bims-cagime 2025-01-19 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–01–19
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.
Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.
Synthetic Lipid Biology.
IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer.
A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer.
KRAS Oncoprotein Signaling in Cancer.
Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis.
Nerves at Play: The Peripheral Nervous System in Extracranial Malignancies.
Nanocarrier imaging at single-cell resolution across entire mouse bodies with deep learning.
Gene expression dynamics in fibroblasts during early-stage murine pancreatic carcinogenesis.
Protocol for quantifying muscle fiber size, number, and central nucleation of mouse skeletal muscle cross-sections using Myotally software.
Probing the physical hallmarks of cancer.
Biotinylated Viscosity Sensitive Cell Membrane Probe for Targeted Imaging and Precise Visualization of Tumor Cells and Tumors.
Identification and characterization of tumor and stromal derived liquid biopsy analytes in pancreatic ductal adenocarcinoma.
Live-cell metabolic analyzer protocol for measuring glucose and lactate metabolic changes in human cells.
Neural invasion severity is a strong predictor of local recurrence in pancreatic ductal adenocarcinoma.
Call to Improve Coding of Cancer-Associated Cachexia.
Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.
CausalXtract, a flexible pipeline to extract causal effects from live-cell time-lapse imaging data.
Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance.
Cancer Research in the Age of Spatial Omics: Lessons from IMAXT.
Impact of aspirin on pancreatic cancer.
Chemistries on the inner leaflet of the cell membrane.
Tension-induced organelle stress: an emerging target in fibrosis.
Revealed: the fatty cells that are the 'bubble wrap' of the body.
Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
The Atlas of Protein-Protein Interactions in Cancer (APPIC)-a webtool to visualize and analyze cancer subtypes.
Pathological complete response following neoadjuvant chemotherapy with PD-1 inhibitor for locally advanced pancreatic cancer: case report.
Targeting MXD1 sensitises pancreatic cancer to trametinib.
Deciphering functional tumor-immune crosstalk through highly multiplexed imaging and deep visual proteomics.
Multi-organelle imaging with dye combinations: targeting the ER, mitochondria, and plasma membrane.

bioRxiv. 2024 Dec 31. pii: 2024.12.30.630679. [Epub ahead of print]

Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.

Natalia M Weinzierl, Jayarani Putri, Kathryn M Spitler, Erin E Talbert.

Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Despite decades of research, therapeutic options for cancer cachexia remain limited. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand mechanisms underlying cachexia. One such model is the Kras LSL-G12D , Ptf1a Cre-ER/+ , Pten flox/flox (KPP) model, which utilizes an inducible Cre recombinase to allow tumor development to be initiated at any age by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 weeks of age. However, mice are still rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 weeks of age (KPP10). Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared to non-tumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that overall survival was significantly shorter in female KPP10 mice compared to KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice.
NEW & NOTEWORTHY: Although male mice experience greater relative body weight losses, similar skeletal muscle and adipose tissue wasting occurs between male and female mice in the Kras LSL-G12D , Ptf1a Cre-ER/+ , Pten flox/flox (KPP) model of pancreatic-cancer induced cachexia. Greater weight loss in males may be related to longer survival. However, differences in tamoxifen dose relative to body weight may have accelerated tumor formation in female mice and therefore may be a relevant consideration for inducible tumor models.

DOI: https://doi.org/10.1101/2024.12.30.630679
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13668

Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.

Daria Neyroud, Andrew C D'Lugos, Enrique J Trevino, Chandler S Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R Deyhle, Justina Brantley, Lam Le, Andrew R Judge, Sarah M Judge.

   BACKGROUND: Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.
METHODS: To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint).
RESULTS: During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.
CONCLUSIONS: In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.

Keywords:  cancer cachexia; inflammatory response; muscle atrophy; muscle fibrosis; pancreatic cancer

DOI:  https://doi.org/10.1002/jcsm.13668
Chem Rev. 2025 Jan 13.

Synthetic Lipid Biology.

Po-Hsun Brian Chen, Xiang-Ling Li, Jeremy M Baskin.

Cells contain thousands of different lipids. Their rapid and redundant metabolism, dynamic movement, and many interactions with other biomolecules have justly earned lipids a reputation as a vexing class of molecules to understand. Further, as the cell's hydrophobic metabolites, lipids assemble into supramolecular structures─most commonly bilayers, or membranes─from which they carry out myriad biological functions. Motivated by this daunting complexity, researchers across disciplines are bringing order to the seeming chaos of biological lipids and membranes. Here, we formalize these efforts as "synthetic lipid biology". Inspired by the idea, central to synthetic biology, that our abilities to understand and build biological systems are intimately connected, we organize studies and approaches across numerous fields to create, manipulate, and analyze lipids and biomembranes. These include construction of lipids and membranes from scratch using chemical and chemoenzymatic synthesis, editing of pre-existing membranes using optogenetics and protein engineering, detection of lipid metabolism and transport using bioorthogonal chemistry, and probing of lipid-protein interactions and membrane biophysical properties. What emerges is a portrait of an incipient field where chemists, biologists, physicists, and engineers work together in proximity─like lipids themselves─to build a clearer description of the properties, behaviors, and functions of lipids and membranes.

DOI: https://doi.org/10.1021/acs.chemrev.4c00761
Nature. 2025 Jan 15.

IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer.

Masataka Amisaki, Abderezak Zebboudj, Hiroshi Yano, Siqi Linsey Zhang, George Payne, Adrienne Kaya Chandra, Rebecca Yu, Pablo Guasp, Zachary M Sethna, Akihiro Ohmoto, Luis A Rojas, Charlotte Cheng, Theresa Waters, Alexander Solovyov, Stephen Martis, Ashley S Doane, Charlotte Reiche, Emmanuel M Bruno, Martina Milighetti, Kevin Soares, Zagaa Odgerel, John Alec Moral, Julia N Zhao, Mithat Gönen, Rui Gardner, Alexei V Tumanov, Abdul G Khan, Olivia Vergnolle, Elisabeth K Nyakatura, Ivo C Lorenz, Manuel Baca, Erin Patterson, Benjamin Greenbaum, David Artis, Taha Merghoub, Vinod P Balachandran.

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LTβ receptor (LTβR) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LTβR-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LTβR+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.

DOI: https://doi.org/10.1038/s41586-024-08426-5
Proc Natl Acad Sci U S A. 2025 Jan 21. 122(3): e2412816122

A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer.

Marco S Messina, Laura Torrente, Aidan T Pezacki, Hanna I Humpel, Erin L Li, Sophia G Miller, Odette Verdejo-Torres, Teresita Padilla-Benavides, Donita C Brady, David W Killilea, Alison N Killilea, Martina Ralle, Nathan P Ward, Jun Ohata, Gina M DeNicola, Christopher J Chang.

  Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel. Coppermycin-1 reacts selectively with Cu(I) to release puromycin, which is then incorporated into nascent peptides during protein translation, thus leaving a permanent and dose-dependent marker for labile copper that can be visualized with standard immunofluorescence assays. We showcase the utility of this platform for screening labile Cu(I) pools across the National Cancer Institute's 60 (NCI-60) human tumor cell line panel, identifying cell types with elevated basal levels of labile copper. Moreover, we use Coppermycin-1 to show that lung cancer cells with heightened activation of nuclear factor-erythroid 2-related factor 2 (NRF2) possess lower resting labile Cu(I) levels and, as a result, have reduced viability when treated with a copper chelator. This work establishes that methods for labile copper detection can be used to assess cuproplasia, an emerging form of copper-dependent cell growth and proliferation, providing a starting point for broader investigations into the roles of transition metal signaling in biology and medicine.

Keywords:  activity-based sensing; antioxidant regulation; cancer metabolism; histochemical copper probe; transition metal signaling

DOI:  https://doi.org/10.1073/pnas.2412816122
N Engl J Med. 2025 Jan 16. 392(3): 296-298

KRAS Oncoprotein Signaling in Cancer.

Piro Lito.

DOI: https://doi.org/10.1056/NEJMcibr2408099
bioRxiv. 2024 Dec 12. pii: 2024.12.10.627730. [Epub ahead of print]

Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis.

Sun Woo Sophie Kang, Lauryn A Brown, Colin B Miller, Katherine M Barrows, Jihye L Golino, Constance M Cultraro, Daniel Feliciano, Mercedes B Cornelius-Muwanuzi, Andy D Tran, Michael Kruhlak, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.

Hepatic lipid accumulation, or Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a significant risk factor for liver cancer. Despite the rising incidence of MASLD, the underlying mechanisms of steatosis and lipotoxicity remain poorly understood. Interestingly, lipid accumulation also occurs during fasting, driven by the mobilization of adipose tissue-derived fatty acids into the liver. However, how hepatocytes adapt to increased lipid flux during nutrient deprivation and what occurs differently in MASLD is not known. To investigate the differences in lipid handling in response to nutrient deficiency and excess, we developed a novel single-cell tissue imaging (scPhenomics) technique coupled with spatial proteomics. Our investigation revealed extensive remodeling of lipid droplet (LD) and mitochondrial topology in response to dietary conditions. Notably, fasted mice exhibited extensive mitochondria-LD interactions, which were rarely observed in Western Diet (WD)-fed mice. Spatial proteomics showed an increase in PLIN5 expression, a known mediator of LD-mitochondria interaction, in response to fasting. To examine the functional role of mitochondria-LD interaction on lipid handling, we overexpressed PLIN5 variants. We found that the phosphorylation state of PLIN5 impacts its capacity to form mitochondria-LD contact sites. PLIN5 S155A promoted extensive organelle interactions, triglyceride (TG) synthesis, and LD expansion in mice fed a control diet. Conversely, PLIN5 S155E expressing cells had fewer LDs and contact sites and contained less TG. Wild-type (WT) PLIN5 overexpression in WD-fed mice reduced steatosis and improved redox state despite continued WD consumption. These findings highlight the importance of organelle interactions in lipid metabolism, revealing a critical mechanism by which hepatocytes maintain homeostasis during metabolic stress. Our study underscores the potential utility of targeting mitochondria-LD interactions for therapeutic intervention.

DOI: https://doi.org/10.1101/2024.12.10.627730
Cancer Discov. 2025 Jan 13. 15(1): 52-68

Nerves at Play: The Peripheral Nervous System in Extracranial Malignancies.

Paola D Vermeer, Anthony C Restaino, Jeffrey L Barr, Dan Yaniv, Moran Amit.

The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. Significance: The continued and growing interest in cancer neuroscience by the scientific and medical communities reflects the rapidly accumulating interdisciplinary understanding of the nervous system's modulation of immune, vascular, and cancer cells' functions in malignancies. Understanding these regulatory functions can identify targets for intervention that may already be clinically available for other indications. This potential brings great excitement and hope for patients with cancer worldwide.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0397
Nat Biotechnol. 2025 Jan 14.

Nanocarrier imaging at single-cell resolution across entire mouse bodies with deep learning.

Jie Luo, Muge Molbay, Ying Chen, Izabela Horvath, Karoline Kadletz, Benjamin Kick, Shan Zhao, Rami Al-Maskari, Inderjeet Singh, Mayar Ali, Harsharan Singh Bhatia, David-Paul Minde, Moritz Negwer, Luciano Hoeher, Gian Marco Calandra, Bernhard Groschup, Jinpeng Su, Ceren Kimna, Zhouyi Rong, Nikolas Galensowske, Mihail Ivilinov Todorov, Denise Jeridi, Tzu-Lun Ohn, Stefan Roth, Alba Simats, Vikramjeet Singh, Igor Khalin, Chenchen Pan, Bernardo A Arús, Oliver T Bruns, Reinhard Zeidler, Arthur Liesz, Ulrike Protzer, Nikolaus Plesnila, Siegfried Ussar, Farida Hellal, Johannes Paetzold, Markus Elsner, Hendrik Dietz, Ali Erturk.

Efficient and accurate nanocarrier development for targeted drug delivery is hindered by a lack of methods to analyze its cell-level biodistribution across whole organisms. Here we present Single Cell Precision Nanocarrier Identification (SCP-Nano), an integrated experimental and deep learning pipeline to comprehensively quantify the targeting of nanocarriers throughout the whole mouse body at single-cell resolution. SCP-Nano reveals the tissue distribution patterns of lipid nanoparticles (LNPs) after different injection routes at doses as low as 0.0005 mg kg-1-far below the detection limits of conventional whole body imaging techniques. We demonstrate that intramuscularly injected LNPs carrying SARS-CoV-2 spike mRNA reach heart tissue, leading to proteome changes, suggesting immune activation and blood vessel damage. SCP-Nano generalizes to various types of nanocarriers, including liposomes, polyplexes, DNA origami and adeno-associated viruses (AAVs), revealing that an AAV2 variant transduces adipocytes throughout the body. SCP-Nano enables comprehensive three-dimensional mapping of nanocarrier distribution throughout mouse bodies with high sensitivity and should accelerate the development of precise and safe nanocarrier-based therapeutics.

DOI: https://doi.org/10.1038/s41587-024-02528-1
iScience. 2025 Jan 17. 28(1): 111572

Gene expression dynamics in fibroblasts during early-stage murine pancreatic carcinogenesis.

Nupur Ohri, Johanna Häußler, Nino Javakhishvili, David Vieweg, Anais Zourelidis, Bogusz Trojanowicz, Monika Haemmerle, Irene Esposito, Markus Glaß, Yoshiaki Sunami, Jörg Kleeff.

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive growth and metastasis, partly driven by fibroblast-mediated stromal interactions. Using RNA sequencing of fibroblasts from early-stage KPC mouse models, we identified significant upregulation of genes involved in adipogenesis, fatty acid metabolism, and the ROS pathway. ANGPTL4, a key adipogenesis regulator, was highly expressed in fibroblasts and promoted pancreatic cancer cell proliferation and migration through paracrine signaling. Notably, cancer cell-driven paracrine signals appear to regulate ANGPTL4 expression in fibroblasts, suggesting that ANGPTL4 may act as a reciprocal factor in a feedback loop that enhances tumor progression. LAMA2, an extracellular matrix gene with reduced expression, suppressed pancreatic cancer cell migration, proliferation, and invasion. This study provides the temporal transcriptional analysis of fibroblast subtypes during early PDAC, highlighting the roles of metabolic reprogramming and ECM remodeling in shaping the tumor microenvironment and identifying potential therapeutic targets.

Keywords:  Biological sciences; Cancer; Genetics

DOI:  https://doi.org/10.1016/j.isci.2024.111572
STAR Protoc. 2025 Jan 10. pii: S2666-1667(24)00720-2. [Epub ahead of print]6(1): 103555

Protocol for quantifying muscle fiber size, number, and central nucleation of mouse skeletal muscle cross-sections using Myotally software.

Pieter Both, Soochi Kim, Jengmin Kang, Marina Arjona, Daniel I Benjamin, Christopher W Nutter, Armon Goshayeshi, Thomas A Rando.

  Here, we present a protocol for using Myotally, a user-friendly software for fast, automated quantification of muscle fiber size, number, and central nucleation from immunofluorescent stains of mouse skeletal muscle cross-sections. We describe steps for installing the software, preparing compatible images, finding the file path, and selecting key parameters like image quality and size limits. We also detail optional features, such as measuring mean fluorescence. By automating these traditionally labor-intensive processes, Myotally improves research efficiency and data consistency.

Keywords:  Cell Biology; Computer sciences; Microscopy

DOI:  https://doi.org/10.1016/j.xpro.2024.103555
Nat Methods. 2025 Jan 15.

Probing the physical hallmarks of cancer.

Hadi T Nia, Lance L Munn, Rakesh K Jain.

The physical microenvironment plays a crucial role in tumor development, progression, metastasis and treatment. Recently, we proposed four physical hallmarks of cancer, with distinct origins and consequences, to characterize abnormalities in the physical tumor microenvironment: (1) elevated compressive-tensile solid stresses, (2) elevated interstitial fluid pressure and the resulting interstitial fluid flow, (3) altered material properties (for example, increased tissue stiffness) and (4) altered physical micro-architecture. As this emerging field of physical oncology is being advanced by tumor biologists, cell and developmental biologists, engineers, physicists and oncologists, there is a critical need for model systems and measurement tools to mechanistically probe these physical hallmarks. Here, after briefly defining these physical hallmarks, we discuss the tools and model systems available for probing each hallmark in vitro, ex vivo, in vivo and in clinical settings. We finally review the unmet needs for mechanistic probing of the physical hallmarks of tumors and discuss the challenges and unanswered questions associated with each hallmark.

DOI: https://doi.org/10.1038/s41592-024-02564-4
Anal Chem. 2025 Jan 16.

Biotinylated Viscosity Sensitive Cell Membrane Probe for Targeted Imaging and Precise Visualization of Tumor Cells and Tumors.

Qianhua Li, Zhoupeng Zheng, Yao Chen, Zhijie Li, Shumin Feng, Guoqiang Feng.

Cancer is a global health challenge that urgently requires more sensitive and effective cancer detection methods. Fluorescence imaging with small molecule fluorescent probes has shown great promise for cancer detection but most of the developed probes lack active tumor cell targeting, which makes them unable to selectively target tumors, thereby reducing the accuracy of in vivo tumor detection. Herein, we report a novel probe Bio-S that combines a viscosity-sensitive and cell membrane targetable fluorescent group with biotin for targeted imaging and precise visualization of tumor cells and tumors. Bio-S exhibits sensitive fluorescence changes for viscosity at ∼660 nm and excellent cell membrane localization and imaging ability (red fluorescence, wash-free, and long-term imaging). Moreover, compared with the nonbiotinylated control probe C6-S, the biotinylated Bio-S can specifically target tumor cell membranes, thereby achieving much higher selectivity and sensitivity in distinguishing tumor cells from normal cells. Mice imaging experiments show that tail vein injection of Bio-S can target tumors and monitor lung cancer metastasis at the in vivo level. Therefore, this work provides an effective new strategy and tool for tumor-targeted detection and precise diagnosis.

DOI: https://doi.org/10.1021/acs.analchem.4c04513
J Exp Clin Cancer Res. 2025 Jan 16. 44(1): 14

Identification and characterization of tumor and stromal derived liquid biopsy analytes in pancreatic ductal adenocarcinoma.

Julian Götze, Kira Meißner, Thais Pereira-Veiga, Yassine Belloum, Svenja Schneegans, Jolanthe Kropidlowski, Joao Gorgulho, Alina Busch, Kim Christin Honselmann, Martin Schönrock, Arne Putscher, Sven Peine, Christine Nitschke, Ronald Simon, Volker Spindler, Jakob Robert Izbicki, Thilo Hackert, Carsten Bokemeyer, Klaus Pantel, Faik Güntaç Uzunoglu, Marianne Sinn, Harriet Wikman.

   BACKGROUND: The lack of predictive biomarkers contributes notably to the poor outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer-associated fibroblasts (CAFs) are the key components of the prominent PDAC stroma. Data on clinical relevance of CAFs entering the bloodstream, known as circulating CAFs (cCAFs) are scarce. Here, we developed a combined liquid biopsy assay to detect cCAFs and circulating tumor cells (CTCs) in metastatic PDAC (mPDAC) and other metastatic gastrointestinal malignancies (mGI). In addition, we evaluated plasma hyaluronan (HA) levels as a complementary surrogate biomarker of the stromal extent in patients with PDAC.
METHODS: A sequential liquid biopsy assay based on a two step-enrichment, combining marker dependent and independent cell enrichment, was established for cCAF and CTC detection and validated in mPDAC and mGI patients. The enriched cells were identified by multiplex immunofluorescence. HA measurement was performed by ELISA on blood samples from healthy blood donors (HD), localized and late-stage PDAC patients.
RESULTS: cCAFs (≥ 1cCAFs/7.5 mL blood) were detected in 95.4% of mPDAC and in 78.2% of mGI patients, with significantly higher numbers in mPDAC compared to mGI patients (mean number 22.7 vs. 11.0; P = 0.0318). mPDAC patients with ≥ 15 cCAFs/7.5 mL blood had a significant shorter median overall survival (mOS 3.2 months (95% confidence interval (CI) 0.801-5.855) vs. 14.2 months (95% CI 6.055-22.332); P = 0.013), whereby CTC levels were not associated with mOS. In mGI neither cCAFs nor CTCs had a significant impact on OS. HA plasma levels in mPDAC patients were significantly higher compared to HD (mean 123.0 ng/mL vs. 74.45 ng/mL, P = 0.015). High HA in localized and late-stage PDAC were associated with a significantly shorter mOS (mOSlocalized PDAC: 12.6 months vs. 23.5 months (P = 0.008); mOSmPDAC: 1.8 months vs. 5.3 months (P = 0.004)).
CONCLUSIONS: Our liquid biopsy assay provides robust detection of cCAFs in mPDAC and mGI patients. The measurement of both circulatory stromal parameters, cCAFs and HA, adds valuable clinical information as they are associated with an unfavorable outcome in PDAC. These results highlight that stromal characteristics unique to PDAC could be leveraged to fill the current gap in discovering predictive biomarkers.

Keywords:  CCAFs; Hyaluronan; Liquid biopsy; PDAC; Stroma

DOI:  https://doi.org/10.1186/s13046-024-03262-x
STAR Protoc. 2025 Jan 10. pii: S2666-1667(24)00683-X. [Epub ahead of print]6(1): 103518

Live-cell metabolic analyzer protocol for measuring glucose and lactate metabolic changes in human cells.

Kenji Miki, Mikako Yagi, Ko Igami, Hiroki Kittaka, Akito Tani, Natsuki Horiuchi, Satoshi Fukumoto, Koji Yoshimoto, Takeshi Uchiumi.

  Understanding metabolic conditions related to glycolysis dependence is crucial for developing new treatments in cancer and regenerative medicine. This protocol details a method for using the live-cell metabolic analyzer (LiCellMo) to measure continuous changes in glucose consumption and lactate production in cultured human cells. LiCellMo provides real-time data on consecutive metabolic changes, improving measurements of these processes in various contexts, including in cancer and regenerative treatments.

Keywords:  cell biology; cell culture; metabolism

DOI:  https://doi.org/10.1016/j.xpro.2024.103518
Surgery. 2025 Jan 10. pii: S0039-6060(24)01005-5. [Epub ahead of print]180 109018

Neural invasion severity is a strong predictor of local recurrence in pancreatic ductal adenocarcinoma.

Stephan Schorn, Anouk Fritz, Georgios Kaissis, Matthias M Gaida, Katja Steiger, Carsten Jäger, Anna Melissa Schlitter, Rickmer Braren, Helmut Friess, Ihsan Ekin Demir, Güralp Onur Ceyhan.

BACKGROUND: In pancreatic ductal adenocarcinoma, neural invasion is being increasingly recognized as an unfavorable predictor of patient outcomes. Neural invasion severity seems to have a stronger clinical impact on patient prognosis than neural invasion status alone. Therefore, this study aims to assess the impact of severity of neural invasion on overall survival and disease-free survival in pancreatic ductal adenocarcinoma.
MATERIALS: To assess the impact of intrapancreatic neural invasion severity, tumor specimens resected from patients with pancreatic ductal adenocarcinoma between 2007 and 2014 were systematically re-evaluated, and neural invasion severity was determined using the standardized neural invasion severity score.
RESULTS: In our cohort (n = 216), an increased neural invasion severity score was associated with markedly shorter overall survival in pancreatic head ductal adenocarcinoma (neural invasion severity score low: 22.8 months vs neural invasion severity score high: 17.6 months: P = .001). An external European validation cohort confirmed these results and showed significantly better survival of patients with lower neural invasion (20.5 vs 15.4 months, P = .026). The disease-free survival time was also substantially decreased in patients with pancreatic head pancreatic ductal adenocarcinoma and increased neural invasion severity (neural invasion severity score low: 19.1 months vs neural invasion severity score high: 10.4 months; P = .004). Moreover, the neural invasion severity score was an important independent factor influencing overall survival (hazards ratio 1.024, P = .04) and disease-free survival (hazards ratio 1.03, P = .01) using an adjusted Cox proportional hazards model. Importantly, higher neural invasion severity score leads to significantly more and earlier local recurrence than to distant tumor recurrence.
CONCLUSION: Neural invasion severity is a powerful independent factor influencing overall survival and local recurrence in patients with pancreatic ductal adenocarcinoma. Therefore, individuals with high neural invasion severity score values should be regarded as a specific subgroup of pancreatic ductal adenocarcinoma patients and may benefit from more tailored postoperative oncologic therapy.

DOI: https://doi.org/10.1016/j.surg.2024.109018
JCO Oncol Pract. 2025 Jan 13. OP2400781

Call to Improve Coding of Cancer-Associated Cachexia.

Marcus D Goncalves, Richard F Dunne, Amy C Moore, Wendy Phillips, Steven B Heymsfield, Justin C Brown, Erin E Talbert, Tobias Janowitz.

Cachexia is a systemic wasting syndrome prevalent in patients with cancer that significantly affects quality of life, health care costs, and therapeutic outcomes. Despite its clinical importance, cachexia is rarely formally diagnosed. This deficiency presents a challenge for effective patient management and care, health care resource allocation, and the advancement of therapeutic approaches. Here, we highlight impedances to the diagnosis and coding of cachexia, including the absence of standardized therapy, a lack of incentives for accurate coding, and overlapping clinical features with other conditions. We differentiate cachexia from related conditions like unintentional weight loss, sarcopenia, frailty, and protein-calorie malnutrition, outlining their distinct clinical features and inter-relations. We propose an approach to enhance diagnostic accuracy and coding for cachexia. This effort will enable better prevalence data, translation of mechanism-based therapy development, patient identification and stratification, and ultimately advanced diagnostics and US Food and Drug Administration-approved treatments for cachexia.

DOI: https://doi.org/10.1200/OP-24-00781
J Biol Chem. 2025 Jan 09. pii: S0021-9258(25)00018-3. [Epub ahead of print] 108171

Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.

Brian A Zalma, Maria Ibrahim, Flavio C Rodriguez-Polanco, Chintan T Bhavsar, Esther M Rodriguez, Eduardo Cararo-Lopes, Saad A Farooq, Jordan L Levy, Ronald C Wek, Eileen White, Tracy G Anthony.

  Amino acid starvation by the chemotherapy agent asparaginase is a potent activator of the integrated stress response (ISR) in liver and can upregulate autophagy in some cell types. We hypothesized that autophagy related 7 (ATG7), a protein that is essential for autophagy and an ISR target gene, was necessary during exposure to asparaginase to maintain liver health. We knocked down Atg7 systemically (Atg7Δ/Δ) or in hepatocytes only (ls-Atg7KO) in mice before exposure to pegylated asparaginase for 5 d. Intact mice injected with asparaginase lost body weight due to reduced food intake and increased energy expenditure. Systemic Atg7 ablation reduced liver protein synthesis and increased liver injury in vehicle-injected mice, but did not further reduce liver protein synthesis, exacerbate steatosis or liver injury, or alter energy expenditure following 5 d asparaginase exposure. Atg7Δ/Δ mice were unexpectantly protected from asparaginase-induced anorexia and weight loss. This protection corresponded with reduced phosphorylation of hepatic GCN2 and blunted increases in ISR gene targets including growth differentiation factor 15 (GDF15), a negative regulator of food intake. Interestingly, asparaginase elevated serum GDF15 and reduced food intake in ls-Atg7KO mice, similar to intact mice. Liver triglycerides and production of the hepatokine fibroblast growth factor 21, another ISR gene target, were suppressed in asparaginase-exposed Atg7Δ/Δ and ls-Atg7KO mice. This work identifies a bidirectional relationship between autophagy and the ISR in the liver during asparaginase, affecting food intake and liver health.

Keywords:  FGF21; GDF15; amino acid; body composition; eukaryotic initiation factor 2 (eIF2); gene expression; polysome profiling; protein synthesis; translation

DOI:  https://doi.org/10.1016/j.jbc.2025.108171
Elife. 2025 Jan 17. pii: RP95485. [Epub ahead of print]13

CausalXtract, a flexible pipeline to extract causal effects from live-cell time-lapse imaging data.

Franck Simon, Maria Colomba Comes, Tiziana Tocci, Louise Dupuis, Vincent Cabeli, Nikita Lagrange, Arianna Mencattini, Maria Carla Parrini, Eugenio Martinelli, Herve Isambert.

  Live-cell microscopy routinely provides massive amounts of time-lapse images of complex cellular systems under various physiological or therapeutic conditions. However, this wealth of data remains difficult to interpret in terms of causal effects. Here, we describe CausalXtract, a flexible computational pipeline that discovers causal and possibly time-lagged effects from morphodynamic features and cell-cell interactions in live-cell imaging data. CausalXtract methodology combines network-based and information-based frameworks, which is shown to discover causal effects overlooked by classical Granger and Schreiber causality approaches. We showcase the use of CausalXtract to uncover novel causal effects in a tumor-on-chip cellular ecosystem under therapeutically relevant conditions. In particular, we find that cancer-associated fibroblasts directly inhibit cancer cell apoptosis, independently from anticancer treatment. CausalXtract uncovers also multiple antagonistic effects at different time delays. Hence, CausalXtract provides a unique computational tool to interpret live-cell imaging data for a range of fundamental and translational research applications.

Keywords:  causal discovery; causal inference; computational biology; granger causality; human; live-cell imaging; systems biology; time-lapse image analysis; tumor on chip

DOI:  https://doi.org/10.7554/eLife.95485
Cancer Res. 2025 Jan 13.

Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance.

Tahereh Ziglari, Nicholas L Calistri, Jennifer M Finan, Daniel S Derrick, Ernesto S Nakayasu, Meagan C Burnet, Jennifer E Kyle, Matthew Hoare, Laura M Heiser, Ferdinando Pucci.

Senescence is a non-proliferative, survival state that cancer cells can enter to escape therapy. In addition to soluble factors, senescence cells secrete extracellular vesicles (EVs), which are important mediators of intercellular communication. To explore the role of senescent cell-derived EVs (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. SenEVs were both necessary and sufficient to trigger immune-mediated clearance of senescent cells, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of senescent cell signaling from antigen-presenting cells to neutrophils. Comprehensive transcriptional and proteomic analyses identified six ligands specific to senEVs, highlighting their role in promoting antigen-presenting cell-T cell adhesion and synapse formation. Antigen-presenting cells activated CCR2+CD4+ TH17 cells, which appeared to inhibit B cell activation, and CD4+ T cells were essential for preventing tumor recurrence. These findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of senescent cells. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of early detection strategies for cancer based on the biology of cellular senescence.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0875
Cancer Discov. 2025 01 13. 15(1): 16-21

Cancer Research in the Age of Spatial Omics: Lessons from IMAXT.

IMAXT Cancer Grand Challenges Consortium

The Imaging and Molecular Annotation of Xenografts and Tumors Cancer Grand Challenges team was set up with the objective of developing the "next generation" of pathology and cancer research by using a combination of single-cell and spatial omics tools to produce 3D molecularly annotated maps of tumors. Its activities overlapped, and in some cases catalyzed, a spatial revolution in biology that saw new technologies being deployed to investigate the roles of tumor heterogeneity and of the tumor micro-environment. See related article by Stratton et al., p. 22 See related article by Bhattacharjee et al., p. 28 See related article by Goodwin et al., p. 34.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1686
Ann Gastroenterol. 2025 Jan-Feb;38(1):38(1): 105

Impact of aspirin on pancreatic cancer.

Christos Zavos.

DOI: https://doi.org/10.20524/aog.2024.0937
Chem Commun (Camb). 2025 Jan 15.

Chemistries on the inner leaflet of the cell membrane.

Wenxue Xie, Yuhan Kong, Cong Ren, Yujian Wen, Maben Ying, Hang Xing.

The cell membrane, characterized by its inherent asymmetry, functions as a dynamic barrier that regulates numerous cellular activities. This Highlight aims to provide the chemistry community with a comprehensive overview of the intriguing and underexplored inner leaflet, encompassing both fundamental biology and emerging synthetic modification strategies. We begin by describing the asymmetric nature of the plasma membrane, with a focus on the distinct roles of lipids, proteins, and glycan chains, highlighting the composition and biofunctions of the inner leaflet and the biological mechanisms that sustain membrane asymmetry. Next, we explore chemical biological strategies for engineering the inner leaflet, including genetic engineering, transmembrane peptides, and liposome fusion-based transport. In the perspective section, we discuss the challenges in developing chemistries for the inner leaflet of the cell membrane, aiming to inspire researchers and collaborators to explore this field and address its unanswered biological questions.

DOI: https://doi.org/10.1039/d4cc05186f
Trends Pharmacol Sci. 2025 Jan 15. pii: S0165-6147(24)00272-4. [Epub ahead of print]

Tension-induced organelle stress: an emerging target in fibrosis.

FuiBoon Kai, Andrew M Leidal, Valerie M Weaver.

  Fibrosis accounts for approximately one-third of disease-related deaths globally. Current therapies fail to cure fibrosis, emphasizing the need to identify new antifibrotic approaches. Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and resultant stiffening of tissue stroma. This stiffening appropriates actomyosin-mediated mechanical tension within cells to ultimately affect cell fate decisions and function. Recent studies demonstrate that subcellular organelles are physically connected to the actin cytoskeleton and sensitive to mechanoperturbations. These insights highlight mechanisms that may contribute to the chronic organelle stress in many fibrotic diseases, including those of the lung and liver. In this review, we discuss the hypothesis that a stiffened fibrotic ECM corrupts intracellular mechanical tension to compromise organelle homeostasis. We summarize potential therapeutics that could intervene in this mechanical dialog and that may have clinical benefit for resolving pathological organelle stress in fibrosis.

Keywords:  actomyosin contractility; extracellular matrix; fibrosis; mechanotransduction; organelle homeostasis

DOI:  https://doi.org/10.1016/j.tips.2024.12.006
Nature. 2025 Jan 09.

Revealed: the fatty cells that are the 'bubble wrap' of the body.

Max Kozlov.



Keywords:  Cell biology

DOI:  https://doi.org/10.1038/d41586-025-00012-7
Nat Metab. 2025 Jan 15.

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.

Janine Tutas, Marianna Tolve, Ebru Özer-Yildiz, Lotte Ickert, Ines Klein, Quinn Silverman, Filip Liebsch, Frederik Dethloff, Patrick Giavalisco, Heike Endepols, Theodoros Georgomanolis, Bernd Neumaier, Alexander Drzezga, Guenter Schwarz, Bernard Thorens, Graziana Gatto, Christian Frezza, Natalia L Kononenko.

Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.

DOI: https://doi.org/10.1038/s42255-024-01196-4
NAR Cancer. 2025 Mar;7(1): zcae047

The Atlas of Protein-Protein Interactions in Cancer (APPIC)-a webtool to visualize and analyze cancer subtypes.

Benjamin Ahn, Charissa Chou, Caden Chou, Jennifer Chen, Amelia Zug, Yigit Baykara, Jessica Claus, Sean M Hacking, Alper Uzun, Ece D Gamsiz Uzun.

Cancer is a complex disease with heterogeneous mutational and gene expression patterns. Subgroups of patients who share a phenotype might share a specific genetic architecture including protein-protein interactions (PPIs). We developed the Atlas of Protein-Protein Interactions in Cancer (APPIC), an interactive webtool that provides PPI subnetworks of 10 cancer types and their subtypes shared by cohorts of patients. To achieve this, we analyzed publicly available RNA sequencing data from patients and identified PPIs specific to 26 distinct cancer subtypes. APPIC compiles biological and clinical information from various databases, including the Human Protein Atlas, Hugo Gene Nomenclature Committee, g:Profiler, cBioPortal and Clue.io. The user-friendly interface allows for both 2D and 3D PPI network visualizations, enhancing the usability and interpretability of complex data. For advanced users seeking greater customization, APPIC conveniently provides all output files for further analysis and visualization on other platforms or tools. By offering comprehensive insights into PPIs and their role in cancer, APPIC aims to support the discovery of tumor subtype-specific novel targeted therapeutics and drug repurposing. APPIC is freely available at https://appic.brown.edu.

DOI: https://doi.org/10.1093/narcan/zcae047
J Gastrointest Oncol. 2024 Dec 31. 15(6): 2692-2705

Pathological complete response following neoadjuvant chemotherapy with PD-1 inhibitor for locally advanced pancreatic cancer: case report.

Junsheng Chen, Da Wang, Fei Xiong, Guanhua Wu, Wenzheng Liu, Qi Wang, Yiyang Kuai, Feng Peng, Yongjun Chen.

   Background: In recent years, the incidence of pancreatic cancer has shown an obvious increasing trend worldwide and even causes a greater disease burden to the mankind. Due to the lack of effective early surveillance methods, patients are often in the middle to advanced stages of their disease at the time of detection, thus losing the opportunity for surgery. The currently available chemotherapy regimens are yet to be further improved to prolong patient survival. The use of immune monotherapy in pancreatic cancer is even more frustrating, with poor therapeutic results.
Case Description: Here, we present two cases of locally advanced pancreatic cancer in which neoadjuvant chemotherapy (gemcitabine with albumin-bound paclitaxel) was administered in combination with a programmed cell death protein 1 (PD-1) inhibitor (tislelizumab), resulting in the opportunity for surgical intervention. Notably, one patient exhibited a pathological complete response, characterized by minimal residual highly intraepithelial neoplasia accompanied by extensive fibrosis and transparency. Genetic testing found that the patient had a KRAS mutation (c.35G>T, p.G12V).
Conclusions: The efficacy of this combination therapy has renewed our interest in the mechanism of action or drug resistance of tumor cells in chemotherapy and immunotherapy. An in-depth study of the possible synergistic mechanisms of action of these drugs will provide new research directions for the treatment of pancreatic cancer.

Keywords:  Combination therapy; KRAS; case report; locally advanced pancreatic cancer; neoadjuvant chemotherapy

DOI:  https://doi.org/10.21037/jgo-24-549
Gut. 2025 Jan 16. pii: gutjnl-2024-333408. [Epub ahead of print]

Targeting MXD1 sensitises pancreatic cancer to trametinib.

Shaoping Zhang, Shuang Deng, Ji Liu, Shuang Liu, Ziming Chen, Shaoqiu Liu, Chunling Xue, Lingxing Zeng, Hongzhe Zhao, Zilan Xu, Sihan Zhao, Yifan Zhou, Xinyi Peng, Xiaoyu Wu, Ruihong Bai, Shaojia Wu, Mei Li, Jian Zheng, Dongxin Lin, Jialiang Zhang, Xudong Huang.

   BACKGROUND: The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear.
OBJECTIVE: We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC.
DESIGN: We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism.
RESULTS: We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation protein 1 (MXD1), which acts as a cofactor of histone methyltransferase mixed lineage leukaemia 1 to increased H3K4 trimethylation in transposable element (TE) loci, enhancing chromatin accessibility and thus the transcription of TEs. Mechanistically, enhanced transcription of TEs produces excessive double-stranded RNAs, leading to the activation of viral mimicry response and downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 expression can recover the drug vulnerability of trametinib-resistant PDAC cells to trametinib.
CONCLUSIONS: Our study has discovered an important mechanism for trametinib resistance and identified MXD1 as a druggable target in treatment of trametinib-resistant PDAC.

Keywords:  CANCER GENETICS; DRUG RESISTANCE

DOI:  https://doi.org/10.1136/gutjnl-2024-333408
Mol Cell. 2025 Jan 08. pii: S1097-2765(24)01041-4. [Epub ahead of print]

Deciphering functional tumor-immune crosstalk through highly multiplexed imaging and deep visual proteomics.

Xiang Zheng, Andreas Mund, Matthias Mann.

  Deciphering the intricate tumor-immune interactions within the microenvironment is crucial for advancing cancer immunotherapy. Here, we introduce mipDVP, an advanced approach integrating highly multiplexed imaging, single-cell laser microdissection, and sensitive mass spectrometry to spatially profile the proteomes of distinct cell populations in a human colorectal and tonsil cancer with high sensitivity. In a colorectal tumor-a representative cold tumor-we uncovered spatial compartmentalization of an immunosuppressive macrophage barrier that potentially impedes T cell infiltration. Spatial proteomic analysis revealed distinct functional states of T cells in different tumor compartments. In a tonsil cancer sample-a hot tumor-we identified significant proteomic heterogeneity among cells influenced by proximity to cytotoxic T cell subtypes. T cells in the tumor parenchyma exhibit metabolic adaptations to hypoxic regions. Our spatially resolved, highly multiplexed strategy deciphers the complex cellular interplay within the tumor microenvironment, offering valuable insights for identifying immunotherapy targets and predictive signatures.

Keywords:  cancer; deep visual proteomics; immunotherapy; mass spectrometry; multiplexed imaging; spatial medicine; spatial proteomics; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.molcel.2024.12.023
J Mater Chem B. 2025 Jan 16.

Multi-organelle imaging with dye combinations: targeting the ER, mitochondria, and plasma membrane.

Yogesh Dubey, Sriram Kanvah.

Multi-organelle imaging allows the visualization of multiple organelles within a single cell, allowing monitoring of the cellular processes in real-time using various fluorescent probes that target specific organelles. However, the limited availability of fluorophores and potential spectral overlap present challenges, and many optimized designs are still in nascency. In this work, we synthesized various sulfonamide-based organic fluorophores that emit in the blue, green, and red regions to target different sub-cellular organelles. By utilizing binary mixtures, we successfully demonstrated multiple imaging of the sub-cellular organelles, such as the endoplasmic reticulum, plasma membrane, and mitochondria in HeLa cells, and dual imaging of the endoplasmic reticulum and mitochondria in A549 lung carcinoma cells with the help of blue and red-emitting fluorophores without any spectral spillover. Additionally, these photostable probes allowed precise cell staining and differentiation, structural features, and live cell dynamics. This approach of utilizing fluorescent mixtures can gain traction for various cellular studies and investigations.

DOI: https://doi.org/10.1039/d4tb02456g