bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2024–10–06
thirty-six papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model.
  2. Inactivation of HIPK2 attenuates KRASG12D activity and prevents pancreatic tumorigenesis.
  3. Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice.
  4. Defining precancer: a grand challenge for the cancer community.
  5. Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer.
  6. Migratory autolysosome disposal mitigates lysosome damage.
  7. Lipid synthesis leads the way for invasive migration.
  8. Aneuploidy as a driver of human cancer.
  9. Protocol to measure and analyze protein interactions in mammalian cells using bioluminescence resonance energy transfer.
  10. Collagen type I PET/MRI enables evaluation of treatment response in pancreatic cancer in pre-clinical and first-in-human translational studies.
  11. Accessing the vasculature in cancer: revising an old hallmark.
  12. Trametinib in combination with hydroxychloroquine or palbociclib in advanced metastatic pancreatic cancer: data from a retrospective, multicentric cohort (AIO AIO-TF/PAK-0123).
  13. MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.
  14. Midkine as a driver of age-related changes and increase in mammary tumorigenesis.
  15. Bridging brain and body in cancer.
  16. p21 regulates expression of ECM components and promotes pulmonary fibrosis via CDK4 and Rb.
  17. uPAR Immuno-PET in Pancreatic Cancer, Aging, and Chemotherapy-Induced Senescence.
  18. Membrane tension sensing formin-binding protein 1 is a neuronal nutrient stress-responsive Golgiphagy receptor.
  19. Calibrating tumor growth and invasion parameters with spectral spatial analysis of cancer biopsy tissues.
  20. Transforming Cancer Research through Informatics.
  21. The Association between Early-Onset Pancreatic Ductal Adenocarcinoma and Patients Survival: A Systematic Review and Meta-Analysis.
  22. The area postrema: a critical mediator of brain-body interactions.
  23. OrgaMapper: a robust and easy-to-use workflow for analyzing organelle positioning.
  24. Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions.
  25. Chemical mapping of the surface interactome of PIEZO1 identifies CADM1 as a modulator of channel inactivation.
  26. TDRD3 functions as a selective autophagy receptor with dual roles in autophagy and modulation of stress granule stability.
  27. Identifying metabolic limitations in the tumor microenvironment.
  28. Membrane Tension Regulation is Required for Wound Repair.
  29. Mechanosensitive fluorescence lifetime probes for investigating the dynamic mechanism of ferroptosis.
  30. CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment.
  31. The role and mechanism of compressive stress in tumor.
  32. Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis.
  33. TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.
  34. Mechanisms and regulation of substrate degradation by the 26S proteasome.
  35. Recommendations for Accurate Lipid Annotation and Semi-absolute Quantification from LC-MS/MS Datasets.
  36. FCS videos: Fluorescence correlation spectroscopy in space and time.
  1. Cancer Discov. 2024 Sep 30.
    Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model.
    Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A DePinho.
      Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0489
  2. J Exp Clin Cancer Res. 2024 Sep 28. 43(1): 265
    Inactivation of HIPK2 attenuates KRASG12D activity and prevents pancreatic tumorigenesis.
    Silvia Sozzi, Isabella Manni, Cristiana Ercolani, Maria Grazia Diodoro, Armando Bartolazzi, Francesco Spallotta, Giulia Piaggio, Laura Monteonofrio, Silvia Soddu, Cinzia Rinaldo, Davide Valente.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) features KRAS mutations in approximately 90% of human cases and excessive stromal response, termed desmoplastic reaction. Oncogenic KRAS drives pancreatic carcinogenesis by acting on both epithelial cells and tumor microenvironment (TME). We have previously shown that Homeodomain-Interacting Protein Kinase 2 (HIPK2) cooperates with KRAS in sustaining ERK1/2 phosphorylation in human colorectal cancers. Here, we investigated whether HIPK2 contributes to oncogenic KRAS-driven tumorigenesis in vivo, in the onset of pancreatic cancer.
    METHODS: We employed an extensively characterized model of KRASG12D-dependent preinvasive PDAC, the Pdx1-Cre;LSL-KRasG12D/+ (KC) mice. In these mice, HIPK2 was inhibited by genetic knockout in the pancreatic epithelial cells (KCH-/-) or by pharmacologic inactivation with the small molecule 5-IodoTubercidin (5-ITu). The development of preneoplastic acinar-to-ductal metaplasia (ADM), intraepithelial neoplasia (PanIN), and their associated desmoplastic reaction were analyzed.
    RESULTS: In Hipk2-KO mice (KCH-/-), ERK phosphorylation was lowered, the appearance of ADM was slowed down, and both the number and pathologic grade of PanIN were reduced compared to Hipk2-WT KC mice. The pancreatic lesion phenotype in KCH-/- mice was characterized by abundant collagen fibers and reduced number of αSMA+ and pSTAT3+ desmoplastic cells. These features were reminiscent of the recently described human "deserted" sub-TME, poor in cells, rich in matrix, and associated with tumor differentiation. In contrast, the desmoplastic reaction of KC mice resembled the "reactive" sub-TME, rich in stromal cells and associated with tumor progression. These observations were confirmed by the pharmacologic inhibition of HIPK2 in KC mice.
    CONCLUSION: This study demonstrates that HIPK2 inhibition weakens oncogenic KRAS activity and pancreatic tumorigenesis providing a rationale for testing HIPK2 inhibitors to mitigate the incidence of PDAC development in high-risk individuals.
    Keywords:  HIPK2; KRAS; Pancreatic tumorigenesis
    DOI:  https://doi.org/10.1186/s13046-024-03189-3
  3. bioRxiv. 2024 Sep 21. pii: 2024.09.17.613547. [Epub ahead of print]
    Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice.
    Martin M Schonk, Jeremy B Ducharme, Daria Neyroud, Rachel L Nosacka, Haley O Tucker, Sarah M Judge, Andrew R Judge.
      Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1 SkmKO ) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.
    NEW & NOTEWORTHY: Here we identify myofiber-derived FoxP1 as a negative regulator of skeletal muscle with sex-specific effects in cancer. Under cancer-free conditions, FoxP1 knockout increased myofiber size in male and female mice. However, in response to pancreatic cancer, FoxP1 was required for muscle wasting and weakness in males but not females. This highlights the need to consider sexual dimorphism in cancer-induced muscle pathologies and provides evidence suggesting that targeting FoxP1 could help mitigate these effects in males.
    DOI:  https://doi.org/10.1101/2024.09.17.613547
  4. Nat Rev Cancer. 2024 Oct 01.
    Defining precancer: a grand challenge for the cancer community.
    Precancer Think Tank Team
      The term 'precancer' typically refers to an early stage of neoplastic development that is distinguishable from normal tissue owing to molecular and phenotypic alterations, resulting in abnormal cells that are at least partially self-sustaining and function outside of normal cellular cues that constrain cell proliferation and survival. Although such cells are often histologically distinct from both the corresponding normal and invasive cancer cells of the same tissue origin, defining precancer remains a challenge for both the research and clinical communities. Once sufficient molecular and phenotypic changes have occurred in the precancer, the tissue is identified as a 'cancer' by a histopathologist. While even diagnosing cancer can at times be challenging, the determination of invasive cancer is generally less ambiguous and suggests a high likelihood of and potential for metastatic disease. The 'hallmarks of cancer' set out the fundamental organizing principles of malignant transformation but exactly how many of these hallmarks and in what configuration they define precancer has not been clearly and consistently determined. In this Expert Recommendation, we provide a starting point for a conceptual framework for defining precancer, which is based on molecular, pathological, clinical and epidemiological criteria, with the goal of advancing our understanding of the initial changes that occur and opportunities to intervene at the earliest possible time point.
    DOI:  https://doi.org/10.1038/s41568-024-00744-0
  5. Nat Commun. 2024 Oct 02. 15(1): 8540
    Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer.
    Vincent de Laat, Halit Topal, Xander Spotbeen, Ali Talebi, Jonas Dehairs, Jakub Idkowiak, Frank Vanderhoydonc, Tessa Ostyn, Peihua Zhao, Maarten Jacquemyn, Michele Wölk, Anna Sablina, Koen Augustyns, Tom Vanden Berghe, Tania Roskams, Dirk Daelemans, Maria Fedorova, Baki Topal, Johannes V Swinnen.
      A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.
    DOI:  https://doi.org/10.1038/s41467-024-52978-z
  6. J Cell Biol. 2024 Dec 02. pii: e202403195. [Epub ahead of print]223(12):
    Migratory autolysosome disposal mitigates lysosome damage.
    Takami Sho, Ying Li, Haifeng Jiao, Li Yu.
      Lysosomes, essential for intracellular degradation and recycling, employ damage-control strategies such as lysophagy and membrane repair mechanisms to maintain functionality and cellular homeostasis. Our study unveils migratory autolysosome disposal (MAD), a response to lysosomal damage where cells expel LAMP1-LC3 positive structures via autolysosome exocytosis, requiring autophagy machinery, SNARE proteins, and cell migration. This mechanism, crucial for mitigating lysosomal damage, underscores the role of cell migration in lysosome damage control and facilitates the release of small extracellular vesicles, highlighting the intricate relationship between cell migration, organelle quality control, and extracellular vesicle release.
    DOI:  https://doi.org/10.1083/jcb.202403195
  7. J Cell Biol. 2024 Oct 07. pii: e202408005. [Epub ahead of print]223(10):
    Lipid synthesis leads the way for invasive migration.
    Laura M Machesky.
      Invasive migration requires cells to break through extracellular matrix barriers, which is an energy-expensive process. In this issue, Park et al. (https://doi.org/10.1083/jcb.202402035) highlight the importance of biosynthesis of fatty acids, phospholipids, and isoprenoids in driving invasive migration of the Caenorhabditis elegans anchor cell through a basement membrane barrier during development.
    DOI:  https://doi.org/10.1083/jcb.202408005
  8. Nat Genet. 2024 Oct 02.
    Aneuploidy as a driver of human cancer.
    Eran Sdeor, Hajime Okada, Ron Saad, Tal Ben-Yishay, Uri Ben-David.
      Aneuploidy, an abnormal chromosome composition, is a major contributor to cancer development and progression and an important determinant of cancer therapeutic responses and clinical outcomes. Despite being recognized as a hallmark of human cancer, the exact role of aneuploidy as a 'driver' of cancer is still largely unknown. Identifying the specific genetic elements that underlie the recurrence of common aneuploidies remains a major challenge of cancer genetics. In this Review, we discuss recurrent aneuploidies and their function as drivers of tumor development. We then delve into the context-dependent identification and functional characterization of the driver genes underlying driver aneuploidies and examine emerging strategies to uncover these driver genes using cancer genomics data and cancer models. Lastly, we explore opportunities for targeting driver aneuploidies in cancer by leveraging the functional consequences of these common genetic alterations.
    DOI:  https://doi.org/10.1038/s41588-024-01916-2
  9. STAR Protoc. 2024 Sep 28. pii: S2666-1667(24)00513-6. [Epub ahead of print]5(4): 103348
    Protocol to measure and analyze protein interactions in mammalian cells using bioluminescence resonance energy transfer.
    Carla Jane Duval, Candy Laura Steffen, Karolina Pavic, Daniel Kwaku Abankwa.
      Bioluminescence resonance energy transfer (BRET) allows to quantitate protein interactions in intact cells. Here, we present a protocol for measuring BRET due to transient interactions of oncogenic K-RasG12V in plasma membrane nanoclusters of HEK293-EBNA cells. We describe steps for seeding, transfecting, and replating cells. We then detail procedures for their preparation for BRET measurements on a CLARIOstar microplate reader and detailed data analysis. For complete details on the use and execution of this protocol, please refer to Steffen et al.1.
    Keywords:  Cell Biology; Cell-based Assays; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2024.103348
  10. Theranostics. 2024 ;14(15): 5745-5761
    Collagen type I PET/MRI enables evaluation of treatment response in pancreatic cancer in pre-clinical and first-in-human translational studies.
    Shadi A Esfahani, Hua Ma, Shriya Krishna, Sergey Shuvaev, Mark Sabbagh, Caitlin Deffler, Nicholas Rotile, Jonah Weigand-Whittier, Iris Y Zhou, Ciprian Catana, Onofrio A Catalano, David T Ting, Pedram Heidari, Eric Abston, Michael Lanuti, Genevieve M Boland, Priyanka Pathak, Hannah Roberts, Kenneth K Tanabe, Motaz Qadan, Carlos Fernandez-Del Castillo, Angela Shih, Aparna R Parikh, Colin D Weekes, Theodore S Hong, Peter Caravan.
      Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. Methods: We evaluated the specificity of 68Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of 68Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68Ga-CBP8 PET/MRI, and five underwent follow up 68Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Results: 68Ga-CBP8 showed specific binding to PDAC compared to non-binding 68Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). 68Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. 68Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher 68Ga-CBP8 uptake in tumor compared to pancreas (SUVmean: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUVmean: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUVmean (R2 = 0.54, P = 0.0007). Conclusions: This study demonstrates the specificity of 68Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.
    Keywords:  PET imaging; fibrosis; pancreatic cancer; treatment response; type I collagen
    DOI:  https://doi.org/10.7150/thno.100116
  11. Trends Cancer. 2024 Oct 01. pii: S2405-8033(24)00170-5. [Epub ahead of print]
    Accessing the vasculature in cancer: revising an old hallmark.
    Adrian L Harris, David J Kerr, Francesco Pezzella, Domenico Ribatti.
      The classic cancer hallmark, inducing angiogenesis, was born out of the long-held notion that tumours could grow only if new vessels were formed. The attempts, based on this premise, to therapeutically restrain angiogenesis in hopes of controlling tumour growth have been less effective than expected. This is partly because primary and metastatic tumours can grow without angiogenesis. The discovery of nonangiogenic cancers and the mechanisms they use to exploit normal vessels, called 'vessel co-option,' has opened a new field in cancer biology. Consequently, the cancer hallmark, 'inducing angiogenesis,' has been modified to 'inducing or accessing vasculature.'
    Keywords:  angiogenesis; cancer and blood vessels, vessel co-option; hallmarks of cancer; nonangiogenic tumours
    DOI:  https://doi.org/10.1016/j.trecan.2024.08.003
  12. J Cancer Res Clin Oncol. 2024 Oct 01. 150(10): 438
    Trametinib in combination with hydroxychloroquine or palbociclib in advanced metastatic pancreatic cancer: data from a retrospective, multicentric cohort (AIO AIO-TF/PAK-0123).
    David Witte, Ina Pretzell, Timm M Reissig, Alexander Stein, Janna-Lisa Velthaus, Annabel Alig, Hanibal Bohnenberger, Maren Knödler, Annika Kurreck, Sabrina Sulzer, Georg Beyer, Klara Dorman, Tabea Fröhlich, Stefanie Hegenberg, Celine Lugnier, Anna Saborowski, Arndt Vogel, Sebastian Lange, Maximilian Reichert, Franziska Flade, Lioba Klaas, Kirsten Utpatel, Heiko Becker, Annalen Bleckmann, Klaus Wethmar, Anke Reinacher-Schick, Christoph Benedikt Westphalen.
       BACKGROUND: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs.
    METHODS: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany.
    RESULTS: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP.
    CONCLUSION: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B.
    Keywords:  Autophagy; CDK inhibitor; MEK inhibitor; Molecular guided treatment; Pancreatic cancer; Targeted therapy
    DOI:  https://doi.org/10.1007/s00432-024-05954-5
  13. Nat Genet. 2024 Oct 02.
    MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.
    TRACERx Consortium
      Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.
    DOI:  https://doi.org/10.1038/s41588-024-01883-8
  14. Cancer Cell. 2024 Sep 26. pii: S1535-6108(24)00350-7. [Epub ahead of print]
    Midkine as a driver of age-related changes and increase in mammary tumorigenesis.
    Pengze Yan, Ernesto Rojas Jimenez, Zheqi Li, Triet Bui, Marco Seehawer, Jun Nishida, Pierre Foidart, Laura E Stevens, Yingtian Xie, Miguel Munoz Gomez, So Yeon Park, Henry W Long, Kornelia Polyak.
      Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.
    Keywords:  aging; breast cancer risk; breast tumorigenesis; mammary tumors; midkine; single-cell profiling
    DOI:  https://doi.org/10.1016/j.ccell.2024.09.002
  15. Genes Dev. 2024 Oct 03.
    Bridging brain and body in cancer.
    Michael Cross, Andrew Dillin, Thales Papagiannakopoulos.
      Recent work has highlighted the central role the brain-body axis plays in not only maintaining organismal homeostasis but also coordinating the body's response to immune and inflammatory insults. Here, we discuss how science is poised to address the many ways that our brain is directly involved with disease. In particular, we feel that combining cutting-edge tools in neuroscience with translationally relevant models of cancer will be critical to understanding how the brain and tumors communicate and modulate each other's behavior.
    Keywords:  brain–body; physiology; symposium
    DOI:  https://doi.org/10.1101/gad.352300.124
  16. EMBO J. 2024 Sep 30.
    p21 regulates expression of ECM components and promotes pulmonary fibrosis via CDK4 and Rb.
    Nurit Papismadov, Naama Levi, Lior Roitman, Amit Agrawal, Yossi Ovadya, Ulysse Cherqui, Reut Yosef, Hagay Akiva, Hilah Gal, Valery Krizhanovsky.
      Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner dependent on CDK4 and Rb phosphorylation. p21 knockout protects mice from the induction of lung fibrosis. Moreover, inducible p21 silencing during fibrosis development alleviates disease pathology, decreasing the inflammatory response and ECM accumulation in the lung, and reducing the amount of senescent cells. Furthermore, p21 silencing limits fibrosis progression even when introduced during disease development. These findings show that one common mechanism regulates both cell cycle progression and expression of ECM components, and suggest that targeting p21 might be a new approach for treating age-related fibrotic pathologies.
    Keywords:  CDK4; Cellular Senescence; Extracellular Matrix (ECM); Fibrosis; p21 (CDKN1A)
    DOI:  https://doi.org/10.1038/s44318-024-00246-7
  17. J Nucl Med. 2024 Oct 03. pii: jnumed.124.268278. [Epub ahead of print]
    uPAR Immuno-PET in Pancreatic Cancer, Aging, and Chemotherapy-Induced Senescence.
    Edwin C Pratt, Riccardo Mezzadra, Amanda Kulick, Spencer Kaminsky, Zachary V Samuels, Angelique Loor, Elisa de Stanchina, Scott W Lowe, Jason S Lewis.
      Identifying cancer therapy resistance is a key time-saving tool for physicians. Part of chemotherapy resistance includes senescence, a persistent state without cell division or cell death. Chemically inducing senescence with the combination of trametinib and palbociclib (TP) yields several tumorigenic and prometastatic factors in pancreatic cancer models with many potential antibody-based targets. In particular, urokinase plasminogen activator receptor (uPAR) has been shown to be a membrane-bound marker of senescence in addition to an oncology target. Methods: Here, 2 antibodies against murine uPAR and human uPAR were developed as immuno-PET agents to noninvasively track uPAR antigen abundance. Results: TP treatment increased cell uptake both in murine KPC cells and in human MiaPaCa2 cells. In vivo, subcutaneously implanted murine KPC tumors had high tumor uptake with the antimurine uPAR antibody independently of TP in young mice, yet uPAR uptake was maintained in aged mice on TP. Mice xenografted with human MiaPaCa2 tumors showed a significant increase in tumor uptake on TP therapy when imaged with the antihuman uPAR antibody. Imaging with either uPAR antibody was found to be more tumor-selective than imaging with [18F]FDG or [18F]F-DPA-714. Conclusion: The use of radiolabeled uPAR-targeting antibodies provides a new antibody-based PET imaging candidate for pancreatic cancer imaging as well as chemotherapy-induced senescence.
    Keywords:  aging; immuno-PET; pancreatic cancer; senescence
    DOI:  https://doi.org/10.2967/jnumed.124.268278
  18. Metabolism. 2024 Sep 26. pii: S0026-0495(24)00268-3. [Epub ahead of print] 156040
    Membrane tension sensing formin-binding protein 1 is a neuronal nutrient stress-responsive Golgiphagy receptor.
    Smita Saha, Anirban Mandal, Akash Ranjan, Debasish Kumar Ghosh.
       BACKGROUND: Nutrient stress-responsive neuronal homeostasis relies on intricate autophagic mechanisms that modulate various organelle integrity and function. The selective autophagy of the Golgi, known as Golgiphagy, regulates secretory processes by modulating vesicle trafficking during nutrient starvation.
    RESULTS: In this study, we explored a genetic screen of BAR-domain-containing proteins to elucidate the role of formin-binding protein 1 (FNBP1) as a Golgiphagy receptor in modulating Golgi dynamics in response to varying nutrient availability in neurons. Mapping the systems network of FNBP1 and its interacting proteins reveals the putative involvement of FNBP1 in autophagy and Golgi-associated processes. While nutrient depletion causes Golgi fragmentation, FNBP1 preferentially localizes to the fragmented Golgi membrane through its 284FEDYTQ289 motif during nutrient stress. Simultaneously, FNBP1 engages in molecular interactions with LC3B through a conserved 131WKQL134 LC3 interacting region, thereby sequestering the fragmented Golgi membrane in neuronal autophagosomes. Increased aggregation of GM130, abnormal clumping of RAB11-positive secretory granules, and enhanced senescent death of FNBP1-depleted starved neurons indicate disruptions of neuronal homeostasis under metabolic stress.
    CONCLUSION: The identification of FNBP1 as a nutrient stress-responsive Golgiphagy receptor expands our insights into the molecular mechanisms underlying Golgiphagy, establishing the crosstalk between nutrient sensing and membrane tension-sensing regulatory autophagic processes of Golgi turnover in neurons.
    Keywords:  Formin-binding protein 1; Golgi fragmentation; Golgiphagy; Golgiphagy receptor; Neuron; Nutrient stress
    DOI:  https://doi.org/10.1016/j.metabol.2024.156040
  19. NPJ Syst Biol Appl. 2024 Oct 02. 10(1): 112
    Calibrating tumor growth and invasion parameters with spectral spatial analysis of cancer biopsy tissues.
    Stefano Pasetto, Michael Montejo, Mohammad U Zahid, Marilin Rosa, Robert Gatenby, Pirmin Schlicke, Roberto Diaz, Heiko Enderling.
      The reaction-diffusion equation is widely used in mathematical models of cancer. The calibration of model parameters based on limited clinical data is critical to using reaction-diffusion equation simulations for reliable predictions on a per-patient basis. Here, we focus on cell-level data as routinely available from tissue biopsies used for clinical cancer diagnosis. We analyze the spatial architecture in biopsy tissues stained with multiplex immunofluorescence. We derive a two-point correlation function and the corresponding spatial power spectral distribution. We show that this data-deduced power spectral distribution can fit the power spectrum of the solution of reaction-diffusion equations that can then identify patient-specific tumor growth and invasion rates. This approach allows the measurement of patient-specific critical tumor dynamical properties from routinely available biopsy material at a single snapshot in time.
    DOI:  https://doi.org/10.1038/s41540-024-00439-0
  20. Cancer Discov. 2024 Oct 04. 14(10): 1779-1782
    Transforming Cancer Research through Informatics.
    Juli D Klemm, Dinah S Singer, Jill P Mesirov.
      For more than three decades, concurrent advances in laboratory technologies and computer science have driven the rise of cancer informatics. Today, software tools for cancer research are indispensable to the entire cancer research enterprise.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0604
  21. F1000Res. 2024 ;13 976
    The Association between Early-Onset Pancreatic Ductal Adenocarcinoma and Patients Survival: A Systematic Review and Meta-Analysis.
    Kaka Renaldi, Andy William.
       Background: In recent years, the incidence of early-onset pancreatic cancer (EOPC) has increased. Several studies comparing the survival of patients with EOPC to those with average-onset pancreatic cancer (AOPC) have reported mixed results. We aimed, therefore, to perform a meta-analysis summarizing the current evidence.
    Methods: We searched the MEDLINE and EMBASE databases for relevant articles published through March 2024. Articles comparing the survival of patients with EOPC - defined as pancreatic ductal adenocarcinoma (PDAC) diagnosed at ≤ 50 years of age - and AOPC were included in the present meta-analysis. The primary outcome was the pooled adjusted hazard ratio (aHR), and the risk of bias analysis was performed using the Quality in Prognostic Factor Studies tool. The meta-analysis was performed using a random-effects model.
    Results: A total of 17 studies were eligible for the primary analysis, the results of which indicated that patients with EOPC had a longer overall survival than those with AOPC (aHR = 0.80; 95% confidence interval [CI], 0.74-0.86; P < 0.001). The rate of distant metastasis was higher in EOPC than AOPC; however, patients with EOPC also received more treatments than those with AOPC.
    Conclusions: Patients with EOPC had a better prognosis than those with AOPC. Clinicians must ensure that patients with PDAC receive early and appropriate treatment to improve their survival.
    Keywords:  Meta-analysis; Pancreatic neoplasms; Survival; Young adult
    DOI:  https://doi.org/10.12688/f1000research.153743.1
  22. Genes Dev. 2024 Oct 03.
    The area postrema: a critical mediator of brain-body interactions.
    Daniëlle van de Lisdonk, Bo Li.
      The dorsal vagal complex contains three structures: the area postrema, the nucleus tractus solitarii, and the dorsal motor nucleus of the vagus. These structures are tightly linked, both anatomically and functionally, and have important yet distinct roles in not only conveying peripheral bodily signals to the rest of the brain but in the generation of behavioral and physiological responses. Reports on the new discoveries in these structures were highlights of the symposium. In this outlook, we focus on the roles of the area postrema in mediating brain-body interactions and its potential utility as a therapeutic target, especially in cancer cachexia.
    Keywords:  brain–body; physiology; symposium
    DOI:  https://doi.org/10.1101/gad.352276.124
  23. BMC Biol. 2024 Sep 30. 22(1): 220
    OrgaMapper: a robust and easy-to-use workflow for analyzing organelle positioning.
    Christopher Schmied, Michael Ebner, Paula Samsó, Rozemarijn Van Der Veen, Volker Haucke, Martin Lehmann.
       BACKGROUND: Eukaryotic cells are highly compartmentalized by a variety of organelles that carry out specific cellular processes. The position of these organelles within the cell is elaborately regulated and vital for their function. For instance, the position of lysosomes relative to the nucleus controls their degradative capacity and is altered in pathophysiological conditions. The molecular components orchestrating the precise localization of organelles remain incompletely understood. A confounding factor in these studies is the fact that organelle positioning is surprisingly non-trivial to address e.g., perturbations that affect the localization of organelles often lead to secondary phenotypes such as changes in cell or organelle size. These phenotypes could potentially mask effects or lead to the identification of false positive hits. To uncover and test potential molecular components at scale, accurate and easy-to-use analysis tools are required that allow robust measurements of organelle positioning.
    RESULTS: Here, we present an analysis workflow for the faithful, robust, and quantitative analysis of organelle positioning phenotypes. Our workflow consists of an easy-to-use Fiji plugin and an R Shiny App. These tools enable users without background in image or data analysis to (1) segment single cells and nuclei and to detect organelles, (2) to measure cell size and the distance between detected organelles and the nucleus, (3) to measure intensities in the organelle channel plus one additional channel, (4) to measure radial intensity profiles of organellar markers, and (5) to plot the results in informative graphs. Using simulated data and immunofluorescent images of cells in which the function of known factors for lysosome positioning has been perturbed, we show that the workflow is robust against common problems for the accurate assessment of organelle positioning such as changes of cell shape and size, organelle size and background.
    CONCLUSIONS: OrgaMapper is a versatile, robust, and easy-to-use automated image analysis workflow that can be utilized in microscopy-based hypothesis testing and screens. It effectively allows for the mapping of the intracellular space and enables the discovery of novel regulators of organelle positioning.
    Keywords:  Data analysis; Fiji; Image analysis; ImageJ; Organelle position; R; Segmentation; Shiny
    DOI:  https://doi.org/10.1186/s12915-024-02015-8
  24. Sci Adv. 2024 Oct 04. 10(40): eadq3591
    Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions.
    Kyle M Flickinger, Kelli M Wilson, Nicholas J Rossiter, Andrea L Hunger, Paresh V Vishwasrao, Tobie D Lee, Carlos A Mellado Fritz, Rebecca M Richards, Matthew D Hall, Jason R Cantor.
      Chemical screens across hundreds of cell lines have shown that the drug sensitivities of human cancers can vary by genotype or lineage. However, most drug discovery studies have relied on culture media that poorly reflect metabolite levels in human blood. Here, we perform drug screens in traditional and Human Plasma-Like Medium (HPLM). Sets of compounds that show conditional anticancer activity span different phases of global development and include non-oncology drugs. Comparisons of the synthetic and serum-derived components that comprise typical media trace sets of conditional phenotypes to nucleotide synthesis substrates. We also characterize a unique dual mechanism for brivudine, a compound approved for antiviral use. Brivudine selectively impairs cell growth in low folate conditions by targeting two enzymes involved in one-carbon metabolism. Cataloged gene essentiality data further suggest that conditional phenotypes for other compounds are linked to off-target effects. Our findings establish general strategies for identifying drug-nutrient interactions and mechanisms of action by exploiting conditional lethality in cancer cells.
    DOI:  https://doi.org/10.1126/sciadv.adq3591
  25. Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2415934121
    Chemical mapping of the surface interactome of PIEZO1 identifies CADM1 as a modulator of channel inactivation.
    Anna K Koster, Oleg Yarishkin, Adrienne E Dubin, Jennifer M Kefauver, Ryan A Pak, Benjamin F Cravatt, Ardem Patapoutian.
      The propeller-shaped blades of the PIEZO1 and PIEZO2 ion channels partition into the plasma membrane and respond to indentation or stretching of the lipid bilayer, thus converting mechanical forces into signals that can be interpreted by cells, in the form of calcium flux and changes in membrane potential. While PIEZO channels participate in diverse physiological processes, from sensing the shear stress of blood flow in the vasculature to detecting touch through mechanoreceptors in the skin, the molecular details that enable these mechanosensors to tune their responses over a vast dynamic range of forces remain largely uncharacterized. To survey the molecular landscape surrounding PIEZO channels at the cell surface, we employed a mass spectrometry-based proteomic approach to capture and identify extracellularly exposed proteins in the vicinity of PIEZO1. This PIEZO1-proximal interactome was enriched in surface proteins localized to cell junctions and signaling hubs within the plasma membrane. Functional screening of these interaction candidates by calcium imaging and electrophysiology in an overexpression system identified the adhesion molecule CADM1/SynCAM that slows the inactivation kinetics of PIEZO1 with little effect on PIEZO2. Conversely, we found that CADM1 knockdown accelerates inactivation of endogenous PIEZO1 in Neuro-2a cells. Systematic deletion of CADM1 domains indicates that the transmembrane region is critical for the observed effects on PIEZO1, suggesting that modulation of inactivation is mediated by interactions in or near the lipid bilayer.
    Keywords:  CADM1; PIEZO1; ion channel; mechanosensation
    DOI:  https://doi.org/10.1073/pnas.2415934121
  26. bioRxiv. 2024 Sep 22. pii: 2024.09.22.614367. [Epub ahead of print]
    TDRD3 functions as a selective autophagy receptor with dual roles in autophagy and modulation of stress granule stability.
    Matthew Deater, Richard E Lloyd.
      Tudor Domain Containing 3 (TDRD3) is a methylarginine-reader protein that functions as a scaffold in the nucleus facilitating transcription, however TDRD3 is also recruited to stress granules (SGs) during the Integrated Stress Response (ISR) although its function therein remains largely unknown. We previously showed that TDRD3 is a novel antiviral restriction factor that is cleaved by virus 2A protease, and plays complex modulatory roles in both interferon and inflammatory signaling during stress and enterovirus infections. Here we have found that TDRD3 contains structural motifs similar to known selective autophagy receptors such as p62/SQSTM1, sharing ubiquitin associated domains (UBA) and LC3 interacting regions (LIR) that anchor cargo destined for autophagosomes to activated LC3 protein coating autophagosome membranes. This is of interest since enteroviruses hijack autophagy machinery to facilitate formation of viral replication factories, virus assembly and egress from the infected cell. Here we explored possible roles of TDRD3 in autophagy, hypothesizing that TDRD3 may function as a specialized selective autophagy receptor. We found that KO of TDRD3 in HeLa cells significantly reduces starvation induced autophagy, while its reintroduction restores it in a dose-dependent manner. Autophagy receptors are degraded during autophagy and expression levels decrease during this time. We found that TDRD3 levels decrease to the same extent as the autophagy receptor p62/SQSTM1 during autophagy, indicating autophagy-targeted turnover in that role. Knockout of TDRD3 or G3BP1 did not make significant changes in overall cell localization of LC3B or p62/SQSTM1, but did result in greater concentration of Lamp2 phagosome marker for phagosomes and phagolysosomes. To test the potential roles of TDRD3 in autophagic processes, we created a series of deletion mutants of TDRD3 lacking either UBA domain or the various LIR motifs that are predicted to interact with LC3B. Microscopic examination of starved cells expressing these variants of TDRD3 showed ΔLIR-TDRD3 had defects in colocalization with LC3B or Lamp2. Further, super resolution microscopy revealed ring structures with TDRD3 interfacing with p62/SQSTM1. In examination of arsenite induced stress granules we found recruitment of TDRD3 variants disrupted normally tight SG condensation, altered the decay rate of SGs upon release from stress and the kinetics of SG formation. We found evidence that the LIR3 motif on TDRD3 is involved in TDRD3 interaction with LC3B in coIP experiments, colocalization studies, and that this motif plays a key role in TDRD3 recruitment to SGs and SG resolution. Overall, these data support a functional role of TDRD3 in selective autophagy in a mode similar to p62/SQSTM1, with specific roles in SG stability and turnover. Enterovirus cleavage of TDRD3 likely affects both antiviral and autophagic responses that the virus controls for replication.
    DOI:  https://doi.org/10.1101/2024.09.22.614367
  27. Sci Adv. 2024 Oct 04. 10(40): eadq7305
    Identifying metabolic limitations in the tumor microenvironment.
    Guillaume Cognet, Alexander Muir.
      Solid tumors are characterized by dysfunctional vasculature that limits perfusion and delivery of nutrients to the tumor microenvironment. Limited perfusion coupled with the high metabolic demand of growing tumors has led to the hypothesis that many tumors experience metabolic stress driven by limited availability of nutrients such as glucose, oxygen, and amino acids in the tumor. Such metabolic stress has important implications for the biology of cells in the microenvironment, affecting both disease progression and response to therapies. Recently, techniques have been developed to identify limiting nutrients and resulting metabolic stresses in solid tumors. These techniques have greatly expanded our understanding of the metabolic limitations in tumors. This review will discuss these experimental tools and the emerging picture of metabolic limitations in tumors arising from recent studies using these approaches.
    DOI:  https://doi.org/10.1126/sciadv.adq7305
  28. Adv Sci (Weinh). 2024 Oct 03. e2402317
    Membrane Tension Regulation is Required for Wound Repair.
    Nikita Raj, Martin S Weiß, Bart E Vos, Sarah Weischer, Frauke Brinkmann, Timo Betz, Britta Trappmann, Volker Gerke.
      Disruptions of the eukaryotic plasma membrane due to chemical and mechanical challenges are frequent and detrimental and thus need to be repaired to maintain proper cell function and avoid cell death. However, the cellular mechanisms involved in wound resealing and restoration of homeostasis are diverse and contended. Here, it is shown that clathrin-mediated endocytosis is induced at later stages of plasma membrane wound repair following the actual resealing of the wound. This compensatory endocytosis occurs near the wound, predominantly at sites of previous early endosome exocytosis which is required in the initial stage of membrane resealing, suggesting a spatio-temporal co-ordination of exo- and endocytosis during wound repair. Using cytoskeletal alterations and modulations of membrane tension and membrane area, membrane tension is identified as a major regulator of the wounding-associated exo- and endocytic events that mediate efficient wound repair. Thus, membrane tension changes are a universal trigger for plasma membrane wound repair modulating the exocytosis of early endosomes required for resealing and subsequent clathrin-mediated endocytosis acting at later stages to restore cell homeostasis and function.
    Keywords:  Ca2+; cellular tension; clathrin‐mediated endocytosis; plasma membrane resealing
    DOI:  https://doi.org/10.1002/advs.202402317
  29. Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2316450121
    Mechanosensitive fluorescence lifetime probes for investigating the dynamic mechanism of ferroptosis.
    Xing Liang, Yuping Zhao, Jun Yan, Qian Zhang, Tony D James, Weiying Lin.
      Deciphering the dynamic mechanism of ferroptosis can provide insights into pathogenesis, which is valuable for disease diagnosis and treatment. However, due to the lack of suitable time-resolved mechanosensitive tools, researchers have been unable to determine the membrane tension and morphology of the plasma membrane and the nuclear envelope during ferroptosis. With this research, we propose a rational strategy to develop robust mechanosensitive fluorescence lifetime probes which can facilitate simultaneous fluorescence lifetime imaging of the plasma membrane and nuclear envelope. Fluorescence lifetime imaging microscopy using the unique mechanosensitive probes reveal a dynamic mechanism for ferroptosis: The membrane tension of both the plasma membrane and the nuclear envelope decreases during ferroptosis, and the nuclear envelope exhibits budding during the advanced stage of ferroptosis. Significantly, the membrane tension of the plasma membrane is always larger than that of the nuclear envelope, and the membrane tension of the nuclear envelope is slightly larger than that of the nuclear membrane bubble. Meanwhile, the membrane lesions are repaired in the low-tension regions through exocytosis.
    Keywords:  fluorescence lifetime imaging; fluorescence lifetime probes; mechanism of ferroptosis; membrane tension; nuclear envelope budding
    DOI:  https://doi.org/10.1073/pnas.2316450121
  30. J Exp Clin Cancer Res. 2024 Oct 03. 43(1): 277
    CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment.
    Jinxin Tao, Yani Gu, Zeyu Zhang, Guihu Weng, Yueze Liu, Jie Ren, Yanan Shi, Jiangdong Qiu, Yuanyang Wang, Dan Su, Ruobing Wang, Yifan Fu, Tao Liu, Liyuan Ye, Wenhao Luo, Hao Chen, Gang Yang, Zhe Cao, Hua Huang, Jianchun Xiao, Bo Ren, Lei You, Taiping Zhang, Yupei Zhao.
       BACKGROUND: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment.
    METHODS: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy.
    RESULTS: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival.
    CONCLUSIONS: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.
    Keywords:  CALB2; CXCL14; Cancer-associated fibroblasts; Inflammatory reprogramming; Metastasis; Organoids; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s13046-024-03201-w
  31. Front Oncol. 2024 ;14 1459313
    The role and mechanism of compressive stress in tumor.
    Min Tan, Bingqi Song, Xinbin Zhao, Jing Du.
      Recent research has revealed the important role of mechanical forces in the initiation and progression of tumors. The interplay between mechanical and biochemical cues affects the function and behavior of tumor cells during the development of solid tumors, especially their metastatic potential. The compression force generated by excessive cell proliferation and the tumor microenvironment widely regulates the progression of solid tumor disease. Tumor cells can sense alterations in compressive stress through diverse mechanosensitive components and adapt their mechanical characteristics accordingly to adapt to environmental changes. Here, we summarize the current role of compressive stress in regulating tumor behavior and its biophysical mechanism from the mechanobiological direction.
    Keywords:  cell extrusion; compressive stress; mechanical force; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2024.1459313
  32. Cancer Lett. 2024 Sep 28. pii: S0304-3835(24)00675-X. [Epub ahead of print]605 217280
    Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis.
    Jianzhou Liu, Bolun Jiang, Wenchao Xu, Qiaofei Liu, Haoran Huang, Xiaoyan Chang, Guoxu Ma, Xudong Xu, Li Zhou, Gary Guishan Xiao, Junchao Guo.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.
    Keywords:  Choline kinase inhibitor; Choline kinase α; Metastasis; Pancreatic ductal adenocarcinoma; mTOR
    DOI:  https://doi.org/10.1016/j.canlet.2024.217280
  33. Cancer Discov. 2024 Oct 02.
    TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.
    Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente.
      Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0134
  34. Nat Rev Mol Cell Biol. 2024 Oct 03.
    Mechanisms and regulation of substrate degradation by the 26S proteasome.
    Connor Arkinson, Ken C Dong, Christine L Gee, Andreas Martin.
      The 26S proteasome is involved in degrading and regulating the majority of proteins in eukaryotic cells, which requires a sophisticated balance of specificity and promiscuity. In this Review, we discuss the principles that underly substrate recognition and ATP-dependent degradation by the proteasome. We focus on recent insights into the mechanisms of conventional ubiquitin-dependent and ubiquitin-independent protein turnover, and discuss the plethora of modulators for proteasome function, including substrate-delivering cofactors, ubiquitin ligases and deubiquitinases that enable the targeting of a highly diverse substrate pool. Furthermore, we summarize recent progress in our understanding of substrate processing upstream of the 26S proteasome by the p97 protein unfoldase. The advances in our knowledge of proteasome structure, function and regulation also inform new strategies for specific inhibition or harnessing the degradation capabilities of the proteasome for the treatment of human diseases, for instance, by using proteolysis targeting chimera molecules or molecular glues.
    DOI:  https://doi.org/10.1038/s41580-024-00778-0
  35. Methods Mol Biol. 2025 ;2855 269-287
    Recommendations for Accurate Lipid Annotation and Semi-absolute Quantification from LC-MS/MS Datasets.
    Michele Wölk, Maria Fedorova.
      Recent developments in LC-MS instrumentation and analytical technologies together with bioinformatics tools supporting high-throughput processing of large omics datasets significantly enhanced our capabilities and efficiency of identification and quantification of lipids in diverse biological materials. However, each biological matrix is characterized by its unique lipid composition, thus requiring optimization of analytical and bioinformatics workflows for each studied lipidome. Here, we describe an integrated workflow for deep lipidome profiling, accurate annotation, and semi-absolute quantification of complex lipidomes based on reversed phase chromatography and high resolution mass spectrometry. This chapter provides details on selection of the optimal extraction protocol, acquisition of LC-MS/MS data for accurate annotation of lipid molecular species, and design of lipidome-specific mixtures of internal standards to assist quantitative analysis of complex, native lipidomes.
    Keywords:  High resolution mass spectrometry; Lipid annotations; Lipidomics; Quantitative lipidomics
    DOI:  https://doi.org/10.1007/978-1-0716-4116-3_16
  36. Biochim Biophys Acta Gen Subj. 2024 Sep 28. pii: S0304-4165(24)00159-4. [Epub ahead of print]1868(11): 130716
    FCS videos: Fluorescence correlation spectroscopy in space and time.
    Thorsten Wohland, Shao Ren Sim, Marc Demoustier, Shambhavi Pandey, Rutuparna Kulkarni, Daniel Aik.
      Fluorescence Correlation Spectroscopy (FCS), invented more than 50 years ago is a widely used tool providing information on molecular processes in a variety of samples from materials to life sciences. In the last two decades FCS was multiplexed and ultimately made into an imaging technique that provided maps of molecular parameters over whole sample cross-section. However, it was still limited by a measurement time on the order of minutes. With the improvement of FCS time resolution to seconds using deep learning, we extend here FCS to so-called FCS videos that can provide information how the molecular parameters determined by Imaging FCS change in space and time. This opens up new possibilities for the investigation of molecular processes. Here, we demonstrate the feasibility of the approach and show FCS video applications to lipid bilayers and cell membranes.
    Keywords:  Fluorescence correlation spectroscopy; Lipid bilayer; Membrane structure and dynamics; Spatiotemporal super-resolution
    DOI:  https://doi.org/10.1016/j.bbagen.2024.130716
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