shape in Cells During Migration Through Collagen Matrices.
    Martin Svoren, Elena Camerini, Merijn van Erp, Feng Wei Yang, Gert-Jan Bakker, Katarina Wolf.
      Fibrillar collagen is an abundant extracellular matrix (ECM) component of interstitial tissues which supports the structure of many organs, including the skin and breast. Many different physiological processes, but also pathological processes such as metastatic cancer invasion, involve interstitial cell migration. Often, cell movement takes place through small ECM gaps and pores and depends upon the ability of the cell and its stiff nucleus to deform. Such nuclear deformation during cell migration may impact nuclear integrity, such as of chromatin or the nuclear envelope, and therefore the morphometric analysis of nuclear shapes can provide valuable insight into a broad variety of biological processes. Here, we describe a protocol on how to generate a cell-collagen model in vitro and how to use confocal microscopy for the static and dynamic visualization of labeled nuclei in single migratory cells. We developed, and here provide, two scripts that (Fidler, Nat Rev Cancer 3(6):453-458, 2003) enable the semi-automated and fast quantification of static single nuclear shape descriptors, such as aspect ratio or circularity, and the nuclear irregularity index that forms a combination of four distinct shape descriptors, as well as (Frantz et al., J Cell Sci 123 (Pt 24):4195-4200, 2010) a quantification of their changes over time. Finally, we provide quantitative measurements on nuclear shapes from cells that migrated through collagen either in the presence or the absence of an inhibitor of collagen degradation, showing the distinctive power of this approach. This pipeline can also be applied to cell migration studied in different assays, ranging from 3D microfluidics to migration in the living organism.
    Keywords:  3D and 4D imaging; Cell migration; Cell-collagen culture; Morphometric analysis; Nuclear irregularity index; Nuclear shape
    DOI:  https://doi.org/10.1007/978-1-0716-2887-4_7
  14. Nat Cell Biol. 2023 Jan 19.
    Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
    Soni Deshwal, Mashun Onishi, Takashi Tatsuta, Tim Bartsch, Eileen Cors, Katharina Ried, Kathrin Lemke, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.
      Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-022-01071-y
  15. Cell. 2023 Jan 19. pii: S0092-8674(22)01571-9. [Epub ahead of print]186(2): 363-381.e19
    Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer.
    Jia-Ren Lin, Shu Wang, Shannon Coy, Yu-An Chen, Clarence Yapp, Madison Tyler, Maulik K Nariya, Cody N Heiser, Ken S Lau, Sandro Santagata, Peter K Sorger.
      Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells characterized by high intratumoral variation. We use highly multiplexed tissue imaging, 3D reconstruction, spatial statistics, and machine learning to identify cell types and states underlying morphological features of known diagnostic and prognostic significance in colorectal cancer. Quantitation of these features in high-plex marker space reveals recurrent transitions from one tumor morphology to the next, some of which are coincident with long-range gradients in the expression of oncogenes and epigenetic regulators. At the tumor invasive margin, where tumor, normal, and immune cells compete, T cell suppression involves multiple cell types and 3D imaging shows that seemingly localized 2D features such as tertiary lymphoid structures are commonly interconnected and have graded molecular properties. Thus, while cancer genetics emphasizes the importance of discrete changes in tumor state, whole-specimen imaging reveals large-scale morphological and molecular gradients analogous to those in developing tissues.
    Keywords:  3D microscopy; PD1-PDL1 interaction; cellular; colorectal cancer; intermixed molecular; large-scale; morphological features; multiplexed imaging; spatial gradients; spatial proteomics; spatial transcriptomics; tertiary lymphoid structures; tumor atlas; tumor budding
    DOI:  https://doi.org/10.1016/j.cell.2022.12.028
  16. Biochim Biophys Acta Biomembr. 2023 Jan 12. pii: S0005-2736(23)00003-2. [Epub ahead of print] 184121
    Membrane reshaping by protein condensates.
    Samsuzzoha Mondal, Tobias Baumgart.
      Proteins can organize into dynamic, functionally important assemblies on fluid membrane surfaces. Phase separation has emerged as an important mechanism for forming such protein assemblies on the membrane during cell signaling, endocytosis, and cytoskeleton regulation. Protein-protein phase separation thus adds novel fluid mosaics to the classical Singer and Nicolson model. Protein condensates formed in this process can modulate membrane morphologies. This is evident from recent reports of protein condensate-driven membrane reshaping in processes such as endocytosis, autophagosome formation, and protein storage vacuole morphogenesis in plants. Lateral phase separation (on the membrane surface) of peripheral curvature coupling proteins can modulate such membrane morphological transitions. Additionally, three-dimensional protein phase separation can result in droplets that through adhesion can affect membrane shape changes. How do these condensate-driven curvature generation mechanisms contrast with the classically recognized scaffolding and amphipathic helix insertion activities of specific membrane remodeling proteins? A salient feature of these condensate-driven membrane activities is that they depend upon both macroscopic features (such as interfacial energies of the condensate, membrane, and cytosol) as well as microscopic, molecular-level interactions (such as protein-lipid binding). This review highlights the current understanding of the mechanisms underlying curvature generation by protein condensates in various biological pathways.
    Keywords:  Condensates; Endocytosis; Membrane curvature; Phase separation
    DOI:  https://doi.org/10.1016/j.bbamem.2023.184121
  17. Biochim Biophys Acta Biomembr. 2023 Jan 13. pii: S0005-2736(22)00242-5. [Epub ahead of print]1865(3): 184104
    The excitable fluid mosaic.
    Thomas Heimburg.
      The Fluid Mosaic Model by Singer & Nicolson proposes that biological membranes consist of a fluid lipid layer into which integral proteins are embedded. The lipid membrane acts as a two-dimensional liquid in which the proteins can diffuse and interact. Until today, this view seems very reasonable and is the predominant picture in the literature. However, there exist broad melting transitions in biomembranes some 10-20 degrees below physiological temperatures that reach up to body temperature. Since they are found below body temperature, Singer & Nicolson did not pay any further attention to the melting process. But this is a valid view only as long as nothing happens. The transition temperature can be influenced by membrane tension, pH, ionic strength and other variables. Therefore, it is not generally correct that the physiological temperature is above this transition. The control over the membrane state by changing the intensive variables renders the membrane as a whole excitable. One expects phase behavior and domain formation that leads to protein sorting and changes in membrane function. Thus, the lipids become an active ingredient of the biological membrane. The melting transition affects the elastic constants of the membrane. This allows for the generation of propagating pulses in nerves and the formation of ion-channel-like pores in the lipid membranes. Here we show that on top of the fluid mosaic concept there exists a wealth of excitable phenomena that go beyond the original picture of Singer & Nicolson.1.
    Keywords:  Domains; Elastic constants; Ion channels; Nerves; Rafts; Thermodynamics
    DOI:  https://doi.org/10.1016/j.bbamem.2022.184104
  18. Nat Metab. 2023 Jan 16.
    Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis.
    Xu Xiao, John Paul Kennelly, Alessandra Ferrari, Bethan L Clifford, Emily Whang, Yajing Gao, Kevin Qian, Jaspreet Sandhu, Kelsey E Jarrett, Madelaine C Brearley-Sholto, Alexander Nguyen, Rohith T Nagari, Min Sub Lee, Sicheng Zhang, Thomas A Weston, Stephen G Young, Steven J Bensinger, Claudio J Villanueva, Thomas Q de Aguiar Vallim, Peter Tontonoz.
      In cell models, changes in the 'accessible' pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.
    DOI:  https://doi.org/10.1038/s42255-022-00722-6
  19. Eur J Cancer. 2022 Dec 27. pii: S0959-8049(22)01816-0. [Epub ahead of print]181 135-144
    A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407).
    Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG)
       AIM: We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC).
    METHODS: Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%.
    RESULTS: Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9-86.0) and 82.5% (95% CI, 70.7-89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9-15.9) and 9.4 months (95% CI, 7.4-12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1-44.8) and 57.1% (95% CI, 41.0-72.3) and 42.1% (95% CI 29.1-55.9) and 85.0% (95% CI, 70.2-94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3-4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm.
    CONCLUSION: GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.
    Keywords:  First-line chemotherapy; Gemcitabine plus nab-paclitaxel; Locally advanced pancreatic cancer; Phase II randomised Trial; mFOLFIRINOX
    DOI:  https://doi.org/10.1016/j.ejca.2022.12.014
  20. Epigenomics. 2023 Jan 17.
    Role of epigenetics in pancreatic ductal adenocarcinoma.
    Somnath Pandey, Vineet K Gupta, Shweta P Lavania.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, associated with poor survival outcomes. Lack of early diagnosis, resistance to conventional therapeutic treatments (including immunotherapy) and recurrence are some of the major hurdles in PDAC and contribute to its poor survival rate. While the risk of genetic predisposition to cancers is widely acknowledged and understood, recent advances in whole-genome and next-generation sequencing techniques have led to the acknowledgment of the role played by epigenetics, especially in PDAC. Epigenetic changes are heritable genetic modifications that influence gene expression without altering the DNA sequence. Epigenetic mechanisms (e.g., DNA methylation, post-translational modification of histone complexes and ncRNA) that result in reversible changes in gene expression are increasingly understood to be responsible for tumor initiation, development and even escape from immune surveillance. Our review seeks to highlight the various components of the epigenetic machinery that are known to be implicated in PDAC initiation and development and the feasibility of targeting these components to identify novel pharmacological strategies that could potentially lead to breakthroughs in PDAC treatment.
    Keywords:  epigenetic mechanism; epigenetics; pancreatic ductal adenocarcinoma; translational medicine; tumor heterogeneity
    DOI:  https://doi.org/10.2217/epi-2022-0177
  21. Cell Res. 2023 Jan 16.
    EMP1+ tumor cells drive metastatic relapse.
    Oscar E Villarreal, Scott Kopetz.
      
    DOI:  https://doi.org/10.1038/s41422-022-00769-w
  22. Cell. 2023 Jan 19. pii: S0092-8674(22)01528-8. [Epub ahead of print]186(2): 235-237
    Coordinated cancer chaos.
    Hendrik A Messal, Jacco van Rheenen.
      Stochastic processes, such as genetic instability and microenvironment evolution, drive tumor heterogeneity, thereby creating the chaotic appearance of tumors in histopathology. In this issue of Cell, Lin et al. reveal that tumors are surprisingly spatially organized from a molecular to tissue scale, indicating that cancers evolve as autonomously patterned systems.
    DOI:  https://doi.org/10.1016/j.cell.2022.12.015
  23. Nat Cancer. 2023 Jan 16.
    Proteogenomic analysis of human pancreatic ductal adenocarcinoma.
      
    DOI:  https://doi.org/10.1038/s43018-022-00478-8
  24. Methods Mol Biol. 2023 ;2625 89-102
    Profiling the Mammalian Lipidome by Quantitative Shotgun Lipidomics.
    Mads Møller Foged, Kenji Maeda, Mesut Bilgin.
      The emerging field of lipidomics presents the systems biology approach to identify and quantify the full lipid repertoire of cells, tissues, and organisms. The importance of the lipidome is demonstrated by a number of biological studies on dysregulation of lipid metabolism in human diseases such as cancer, diabetes, and neurodegenerative diseases. Exploring changes and regulations in the huge networks of lipids and their metabolic pathways requires a lipidomics methodology: advanced mass spectrometry that resolves the complexity of the lipidome. Here, we report a comprehensive protocol of quantitative shotgun lipidomics that enables identification and quantification of hundreds of molecular lipid species, covering a wide range of lipid classes, extracted from cultured mammalian cells.
    Keywords:  Lipid extraction; Lipidome profiling; Lipidomics; Mammalian cells; Mass spectrometry; Quantification; Shotgun lipidomics; Systems biology
    DOI:  https://doi.org/10.1007/978-1-0716-2966-6_8
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