bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–01–08
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Hallmarks of aging: An expanding universe.
  2. Lactate metabolism is essential in early-onset mitochondrial myopathy.
  3. The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis.
  4. Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU).
  5. Identification of circulating plasma ceramides as a potential sexually dimorphic biomarker of pancreatic cancer-induced cachexia.
  6. Meta-hallmarks of aging and cancer.
  7. CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy.
  8. Generation of orthotopic patient-derived xenograft models for pancreatic cancer using tumor slices.
  9. MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.
  10. Dormant cancer cells: programmed quiescence, senescence, or both?
  11. Watching Living Cells in Action in the Exocrine Pancreas: The Palade Prize Lecture.
  12. MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.
  13. Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.
  14. STAT proteins in cancer: orchestration of metabolism.
  15. Borderline Resectable Pancreatic Cancer: Challenges for Clinical Management.
  16. Use of a dual genetic system to decipher exocrine cell fate conversions in the adult pancreas.
  17. Experimental models for ageing research.
  18. Quantification of Invadopodia Formation and Matrix Degradation Activity.
  19. Lamc2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth.
  20. Time-tagged ticker tapes for intracellular recordings.
  21. RAS nanoclusters are cell surface transducers that convert extracellular stimuli to intracellular signaling.
  22. Measuring Cellular Traction Forces with Micropillar Arrays.
  23. Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front.
  24. Laser-Assisted Single-Cell Labeling and Capture.
  25. Intravital Microscopy of the Metastatic Pulmonary Environment.
  26. Collective directional migration drives the formation of heteroclonal cancer cell clusters.
  27. The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.
  28. Solid-phase capture and profiling of open chromatin by spatial ATAC.
  29. The genomic regulation of metastatic dormancy.
  30. Assessment of stromal SCD-induced drug resistance of PDAC using 3D-printed zPDX model chips.
  1. Cell. 2022 Dec 26. pii: S0092-8674(22)01377-0. [Epub ahead of print]
    Hallmarks of aging: An expanding universe.
    Carlos López-Otín, Maria A Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer.
      Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
    DOI:  https://doi.org/10.1016/j.cell.2022.11.001
  2. Sci Adv. 2023 Jan 04. 9(1): eadd3216
    Lactate metabolism is essential in early-onset mitochondrial myopathy.
    Zhenkang Chen, Bogdan Bordieanu, Rushendhiran Kesavan, Nicholas P Lesner, Siva Sai Krishna Venigalla, Spencer D Shelton, Ralph J DeBerardinis, Prashant Mishra.
      Myopathies secondary to mitochondrial electron transport chain (ETC) dysfunction can result in devastating disease. While the consequences of ETC defects have been extensively studied in culture, little in vivo data are available. Using a mouse model of severe, early-onset mitochondrial myopathy, we characterized the proteomic, transcriptomic, and metabolic characteristics of disease progression. Unexpectedly, ETC dysfunction in muscle results in reduced expression of glycolytic enzymes in our animal model and patient muscle biopsies. The decrease in glycolysis was mediated by loss of constitutive Hif1α signaling, down-regulation of the purine nucleotide cycle enzyme AMPD1, and activation of AMPK. In vivo isotope tracing experiments indicated that myopathic muscle relies on lactate import to supply central carbon metabolites. Inhibition of lactate import reduced steady-state levels of tricarboxylic acid cycle intermediates and compromised the life span of myopathic mice. These data indicate an unexpected mode of metabolic reprogramming in severe mitochondrial myopathy that regulates disease progression.
    DOI:  https://doi.org/10.1126/sciadv.add3216
  3. Nat Commun. 2023 Jan 03. 14(1): 1
    The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis.
    Lu Han, Yongxia Wu, Kun Fang, Sean Sweeney, Ulyss K Roesner, Melodie Parrish, Khushbu Patel, Tom Walter, Julia Piermattei, Anthony Trimboli, Julia Lefler, Cynthia D Timmers, Xue-Zhong Yu, Victor X Jin, Michael T Zimmermann, Angela J Mathison, Raul Urrutia, Michael C Ostrowski, Gustavo Leone.
      Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-022-34464-6
  4. Front Immunol. 2022 ;13 1060957
    Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU).
    S M Zahid Hosen, Md Nazim Uddin, Zhihong Xu, Benjamin J Buckley, Chamini Perera, Tony C Y Pang, Alpha Raj Mekapogu, Mohammad Ali Moni, Faiyaz Notta, Steven Gallinger, Ron Pirola, Jeremy Wilson, Marie Ranson, David Goldstein, Minoti Apte.
       Background: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition.
    Methods: This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis.
    Results: Our analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis.
    Conclusion: Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU.
    Keywords:  ECM degradation; EMT; PLAU; immune suppression and basal subtype type of PDAC; pancreatic stellate cells; proliferation; stemness
    DOI:  https://doi.org/10.3389/fimmu.2022.1060957
  5. JCSM Rapid Commun. 2022 Jul-Dec;5(2):5(2): 254-265
    Identification of circulating plasma ceramides as a potential sexually dimorphic biomarker of pancreatic cancer-induced cachexia.
    Jeffery M Chakedis, Mary E Dillhoff, Carl R Schmidt, Priyani V Rajasekera, David C Evans, Terence M Williams, Denis C Guttridge, Erin E Talbert.
       Background: Cancer patients who exhibit cachexia lose weight and have low treatment tolerance and poor outcomes compared to cancer patients without weight loss. Despite the clear increased risk for patients, diagnosing cachexia still often relies on self-reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes.
    Methods: Targeted metabolomics, that included panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer (n=10/group, equally divided by sex). Additional patient samples were analyzed (total n=95) and Receiver Operating Characteristic (ROC) analyses were performed to establish if any metabolite could effectively serve as a biomarker of cachexia.
    Results: Targeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared to either non-cachectic PDAC patients or patients without cancer. The ratio of C18-ceramide to C24-ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only altered in cachectic males.
    Conclusions: Our findings identify C18:C24 as a potentially new biomarker of PDAC-induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia.
    DOI:  https://doi.org/10.1002/rco2.68
  6. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00492-2. [Epub ahead of print]35(1): 12-35
    Meta-hallmarks of aging and cancer.
    Carlos López-Otín, Federico Pietrocola, David Roiz-Valle, Lorenzo Galluzzi, Guido Kroemer.
      Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
    Keywords:  aging; cancer; carcinogenesis; metabolism; oncogenesis; tumor progression
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.001
  7. Cell Rep Med. 2022 Dec 22. pii: S2666-3791(22)00442-6. [Epub ahead of print] 100878
    CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy.
    Mahrukh A Huseni, Lifen Wang, Joanna E Klementowicz, Kobe Yuen, Beatrice Breart, Christine Orr, Li-Fen Liu, Yijin Li, Vinita Gupta, Congfen Li, Deepali Rishipathak, Jing Peng, Yasin Şenbabaoǧlu, Zora Modrusan, Shilpa Keerthivasan, Shravan Madireddi, Ying-Jiun Chen, Eleanor J Fraser, Ning Leng, Habib Hamidi, Hartmut Koeppen, James Ziai, Kenji Hashimoto, Marcella Fassò, Patrick Williams, David F McDermott, Jonathan E Rosenberg, Thomas Powles, Leisha A Emens, Priti S Hegde, Ira Mellman, Shannon J Turley, Mark S Wilson, Sanjeev Mariathasan, Luciana Molinero, Mark Merchant, Nathaniel R West.
      Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.
    Keywords:  CD8 T cell; IL-6; PD-L1; atezolizumab; cancer; checkpoint blockade immunotherapy; clinical trial; interleukin 6
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100878
  8. STAR Protoc. 2022 Dec 16. pii: S2666-1667(22)00779-1. [Epub ahead of print]3(4): 101899
    Generation of orthotopic patient-derived xenograft models for pancreatic cancer using tumor slices.
    Alvaro Curiel-Garcia, Amanda R Decker-Farrell, Stephen A Sastra, Kenneth P Olive.
      Orthotopic patient-derived xenograft models recapitulate the genomic complexity of the original tumor and some aspects of local microenvironment, useful for rapid development and validation of personalized treatment strategies. Here, we precisely describe a protocol for generating tumor slices from human or murine-derived pancreatic cancer. They are then implanted directly into the murine pancreas, monitored using ultrasound, with a 90% success rate. This assay creates a clinically relevant in vivo model facilitating personalized treatment development.
    Keywords:  Cancer; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2022.101899
  9. EMBO Rep. 2023 Jan 02. e55643
    MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.
    Shashi Anand, Mohammad Aslam Khan, Haseeb Zubair, Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Sachin Kumar Deshmukh, Shafquat Azim, Sanjeev Kumar Srivastava, Seema Singh, Ajay Pratap Singh.
      Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia.
    Keywords:  HIF1α; MYB; hypoxia; metabolic reprogramming; pancreatic cancer
    DOI:  https://doi.org/10.15252/embr.202255643
  10. Cancer Metastasis Rev. 2023 Jan 04.
    Dormant cancer cells: programmed quiescence, senescence, or both?
    Kevin Truskowski, Sarah R Amend, Kenneth J Pienta.
      Metastasis is the overwhelming driver of cancer mortality, accounting for the majority of cancer deaths. Many patients present with metastatic relapse years after eradication of the primary lesion. Disseminated cancer cells can undergo a durable proliferative arrest and lie dormant in secondary tissues before reentering the cell cycle to seed these lethal relapses. This process of cancer cell dormancy remains poorly understood, largely due to difficulties in studying these dormant cells. In the face of these challenges, the application of knowledge from the cellular senescence and quiescence fields may help to guide future thinking on the study of dormant cancer cells. Both senescence and quiescence are common programs of proliferative arrest that are integral to tissue development and homeostasis. Despite phenotypic differences, these two states also share common characteristics, and both likely play a role in cancer dormancy and delayed metastatic relapse. Understanding the cell biology behind these states, their overlaps and unique characteristics is critical to our future understanding of dormant cancer cells, as these cells likely employ some of the same molecular programs to promote survival and dissemination. In this review, we highlight the biology underlying these non-proliferative states, relate this knowledge to what we currently know about dormant cancer cells, and discuss implications for future work toward targeting these elusive metastatic seeds.
    Keywords:  Cancer; Cell cycle; Dormancy; Metastasis; Quiescence; Senescence
    DOI:  https://doi.org/10.1007/s10555-022-10073-z
  11. Function (Oxf). 2023 ;4(1): zqac061
    Watching Living Cells in Action in the Exocrine Pancreas: The Palade Prize Lecture.
    Ole H Petersen.
      George Palade's pioneering electron microscopical studies of the pancreatic acinar cell revealed the intracellular secretory pathway from the rough endoplasmic reticulum at the base of the cell to the zymogen granules in the apical region. Palade also described for the first time the final stage of exocytotic enzyme secretion into the acinar lumen. The contemporary studies of the mechanism by which secretion is acutely controlled, and how the pancreas is destroyed in the disease acute pancreatitis, rely on monitoring molecular events in the various identified pancreatic cell types in the living pancreas. These studies have been carried out with the help of high-resolution fluorescence recordings, often in conjunction with patch clamp current measurements. In such studies we have gained much detailed information about the regulatory events in the exocrine pancreas in health as well as disease, and new therapeutic opportunities have been revealed.
    Keywords:  acinar cell; acute pancreatitis; calcium signaling; exocrine pancreas; imaging; live morphology; pancreatic immune cell; secretion; stellate cell
    DOI:  https://doi.org/10.1093/function/zqac061
  12. Nat Cell Biol. 2023 Jan 05.
    MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.
    Jihong Cui, Chi Zhang, Ji-Eun Lee, Boris A Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip M Galbo, Dayle Q Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo.
      Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal-epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically.
    DOI:  https://doi.org/10.1038/s41556-022-01045-0
  13. Cancer Res. 2023 Jan 03. pii: CAN-22-2045. [Epub ahead of print]
    Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.
    Seung Joon Park, Hee Chan Yoo, Eunyong Ahn, Enzhi Luo, Yeabeen Kim, Yulseung Sung, Ya Chun Yu, Kibum Kim, Do Sik Min, Hee Seung Lee, Geum-Sook Hwang, TaeJin Ahn, Junjeong Choi, Seungmin Bang, Jung Min Han.
      Pancreatic ductal adenocarcinoma (PDAC) exhibits severe hypoxia, which is associated with chemoresistance and worse patient outcome. It has been reported that hypoxia induces metabolic reprogramming in cancer cells. However, it is not well known whether metabolic reprogramming contributes to hypoxia. Here, we established that increased glutamine catabolism is a fundamental mechanism inducing hypoxia, and thus chemoresistance, in PDAC cells. An extracellular matrix (ECM) component-based in vitro 3D cell printing model with patient-derived PDAC cells that recapitulates the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared to chemoresponsive PDAC cells. The augmented glutamine metabolic flux increased the oxygen consumption rate via mitochondrial oxidative phosphorylation (OXPHOS), promoting hypoxia and hypoxia-induced chemoresistance. Targeting glutaminolysis relieved hypoxia and improved chemotherapy efficacy in vitro and in vivo. This work suggests that targeting the glutaminolysis-OXPHOS-hypoxia axis is a novel therapeutic target for treating patients with chemoresistant PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2045
  14. Nat Rev Cancer. 2023 Jan 03.
    STAT proteins in cancer: orchestration of metabolism.
    Yi-Jia Li, Chunyan Zhang, Antons Martincuks, Andreas Herrmann, Hua Yu.
      Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00537-3
  15. Cancer Manag Res. 2022 ;14 3589-3598
    Borderline Resectable Pancreatic Cancer: Challenges for Clinical Management.
    Ali Fawaz, Omar Abdel-Rahman.
       Background: Pancreatic ductal adenocarcinoma (PDAC) remains a significant worldwide health problem with a poor prognosis. A borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) is a tumor with limited vascular involvement that is technically resectable but with a high risk of positive margins (R1 resection).
    Objective: To identify the current challenges that exist in the management of BR-PDAC.
    Methods: A review of the literature was conducted to identify articles discussing the definitions and management of BR-PDAC.
    Key Findings: Several anatomic definitions of BR-PDAC exist, and there is significant heterogeneity in their utilization across published trials. To improve the odds of a margin negative (R0) resection, a neoadjuvant treatment approach involving chemotherapy with or without radiation is currently preferred. While supporting the efficacy of a neoadjuvant approach in BR-PDAC, the largest published randomized trials have utilized older gemcitabine-based regimens. Recently published Phase II evidence and meta-analyses have supported the use of modern multi-agent regimens such as FOLFIRINOX. The utility of adding radiation to a chemotherapy backbone remains in question. Due to remnant fibrosis and edema following neoadjuvant therapy, accurately selecting patients for resection based on a restaging CT scan is challenging. Furthermore, the role of adjuvant therapy in BR-PDAC patients receiving neoadjuvant therapy needs to be defined.
    Conclusion: Though progress has been made, the optimal management of BR-PDAC is uncertain. Phase III trials utilizing modern chemotherapeutic regimens are needed to establish a standard of care.
    Keywords:  borderline resectable disease; neoadjuvant chemotherapy; pancreatic cancer; surgery
    DOI:  https://doi.org/10.2147/CMAR.S340719
  16. Cell Discov. 2023 Jan 03. 9(1): 1
    Use of a dual genetic system to decipher exocrine cell fate conversions in the adult pancreas.
    Huan Zhao, Xiuzhen Huang, Zixin Liu, Liang Lai, Ruilin Sun, Ruling Shen, Yan Li, Lingjuan He, Wenjuan Pu, Zan Lv, Yi Li, Ximeng Han, Xiuxiu Liu, Bin Zhou.
      Unraveling cell fate plasticity during tissue homeostasis and repair can reveal actionable insights for stem cell biology and regenerative medicine. In the pancreas, it remains controversial whether lineage transdifferentiation among the exocrine cells occur under pathophysiological conditions. Here, to address this question, we used a dual recombinase-mediated genetic system that enables simultaneous tracing of pancreatic acinar and ductal cells using two distinct genetic reporters, avoiding the "ectopic" labeling by Cre-loxP recombination system. We found that acinar-to-ductal transdifferentiation occurs after pancreatic duct ligation or during caerulein-induced pancreatitis, but not during homeostasis or after partial pancreatectomy. On the other hand, pancreatic ductal cells contribute to new acinar cells after significant acinar cell loss. By genetic tracing of cell proliferation, we also quantify the cell proliferation dynamics and deduce the turnover rate of pancreatic exocrine lineages during homeostasis. Together, these results suggest that the lineage transdifferentiation happens between acinar cells and ductal cells in the pancreatic exocrine glands under specific conditions.
    DOI:  https://doi.org/10.1038/s41421-022-00485-0
  17. Histol Histopathol. 2022 Dec 16. 18576
    Experimental models for ageing research.
    Luana Toniolo, Giuseppe Sirago, Emiliana Giacomello.
      Ageing is a biological process caused by the malfunctioning of multiple cellular mechanisms, ascribable to nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These ageing pillars have three common traits: (i) they appear during normal ageing; (ii) their experimental intensification accelerates ageing; and (iii) their experimental reduction delays ageing. The evidence that the elderly are more prone to develop pathologies such as cancer, diabetes and degenerative diseases, together with data showing that the elderly population is steadily increasing, has stimulated an important effort to find specific countermeasures to physiological ageing. Unfortunately, the investigation of ageing processes and the search for countermeasures in humans is very difficult. Therefore, researchers must rely on a wide range of experimental models that span from unicellular to more complex organisms. Unfortunately, experimental models are not devoid of pitfalls, flaws or obstacles that can have an impact in ageing research. In the present review we describe the most exploited experimental models in the field, such as in vitro, animal and human models, highlighting the characteristics that justify their application in the laboratory routine, and translation to human research.
    DOI:  https://doi.org/10.14670/HH-18-576
  18. Methods Mol Biol. 2023 ;2600 185-196
    Quantification of Invadopodia Formation and Matrix Degradation Activity.
    Jubina Balan Venghateri, Benjamin Geiger.
      Cancer cells possess a remarkable capacity to dissociate from a primary tumor, invade the surrounding tissues and vasculature, and eventually form metastases in distant organs. This complex and multistep process remains one of the major causes of mortality in cancer patients worldwide. Multiple studies have highlighted the role of actin-rich structures called invadopodia ("invasive feet"), which adhere to the matrix, contain and secrete matrix-degrading proteinases, and apply protrusive forces generated by the actin cytoskeleton, which drive the invasive process. Here, we describe a fluorescent microscopy-based protocol for imaging and quantifying both invadopodia formation and matrix degradation.
    Keywords:  Actin cytoskeleton; Cancer cell lines; Extracellular matrix (ECM); Fluorescent microscopy; Fluorescently labeled gelatin; Gelatin degradation; Image processing; Invadopodia; Invasion; Metastasis
    DOI:  https://doi.org/10.1007/978-1-0716-2851-5_12
  19. Clin Cancer Res. 2023 Jan 06. pii: CCR-22-0794. [Epub ahead of print]
    Lamc2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth.
    Oihane Erice, Shruthi Narayanan, Iker Feliu, Rodrigo Entrialgo-Cadierno, Antonia Malinova, Caterina Vicentini, Elizabeth Guruceaga, Pietro Delfino, Marija Trajkovic-Arsic, Haritz Moreno, Karmele Valencia, Ester Blanco, Irati Macaya, Daniel Öhlund, Purvesh Khatri, Fernando Lecanda, Aldo Scarpa, Jens T Siveke, Vincenzo Corbo, Mariano Ponz-Sarvise, Silvestre Vicent.
       PURPOSE: The identification of PDAC dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here we investigated the cellular, functional and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies.
    EXPERIMENTAL DESIGN: LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA sequencing, and publicly available gene expression datasets from experimental and clinical studies queried for human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated.
    RESULTS: LAMC2 was upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors. A LAMC2-regulated network was featured in PDAC including classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a functional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2 inhibitors that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids.
    CONCLUSIONS: LAMC2 is a molecular target in PDAC which regulates a transcriptional network that unveils a dual drug combination for cancer treatment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0794
  20. Nat Biotechnol. 2023 Jan 02.
    Time-tagged ticker tapes for intracellular recordings.
    Dingchang Lin, Xiuyuan Li, Eric Moult, Pojeong Park, Benjamin Tang, Hao Shen, Jonathan B Grimm, Natalie Falco, Bill Z Jia, David Baker, Luke D Lavis, Adam E Cohen.
      Recording transcriptional histories of a cell would enable deeper understanding of cellular developmental trajectories and responses to external perturbations. Here we describe an engineered protein fiber that incorporates diverse fluorescent marks during its growth to store a ticker tape-like history. An embedded HaloTag reporter incorporates user-supplied dyes, leading to colored stripes that map the growth of each individual fiber to wall clock time. A co-expressed eGFP tag driven by a promoter of interest records a history of transcriptional activation. High-resolution multi-spectral imaging on fixed samples reads the cellular histories, and interpolation of eGFP marks relative to HaloTag timestamps provides accurate absolute timing. We demonstrate recordings of doxycycline-induced transcription in HEK cells and cFos promoter activation in cultured neurons, with a single-cell absolute accuracy of 30-40 minutes over a 12-hour recording. The protein-based ticker tape design we present here could be generalized to achieve massively parallel single-cell recordings of diverse physiological modalities.
    DOI:  https://doi.org/10.1038/s41587-022-01524-7
  21. FEBS Lett. 2023 Jan 03.
    RAS nanoclusters are cell surface transducers that convert extracellular stimuli to intracellular signaling.
    Yong Zhou, John F Hancock.
      Mutations of RAS oncogenes (HRAS, KRAS and NRAS) can contribute to the development of cancers and genetic disorders (RASopathies). The spatiotemporal organization of RAS is an important property that warrants further investigation. In order to function, wild-type or oncogenic mutants of RAS must be localized to the inner leaflet of the plasma membrane (PM), which is driven by interactions between their C-terminal membrane-anchoring domains and PM lipids. The isoform-specific RAS-lipid interactions promote the formation of nanoclusters on the PM. As main sites for effector recruitment, these nanoclusters are biologically important. Since the spatial distribution of lipids is sensitive to changing environments, such as mechanical and electrical perturbations, RAS nanoclusters act as transducers to convert external stimuli to intracellular mitogenic signaling. As such, effective inhibition of RAS oncogenesis requires consideration of the complex interplay between RAS nanoclusters and various cell surface and extracellular stimuli. In this Review, we discuss in detail how, by sorting specific lipids in the PM, RAS nanoclusters act as transducers to convert external stimuli into intracellular signaling.
    Keywords:  RAS small GTPases; electron microscopy; membrane curvature; nanoclusters; phosphatidylserine; plasma membrane
    DOI:  https://doi.org/10.1002/1873-3468.14569
  22. Methods Mol Biol. 2023 ;2600 197-206
    Measuring Cellular Traction Forces with Micropillar Arrays.
    Malak Amer, Haguy Wolfenson.
      Accurately evaluating cellular forces is critical for studying mechanosensing and mechanotransduction processes, and it necessitates sensitive measurements on the piconewton scale. Here we describe a specialized method that employs elastic polydimethylsiloxane (PDMS) micropillar arrays, which cells can adhere to and bend. The flexibility of the pillars correlates with their heights; the longer they are, the easier they are to bend. Thus, an array of taller pillars mimics a relatively soft substrate that readily yields in response to cellular forces. Tracking cell movements and pillar displacements using live-cell microscopy enables the calculation of cellular forces and the tracking of their dynamic features throughout early and late stages of cell spreading on the pillars. This technique offers the advantage of high spatial and temporal resolution analyses and constitutes a method to investigate the effect of substrate rigidities on cellular functions.
    Keywords:  Cellular forces; Displacement; Live-cell imaging; Micropillar arrays; PDMS; time curves
    DOI:  https://doi.org/10.1007/978-1-0716-2851-5_13
  23. J Cancer Res Clin Oncol. 2023 Jan 02.
    Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front.
    Shuang Fei, Kenoki Ohuchida, Shin Kibe, Zilong Yan, Chika Iwamoto, Tomohiko Shinkawa, Bo Zhang, Jun Kawata, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura.
       PURPOSE: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism.
    METHODS: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro.
    RESULTS: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density.
    CONCLUSION: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.
    Keywords:  Angiogenesis; Cancer-associated acinar-to-ductal metaplasia; Liver metastasis; Macrophages; Pancreatic cancer; Prognosis
    DOI:  https://doi.org/10.1007/s00432-022-04554-5
  24. Methods Mol Biol. 2023 ;2614 357-368
    Laser-Assisted Single-Cell Labeling and Capture.
    Nicolas Desjardins-Lecavalier, Graziana Modica, Santiago Costantino.
      Single-cell technologies have become critical tools to understand and characterize the complex dynamics that govern biological systems, from embryonic development to cancer heterogeneity. In this context, identification and capture of live individual cells in heterogenous ensembles typically rely on genetic manipulations that encode fluorescent probes. However, a precise understanding of how several molecular components interact to yield the phenotype of interest is a prerequisite to distinguishing and isolating such target cells based on fluorescence alone. Indeed, cellular phenotypes associated with migration, shape, location, or intracellular protein distribution play critical and well-understood roles in cancer biology, but the technologies to tag and isolate cells based on information obtained from imaging are not readily available.Cell labeling via photobleaching (CLaP) and single-cell magneto-optical capture (scMOCa) represent convenient and cost-effective systems for labeling, capturing, and expanding single cells from a heterogenous population, without altering cellular physiology and therefore enabling not only transcriptomic profiling but also biological characterization of target cells. Both techniques allow capturing cells after observation and permit researchers to choose target cells based on information obtained from images. The implementation of these technologies only needs the lasers of a confocal microscope and low-cost, commercially available chemical reagents. Here, we describe a detailed protocol to set up and perform CLaP and scMOCa and highlight critical points for optimal performance.
    Keywords:  CLaP; Laser scanning microscope; Photobleaching; Single-cell capture; Single-cell tag; scMOCa
    DOI:  https://doi.org/10.1007/978-1-0716-2914-7_21
  25. Methods Mol Biol. 2023 ;2614 383-396
    Intravital Microscopy of the Metastatic Pulmonary Environment.
    Liane Babes, Bryan George Yipp, Donna Lorraine Senger.
      Real-time in vivo imaging has become an integral tool for the investigation and understanding of cellular processes in health and disease at single-cell resolution. This includes the dynamic and complex cellular interactions that occur during cancer progression and the subsequent metastatic dissemination of tumor cells to sites distant from the primary tumor. Herein we outline the methodology for the establishment and intravital imaging of the pulmonary metastatic niche, a preferred site of metastasis for many cancers, and describe the implementation of a lung window to visualize and dissect the intricate behaviour of multiple cell types within this environment. We also address the advantages and limitations of this high-resolution technology.
    Keywords:  Breast cancer metastasis to the lung; Intravital imaging; Leukocyte recruitment; Lung; Lung intravital imaging; Lung metastasis; Lung metastatic environment; Melanoma metastasis to the lung; Neutrophils
    DOI:  https://doi.org/10.1007/978-1-0716-2914-7_23
  26. Mol Oncol. 2023 Jan 01.
    Collective directional migration drives the formation of heteroclonal cancer cell clusters.
    Miriam Palmiero, Isabel Cantarosso, Laura di Blasio, Valentina Monica, Barbara Peracino, Luca Primo, Alberto Puliafito.
      Metastasisation occurs through the acquisition of invasive and survival capabilities that allow tumour cells to colonise distant sites. While the role of multicellular aggregates in cancer dissemination is acknowledged, the mechanisms that drive the formation of multi-clonal cell aggregates are not fully elucidated. Here we show that cancer cells of different tissue of origins can perform collective directional migration and can actively form heteroclonal aggregates in 3D, through a proliferation-independent mechanism. Coalescence of distant cell clusters is mediated by subcellular actin-rich protrusions and multicellular outgrowths that extend towards neighbouring aggregates. Coherently, perturbation of cytoskeletal dynamics impairs collective migration while myosin II activation is necessary for multicellular movements. We put forward the hypothesis that cluster attraction is mediated by secreted soluble factors. Such a hypothesis is consistent with the abrogation of aggregation by inhibition of PI3K/AKT/mTOR and MEK/ERK, the chemoattracting activity of conditioned culture media and with a wide screening on secreted proteins. Our results present a novel collective migration model and shed light on the mechanisms of formation of heteroclonal aggregates in cancer.
    Keywords:  3D models; collective migration; directional migration; heterogeneity; imaging; protrusions
    DOI:  https://doi.org/10.1002/1878-0261.13369
  27. Nat Commun. 2023 Jan 03. 14(1): 39
    The mitochondrial Hsp70 controls the assembly of the F1FO-ATP synthase.
    Jiyao Song, Liesa Steidle, Isabelle Steymans, Jasjot Singh, Anne Sanner, Lena Böttinger, Dominic Winter, Thomas Becker.
      The mitochondrial F1FO-ATP synthase produces the bulk of cellular ATP. The soluble F1 domain contains the catalytic head that is linked via the central stalk and the peripheral stalk to the membrane embedded rotor of the FO domain. The assembly of the F1 domain and its linkage to the peripheral stalk is poorly understood. Here we show a dual function of the mitochondrial Hsp70 (mtHsp70) in the formation of the ATP synthase. First, it cooperates with the assembly factors Atp11 and Atp12 to form the F1 domain of the ATP synthase. Second, the chaperone transfers Atp5 into the assembly line to link the catalytic head with the peripheral stalk. Inactivation of mtHsp70 leads to integration of assembly-defective Atp5 variants into the mature complex, reflecting a quality control function of the chaperone. Thus, mtHsp70 acts as an assembly and quality control factor in the biogenesis of the F1FO-ATP synthase.
    DOI:  https://doi.org/10.1038/s41467-022-35720-5
  28. Nat Biotechnol. 2023 Jan 05.
    Solid-phase capture and profiling of open chromatin by spatial ATAC.
    Enric Llorens-Bobadilla, Margherita Zamboni, Maja Marklund, Nayanika Bhalla, Xinsong Chen, Johan Hartman, Jonas Frisén, Patrik L Ståhl.
      Current methods for epigenomic profiling are limited in their ability to obtain genome-wide information with spatial resolution. We introduce spatial ATAC, a method that integrates transposase-accessible chromatin profiling in tissue sections with barcoded solid-phase capture to perform spatially resolved epigenomics. We show that spatial ATAC enables the discovery of the regulatory programs underlying spatial gene expression during mouse organogenesis, lineage differentiation and in human pathology.
    DOI:  https://doi.org/10.1038/s41587-022-01603-9
  29. Cancer Metastasis Rev. 2023 Jan 05.
    The genomic regulation of metastatic dormancy.
    Irwin H Gelman.
      The genomics and pathways governing metastatic dormancy are critically important drivers of long-term patient survival given the considerable portion of cancers that recur aggressively months to years after initial treatments. Our understanding of dormancy has expanded greatly in the last two decades, with studies elucidating that the dormant state is regulated by multiple genes, microenvironmental (ME) interactions, and immune components. These forces are exerted through mechanisms that are intrinsic to the tumor cell, manifested through cross-talk between tumor and ME cells including those from the immune system, and regulated by angiogenic processes in the nascent micrometastatic niche. The development of new in vivo and 3D ME models, as well as enhancements to decades-old tumor cell pedigree models that span the development of metastatic dormancy to aggressive growth, has helped fuel what arguably is one of the least understood areas of cancer biology that nonetheless contributes immensely to patient mortality. The current review focuses on the genes and molecular pathways that regulate dormancy via tumor-intrinsic and ME cells, and how groups have envisioned harnessing these therapeutically to benefit patient survival.
    Keywords:  Dormancy; Dormancy reawakening; Genomics; Metastasis
    DOI:  https://doi.org/10.1007/s10555-022-10076-w
  30. iScience. 2023 Jan 20. 26(1): 105723
    Assessment of stromal SCD-induced drug resistance of PDAC using 3D-printed zPDX model chips.
    Chuntao Wu, Beiyuan Hu, Lei Wang, Xia Wu, Haitao Gu, Hanguang Dong, Jiuliang Yan, Zihao Qi, Qi Zhang, Huan Chen, Bo Yu, Sheng Hu, Yu Qian, Shuang Dong, Qiang Li, Xu Wang, Jiang Long.
      Lipid metabolism is extensively reprogrammed in pancreatic ductal adenocarcinoma (PDAC). Stearoyl-coenzyme A desaturase (SCD) is a critical lipid regulator that was unexplored in PDAC. Here, we characterized the existence of cancer-associated fibroblasts (CAFs) with high SCD expression, and revealed them as an unfavorable prognostic factor. Therefore, primary CAFs and pancreatic cancer cells were harvested and genetically labeled. The mixture of CAFs and cancer cells were co-injected into scd-/-; prkdc-/-, or hIGF1/INS-expressing zebrafish to generate patient-derived xenograft models (zPDX). The models were aligned in 3D-printed chips for semi-automatic drug administration and high-throughput scanning. The results showed that chaperoning of the SCD-high CAFs significantly improved the drug resistance of pancreatic cancer cells against gemcitabine and cisplatin, while the administration of SCD inhibitors neutralized the protective effect. Our studies revealed the prognostic and therapeutic value of stromal SCD in PDAC, and proposed the application of zPDX model chips for drug testing.
    Keywords:  Cancer; Lipid; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2022.105723
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