bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023‒09‒17
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Screening in serum-derived medium reveals differential response to compounds targeting metabolism.
  2. Mouse Models of Metastasis and Dormancy.
  3. Stress granules and hormetic adaptation of cancer.
  4. Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
  5. The Role of Stroma in Cancer Metabolism.
  6. Death-seq identifies regulators of cell death and senolytic therapies.
  7. ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover.
  8. Tumor microenvironmental nutrients, cellular responses, and cancer.
  9. Enhanced antitumour immunity following neoadjuvant chemoradiotherapy mediates a favourable prognosis in women with resected pancreatic cancer.
  10. Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis.
  11. Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression.
  12. Treating metastatic pancreatic ductal adenocarcinoma: NALIRIFOX as new standard?
  13. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.
  14. Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer.
  15. Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma.
  16. Cell membrane targetable NIR fluorescent polarity probe for selective visualization of cancer cells and early tumor.
  17. Bridging live-cell imaging and next-generation cancer treatment.
  18. pH sensing at the intersection of tissue homeostasis and inflammation.
  19. Oncogenic BRAF noncanonically promotes tumor metastasis by mediating VASP phosphorylation and filopodia formation.
  20. ATG4B and ATG4A loss result in two-stage cell cycle defects in pancreatic ductal adenocarcinoma cells.
  21. Multifaceted collagen-DDR1 signaling in cancer.
  22. Tumor suppressor p53 mediates interleukin-6 expression to enable cancer cell evasion of genotoxic stress.
  23. Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles.
  24. Allele-specific expression reveals genetic drivers of tissue regeneration in mice.
  25. Obesity-induced and weight-loss-induced physiological factors affecting weight regain.
  26. Patient-Derived-Xenografts in Mice: A Preclinical Platform for Cancer Research.
  27. Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.
  28. Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane.
  29. Real time ex vivo chemosensitivity assay for pancreatic adenocarcinoma.
  30. Oxyhaemoglobin saturation NIR-IIb imaging for assessing cancer metabolism and predicting the response to immunotherapy.
  31. Community-developed checklists for publishing images and image analyses.
  1. Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00279-9. [Epub ahead of print]
    Screening in serum-derived medium reveals differential response to compounds targeting metabolism.
    Keene L Abbott, Ahmed Ali, Dominick Casalena, Brian T Do, Raphael Ferreira, Jaime H Cheah, Christian K Soule, Amy Deik, Tenzin Kunchok, Daniel R Schmidt, Steffen Renner, Sophie E Honeder, Michelle Wu, Sze Ham Chan, Tenzin Tseyang, Andrew T Stoltzfus, Sarah L J Michel, Daniel Greaves, Peggy P Hsu, Christopher W Ng, Chelsea J Zhang, Ali Farsidjani, Johnathan R Kent, Maria Lucia L Madariaga, Iva Monique T Gramatikov, Nicholas J Matheson, Caroline A Lewis, Clary B Clish, Matthew G Rees, Jennifer A Roth, Lesley Mathews Griner, Alexander Muir, Douglas S Auld, Matthew G Vander Heiden.
      A challenge for screening new anticancer drugs is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels, which can influence cell metabolism and drug sensitivity. A general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To address this, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We screened several small molecule libraries and found that compounds targeting metabolic enzymes were differentially effective in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.
    Keywords:  Cancer cell metabolism; Culture media; Drug sensitivity; High-throughput screening; Nutrient environment; Phenotypic drug screening; Physiologic media
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.007
  2. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041386. [Epub ahead of print]
    Mouse Models of Metastasis and Dormancy.
    Ahmed Mahmoud, Karuna Ganesh.
      Metastasis is the ultimate and often lethal stage of cancer. Metastasis occurs in three phases that may vary across individuals: First, dissemination from the primary tumor. Second, tumor dormancy at the metastatic site where micrometastatic cancer cells remain quiescent or, in dynamic cycles of proliferation and elimination, remaining clinically undetectable. Finally, cancer cells are able to overcome microenvironmental constraints for outgrowth, or the formation of clinically detectable macrometastases that colonize distant organs and are largely incurable. A variety of approaches have been used to model metastasis to elucidate molecular mechanisms and identify putative therapeutic targets. In particular, metastatic dormancy has been challenging to model in vivo due to the sparse numbers of cancer cells in micrometastasis nodules and the long latency times required for tumor outgrowth. Here, we review state-of-the art genetically engineered mouse, syngeneic, and patient-derived xenograft approaches for modeling metastasis and dormancy. We describe the advantages and limitations of various metastasis models, novel findings enabled by such approaches, and highlight opportunities for future improvement.
    DOI:  https://doi.org/10.1101/cshperspect.a041386
  3. Trends Cancer. 2023 Sep 11. pii: S2405-8033(23)00165-6. [Epub ahead of print]
    Stress granules and hormetic adaptation of cancer.
    Alexandra Redding, Elda Grabocka.
      Cell stress is inherent to cancer and a key driver of tumorigenesis. Recent studies have proposed that cell stress promotes tumorigenesis through non-membranous organelles known as stress granules (SGs). While the biology of SGs is an emerging field, all studies to date point to the enhanced ability of cancer cells to form SGs compared with normal cells, a heightened dependence on SGs for survival under adverse conditions and for chemotherapy resistance, and the dependence of tumors on SGs for growth. Why cancer cells become dependent on SGs and how SGs promote tumorigenesis remain to be elucidated. Here, we attempt to provide a framework for answering these questions by framing SGs as a hormetic response to tumor-associated stress stimuli.
    Keywords:  cell fitness; hormesis; stress adaptation; stress granules; tumor-associated stress stimuli
    DOI:  https://doi.org/10.1016/j.trecan.2023.08.005
  4. Cancer Res. 2023 Sep 11.
    Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
    Ruowen Zhang, Xiaogang Peng, James Xianxing Du, Rebecca Boohaker, Igor L Estevao, Brian I Grajeda, Marc B Cox, Igor C Almeida, Weiqin Lu.
      Pancreatic cancer is a highly lethal disease with obesity as one of the risk factors. Oncogenic KRAS mutations are prevalent in pancreatic cancer and can rewire lipid metabolism by altering fatty acid (FA) uptake, FA oxidation (FAO), and lipogenesis. Identification of the underlying mechanisms could lead to improved therapeutic strategies for treating KRAS mutant pancreatic cancer. Here, we observed that KRASG12D upregulated the expression of SLC25A1, a citrate transporter that is a key metabolic switch to mediate FAO, fatty acid synthesis (FAS), glycolysis, and gluconeogenesis. In genetically engineered mouse models and human pancreatic cancer cells, KRASG12D induced SLC25A1 upregulation via GLI1, which directly stimulated SLC25A1 transcription by binding its promoter. The enhanced expression of SLC25A1 increased levels of cytosolic citrate, FAs, and key enzymes in lipid metabolism. In addition, a high-fat diet (HFD) further stimulated the KRASG12D-GLI1-SLC25A1 axis and the associated increase in citrate and FAs. Pharmacological inhibition of SLC25A1 and upstream GLI1 significantly suppressed pancreatic tumorigenesis in KrasG12D/+ mice on a HFD. These results reveal a KRASG12D-GLI1-SLC25A1 regulatory axis with SLC25A1 as an important node that regulates lipid metabolism during pancreatic tumorigenesis, thus indicating an intervention strategy for oncogenic KRAS-driven pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2679
  5. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]
    The Role of Stroma in Cancer Metabolism.
    Alec C Kimmelman, Mara H Sherman.
      The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.
    DOI:  https://doi.org/10.1101/cshperspect.a041540
  6. Cell Metab. 2023 Sep 05. pii: S1550-4131(23)00303-0. [Epub ahead of print]
    Death-seq identifies regulators of cell death and senolytic therapies.
    Alex Colville, Jie-Yu Liu, Cristina Rodriguez-Mateo, Samantha Thomas, Heather D Ishak, Ronghao Zhou, Julian D D Klein, David W Morgens, Armon Goshayeshi, Jayesh S Salvi, David Yao, Kaitlyn Spees, Scott J Dixon, Chun Liu, June-Wha Rhee, Celine Lai, Joseph C Wu, Michael C Bassik, Thomas A Rando.
      Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263. The screen also identified inducers of cell death and senescent cell clearance in models of age-related diseases by a related compound, ABT-199, which alone is not senolytic but exhibits less toxicity than ABT-263. Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identifies drug targets for the treatment of diverse pathological states such as senescence, cancer, and fibrosis.
    Keywords:  CRISPR; Death-seq; cell death; death screen; genome-wide; positive selection; pulmonary fibrosis; senescence; senolytics; synthetic lethality
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.008
  7. Protein Cell. 2023 Sep 14. 14(9): 653-667
    ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover.
    Maomao Pu, Wenhui Zheng, Hongtao Zhang, Wei Wan, Chao Peng, Xuebo Chen, Xinchang Liu, Zizhen Xu, Tianhua Zhou, Qiming Sun, Dante Neculai, Wei Liu.
      Lipophagy, the selective engulfment of lipid droplets (LDs) by autophagosomes for lysosomal degradation, is critical to lipid and energy homeostasis. Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes. This function of ORP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs. Upon lipophagy induction, ORP8 has increased localization on LDs and is phosphorylated by AMPK, thereby enhancing its affinity for LC3/GABARAPs. Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride. Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice, and Osbpl8-/- mice exhibit liver lipid clearance defects. Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.
    Keywords:  ORP8; autophagy; lipid; lipophagy
    DOI:  https://doi.org/10.1093/procel/pwac063
  8. Cell Chem Biol. 2023 Sep 01. pii: S2451-9456(23)00281-7. [Epub ahead of print]
    Tumor microenvironmental nutrients, cellular responses, and cancer.
    Graham P Lobel, Yanqing Jiang, M Celeste Simon.
      Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.
    Keywords:  Cancer metabolism; cancer therapeutics; cancer-associated fibroblasts; immune cell metabolism; nutrient exchange; stress responses; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.011
  9. Gut. 2023 Sep 14. pii: gutjnl-2023-330480. [Epub ahead of print]
    Enhanced antitumour immunity following neoadjuvant chemoradiotherapy mediates a favourable prognosis in women with resected pancreatic cancer.
    Dutch Pancreatic Cancer Group (DPCG)
      BACKGROUND: This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT).METHODS: Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling.
    RESULTS: The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling.
    CONCLUSION: PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.
    Keywords:  CHEMOTHERAPY; MACROPHAGES; PANCREATIC CANCER; PANCREATIC SURGERY; RADIOTHERAPY
    DOI:  https://doi.org/10.1136/gutjnl-2023-330480
  10. J Clin Invest. 2023 Sep 15. pii: e161847. [Epub ahead of print]133(18):
    Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis.
    Tomonori Masuda, Akihisa Fukuda, Go Yamakawa, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Yuichi Fukunaga, Munemasa Nagao, Osamu Araki, Takaaki Yoshikawa, Satoshi Ogawa, Kenji Masuo, Norihiro Goto, Yukiko Hiramatsu, Yu Muta, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Toshihiko Masui, Etsuro Hatano, Tomoko Matsuzaki, Makoto Noda, Hiroshi Seno.
      RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.
    Keywords:  Cancer; Gastroenterology; Mouse models; Oncology; Tumor suppressors
    DOI:  https://doi.org/10.1172/JCI161847
  11. Genes Dis. 2024 Mar;11(2): 921-934
    Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression.
    Hui-Qing Zhang, Fanyang Kong, Xiangyu Kong, Tingting Jiang, Muyuan Ma, Shaojiang Zheng, Junli Guo, Keping Xie.
      Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), also known as lysine (K)-specific demethylase 6A (KDM6A), functions as a tumor suppressor gene or oncogene depending on the tumor type and context. However, its tumor-suppressive mechanisms remain largely unknown. Here, we investigated the clinical significance and biological effects of UTX expression in pancreatic ductal adenocarcinoma (PDA) and determined the potential mechanisms of its dysregulation. UTX expression and its association with clinicopathologic characteristics of PDA patients were analyzed using immunohistochemistry. UTX mRNA and protein expression and their regulation in PDA cell lines were measured using quantitative polymerase chain reaction and Western blot analyses. The biological functions of UTX in PDA cell growth, migration, and invasion were determined using gain- and loss-of-function assays with both in vitro and in vivo animal models. UTX expression was reduced in human PDA cell lines and specimens. Low UTX expression was associated with poor differentiation and prognosis in PDA. Forced UTX expression inhibited PDA proliferation, migration, and invasion in vitro and PDA growth and metastasis in vivo, whereas knockdown of UTX expression did the opposite. Mechanistically, UTX expression was trans-activated by GATA6 activation. GATA6-mediated PDA progression could be blocked, at least partially, by silencing UTX expression. In conclusion, loss of GATA6-mediated UTX expression was evident in human PDA and restored UTX expression suppressed PDA growth and metastasis. Thus, UTX is a tumor suppressor in PDA and may serve as a prognostic biomarker and therapeutic target.
    Keywords:  Growth; Invasion; Metastasis; Pancreatic cancer; UTX
    DOI:  https://doi.org/10.1016/j.gendis.2023.01.019
  12. Lancet. 2023 Sep 11. pii: S0140-6736(23)01521-0. [Epub ahead of print]
    Treating metastatic pancreatic ductal adenocarcinoma: NALIRIFOX as new standard?
    Marc G Besselink, Johanna W Wilmink.
      
    DOI:  https://doi.org/10.1016/S0140-6736(23)01521-0
  13. Lancet. 2023 Sep 11. pii: S0140-6736(23)01366-1. [Epub ahead of print]
    NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.
    Zev A Wainberg, Davide Melisi, Teresa Macarulla, Roberto Pazo Cid, Sreenivasa R Chandana, Christelle De La Fouchardière, Andrew Dean, Igor Kiss, Woo Jin Lee, Thorsten O Goetze, Eric Van Cutsem, A Scott Paulson, Tanios Bekaii-Saab, Shubham Pant, Richard A Hubner, Zhimin Xiao, Huanyu Chen, Fawzi Benzaghou, Eileen M O'Reilly.
      BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC).METHODS: NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235.
    FINDINGS: Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel-gemcitabine, 387; median follow-up 16·1 months [IQR 13·4-19·1]). Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine (hazard ratio 0·83; 95% CI 0·70-0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel-gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel-gemcitabine group.
    INTERPRETATION: Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC.
    FUNDING: Ipsen.
    TRANSLATION: For the plain language summary see Supplementary Materials section.
    DOI:  https://doi.org/10.1016/S0140-6736(23)01366-1
  14. Eur J Cancer. 2023 Aug 21. pii: S0959-8049(23)00395-7. [Epub ahead of print]193 113293
    Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer.
    Carl-Stephan Leonhardt, Dietmar Pils, Motaz Qadan, Charlotte Gustorff, Klaus Sahora, Ulla Klaiber, Andrew L Warshaw, Gerald Prager, Cristina R Ferrone, Keith D Lillemoe, Martin Schindl, Oliver Strobel, Carlos Fernández-Del Castillo, Thomas Hank.
      INTRODUCTION: Smoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC.METHODS: All patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points.
    RESULTS: Out of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13-4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25-0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection.
    CONCLUSION: The present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.
    Keywords:  Cigarette; FOLFIRINOX; NAT; Neoadjuvant therapy; PDAC; Pancreatic cancer; Pancreatic surgery; Prognostic factors; Smoking; Survival
    DOI:  https://doi.org/10.1016/j.ejca.2023.113293
  15. Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2303224120
    Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma.
    Maryam Yousefi, Laura Andrejka, Márton Szamecz, Monte M Winslow, Dmitri A Petrov, Gábor Boross.
      Cancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with the inactivation of additional tumor suppressor genes. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations that drive the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order.
    Keywords:  cancer evolution; fitness landscapes; mouse models; quantitative
    DOI:  https://doi.org/10.1073/pnas.2303224120
  16. Anal Chim Acta. 2023 Oct 16. pii: S0003-2670(23)00969-8. [Epub ahead of print]1278 341748
    Cell membrane targetable NIR fluorescent polarity probe for selective visualization of cancer cells and early tumor.
    Wenlong Zhu, Qianhua Li, Shengyi Gong, Guoqiang Feng.
      The development of a sensitive method for early cancer diagnosis is very important because the early diagnosis of cancer is crucial in preventing the spread of cancer cells and improving patient survival rates. Recent studies showed that cancer cell membranes have lower polarity than normal cell membranes, which provides a new approach for cancer diagnosis at the cell membrane level. We developed herein a highly sensitive cell membrane polarity probe (Cal-M) for early diagnosis of cancer. This probe has low cytotoxicity, good photostability, near-infrared (NIR) fluorescence emission (>700 nm), large Stokes shift, high sensitivity for polarity, excellent cell membrane localization performance, and the ability to selectively light up cancer cells. Using this probe staining, the fluorescence of cancer cells is ∼63 times higher than that of normal cells, demonstrating excellent sensitivity and selectivity of Cal-M. This probe was also successfully used to detect polarity changes on cancer cell membranes and selectively visualize tumors in mice. Notably, the tumor could be visualized sensitively with a size as small as 1.37 mm3, indicating that Cal-M is promising for early diagnosis of tumors.
    Keywords:  Cancer cells; Cell membrane; Early tumor diagnosis; NIR fluorescent probe; Polarity
    DOI:  https://doi.org/10.1016/j.aca.2023.341748
  17. Nat Rev Cancer. 2023 Sep 13.
    Bridging live-cell imaging and next-generation cancer treatment.
    Maria Alieva, Amber K L Wezenaar, Ellen J Wehrens, Anne C Rios.
      By providing spatial, molecular and morphological data over time, live-cell imaging can provide a deeper understanding of the cellular and signalling events that determine cancer response to treatment. Understanding this dynamic response has the potential to enhance clinical outcome by identifying biomarkers or actionable targets to improve therapeutic efficacy. Here, we review recent applications of live-cell imaging for uncovering both tumour heterogeneity in treatment response and the mode of action of cancer-targeting drugs. Given the increasing uses of T cell therapies, we discuss the unique opportunity of time-lapse imaging for capturing the interactivity and motility of immunotherapies. Although traditionally limited in the number of molecular features captured, novel developments in multidimensional imaging and multi-omics data integration offer strategies to connect single-cell dynamics to molecular phenotypes. We review the effect of these recent technological advances on our understanding of the cellular dynamics of tumour targeting and discuss their implication for next-generation precision medicine.
    DOI:  https://doi.org/10.1038/s41568-023-00610-5
  18. Trends Immunol. 2023 Sep 14. pii: S1471-4906(23)00162-X. [Epub ahead of print]
    pH sensing at the intersection of tissue homeostasis and inflammation.
    Stephanie Hajjar, Xu Zhou.
      pH is tightly maintained at cellular, tissue, and systemic levels, and altered pH - particularly in the acidic range - is associated with infection, injury, solid tumors, and physiological and pathological inflammation. However, how pH is sensed and regulated and how it influences immune responses remain poorly understood at the tissue level. Applying conceptual frameworks of homeostatic and inflammatory circuitries, we categorize cellular and tissue components engaged in pH regulation, drawing parallels from established cases in physiology. By expressing various intracellular (pHi) and extracellular pH (pHe)-sensing receptors, the immune system may integrate information on tissue and cellular states into the regulation of homeostatic and inflammatory programs. We introduce the novel concept of resistance and adaptation responses to rationalize pH-dependent immunomodulation intertwined with homeostatic equilibrium and inflammatory control. We discuss emerging challenges and opportunities in understanding the immunological roles of pH sensing, which might reveal new strategies to combat inflammation and restore tissue homeostasis.
    Keywords:  acidic environment; adaptation; inflammatory response; pH homeostasis; pH sensing; resistance
    DOI:  https://doi.org/10.1016/j.it.2023.08.008
  19. Oncogene. 2023 Sep 09.
    Oncogenic BRAF noncanonically promotes tumor metastasis by mediating VASP phosphorylation and filopodia formation.
    Wenting Pan, Yihao Tian, Qian Zheng, Zelin Yang, Yulong Qiang, Zun Zhang, Nan Zhang, Jie Xiong, Xin Zhu, Lei Wei, Feng Li.
      BRAF is frequently mutated in various cancer types and contributes to tumorigenesis and metastasis. As an important switch in RAS signaling pathway, BRAF typically enables the activation of MEK and ERK, and its mutation significantly promotes metastasis. However, whether BRAF could stimulate metastasis via a distinct manner is still unknown. Herein, we found that a portion of the BRAF protein localized at the plasma membrane and that the BRAFV600E mutation led to abundant formation of filopodia, which is a hallmark of invasive cancer cells. Mechanistically, BRAF physically interacts with the pseudopod formation-related protein Vasodilator-stimulated phosphoprotein (VASP), and BRAF specifically catalyzes VASP phosphorylation at Ser157. VASP depletion or disruption of Ser157 phosphorylation preferentially reduced the motility, invasion and metastasis of tumor cells harboring oncogenic BRAF or KRAS. Moreover, in clinical cancer tissues, BRAFV600E was positively correlated with the extent of invasion, and tissues with BRAFV600E expression exhibited elevated levels of VASP Ser157 phosphorylation. Our study therefor reveals a noncanonical mechanism by which oncogenic BRAF or KRAS promotes metastasis, suggests that VASP Ser157 phosphorylation might serve as a valuable therapeutic target in BRAF or KRAS mutant cancers.
    DOI:  https://doi.org/10.1038/s41388-023-02829-w
  20. J Cell Sci. 2023 Sep 13. pii: jcs.260644. [Epub ahead of print]
    ATG4B and ATG4A loss result in two-stage cell cycle defects in pancreatic ductal adenocarcinoma cells.
    Paalini Sathiyaseelan, Suganthi Chittaranjan, Steve E Kalloger, Jennifer Chan, Nancy E Go, Mario A Jardon, Cally J Ho, Theodore Hui, Jing Xu, Christine Chow, Dongxia Gao, Fraser D Johnson, William W Lockwood, Gregg B Morin, Daniel J Renouf, David F Schaeffer, Sharon M Gorski.
      Pancreatic ductal adenocarcinoma (PDAC) exhibits elevated levels of autophagy which promote tumor progression and treatment resistance. ATG4B is an autophagy-related cysteine protease under consideration as a potential therapeutic target, but is largely unexplored in PDAC. Here, we investigated the clinical and functional relevance of ATG4B expression in PDAC. Using two PDAC patient cohorts, we found that low ATG4B mRNA or protein expression is associated with worse patient survival outcomes, poorly differentiated PDAC tumors, and lack of survival benefit from adjuvant chemotherapy. In PDAC cell lines, ATG4B knockout reduced proliferation, abolished LC3B processing, reduced GABARAP and GABARAPL1 levels but increased ATG4A levels. ATG4B and ATG4A double knockout lines displayed a further reduction in proliferation, characterized by delays in G1/S-phase transition and mitosis. Pro-LC3B accumulated aberrantly at the centrosome with a concomitant increase in centrosomal proteins PCM1 and CEP131, which was rescued by exogenous ATG4B. The two-stage cell cycle defects following ATG4B and ATG4A loss have important therapeutic implications for PDAC.
    Keywords:  ATG4A; ATG4B; Autophagy; CEP131; Centrosome; Doryphagy; GABARAP; PCM1; PDAC; Pancreatic cancer; Pro-LC3B
    DOI:  https://doi.org/10.1242/jcs.260644
  21. Trends Cell Biol. 2023 Sep 12. pii: S0962-8924(23)00167-8. [Epub ahead of print]
    Multifaceted collagen-DDR1 signaling in cancer.
    Hua Su, Michael Karin.
      In addition to immune cells and fibroblasts, the tumor microenvironment (TME) comprises an extracellular matrix (ECM) which contains collagens (COLs) whose architecture and remodeling dictate cancer development and progression. COL receptors expressed by cancer cells sense signals generated by microenvironmental alterations in COL state to regulate cell behavior and metabolism. Discoidin domain receptor 1 (DDR1) is a key sensor of COL fiber state and composition that controls tumor cell metabolism and growth, response to therapy, and patient survival. This review focuses on DDR1 to NRF2 signaling, its modulation of autophagy and macropinocytosis (MP), and its role in cancer and other diseases. Elucidating the regulation of DDR1 activity and expression under different pathophysiological conditions will facilitate the discovery of new therapeutics.
    Keywords:  DDR1; autophagy; cancer; collagen; collagen receptors; macropinocytosis
    DOI:  https://doi.org/10.1016/j.tcb.2023.08.003
  22. Cell Death Discov. 2023 Sep 11. 9(1): 340
    Tumor suppressor p53 mediates interleukin-6 expression to enable cancer cell evasion of genotoxic stress.
    Trinh T T Phan, Nam V Truong, Wen-Guey Wu, Yi-Chun Su, Tzu-Sheng Hsu, Lih-Yuan Lin.
      The tumor suppressor p53 primarily functions as a mediator of DNA damage-induced cell death, thereby contributing to the efficacy of genotoxic anticancer therapeutics. Here, we show, on the contrary, that cancer cells can employ genotoxic stress-induced p53 to acquire treatment resistance through the production of the pleiotropic cytokine interleukin (IL)-6. Mechanistically, DNA damage, either repairable or irreparable, activates p53 and stimulates Caspase-2-mediated cleavage of its negative regulator mouse double minute 2 (MDM2) creating a positive feedback loop that leads to elevated p53 protein accumulation. p53 transcriptionally controls the major adenosine triphosphate (ATP) release channel pannexin 1 (Panx1), which directs IL-6 induction via a mechanism dependent on the extracellular ATP-activated purinergic P2 receptors as well as their downstream intracellular calcium (iCa2+)/PI3K/Akt/NF-ĸB signaling pathway. Thus, p53 silencing impairs Panx1 and IL-6 expression and renders cancer cells sensitive to genotoxic stress. Moreover, we confirm that IL-6 hampers the effectiveness of genotoxic anticancer agents by mitigating DNA damage, driving the expression of anti-apoptotic Bcl-2 family genes, and maintaining the migratory and invasive properties of cancer cells. Analysis of patient survival and relevant factors in lung cancer and pan-cancer cohorts supports the prognostic and clinical values of Panx1 and IL-6. Notably, IL-6 secreted by cancer cells during genotoxic treatments promotes the polarization of monocytic THP-1-derived macrophages into an alternative (M2-like) phenotype that exhibits impaired anti-survival activities but enhanced pro-metastatic effects on cancer cells as compared to nonpolarized macrophages. Our study reveals the precise mechanism for genotoxic-induced IL-6 and suggests that targeting p53-mediated IL-6 may improve the responsiveness of cancer cells to genotoxic anticancer therapy.
    DOI:  https://doi.org/10.1038/s41420-023-01638-0
  23. Nat Commun. 2023 Sep 13. 14(1): 5644
    Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles.
    Ewa Sitarska, Silvia Dias Almeida, Marianne Sandvold Beckwith, Julian Stopp, Jakub Czuchnowski, Marc Siggel, Rita Roessner, Aline Tschanz, Christer Ejsing, Yannick Schwab, Jan Kosinski, Michael Sixt, Anna Kreshuk, Anna Erzberger, Alba Diz-Muñoz.
      To navigate through diverse tissues, migrating cells must balance persistent self-propelled motion with adaptive behaviors to circumvent obstacles. We identify a curvature-sensing mechanism underlying obstacle evasion in immune-like cells. Specifically, we propose that actin polymerization at the advancing edge of migrating cells is inhibited by the curvature-sensitive BAR domain protein Snx33 in regions with inward plasma membrane curvature. The genetic perturbation of this machinery reduces the cells' capacity to evade obstructions combined with faster and more persistent cell migration in obstacle-free environments. Our results show how cells can read out their surface topography and utilize actin and plasma membrane biophysics to interpret their environment, allowing them to adaptively decide if they should move ahead or turn away. On the basis of our findings, we propose that the natural diversity of BAR domain proteins may allow cells to tune their curvature sensing machinery to match the shape characteristics in their environment.
    DOI:  https://doi.org/10.1038/s41467-023-41173-1
  24. Cell Stem Cell. 2023 Sep 13. pii: S1934-5909(23)00293-X. [Epub ahead of print]
    Allele-specific expression reveals genetic drivers of tissue regeneration in mice.
    Katya L Mack, Heather E Talbott, Michelle F Griffin, Jennifer B L Parker, Nicholas J Guardino, Amanda F Spielman, Michael F Davitt, Shamik Mascharak, Mauricio Downer, Annah Morgan, Caleb Valencia, Deena Akras, Mark J Berger, Derrick C Wan, Hunter B Fraser, Michael T Longaker.
      In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" Murphy Roths Large (MRL) mice have the unusual ability to regenerate ear punch wounds; however, the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we used allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major cell populations (immune, fibroblast, and endothelial), we found that genes with cis-regulatory differences specifically in fibroblasts were associated with wound-healing pathways and also co-localized with quantitative trait loci for ear wound-healing. Ectopic treatment with one of these proteins, complement factor H (CFH), accelerated wound repair and induced regeneration in typically fibrotic wounds. Through single-cell RNA sequencing (RNA-seq), we observed that CFH treatment dramatically reduced immune cell recruitment to wounds, suggesting a potential mechanism for CFH's effect. Overall, our results provide insights into the molecular drivers of regeneration with potential clinical implications.
    Keywords:  fibroblasts; fibrosis; gene expression analysis; genetics; genomics; regeneration; wound healing
    DOI:  https://doi.org/10.1016/j.stem.2023.08.010
  25. Nat Rev Endocrinol. 2023 Sep 11.
    Obesity-induced and weight-loss-induced physiological factors affecting weight regain.
    Marleen A van Baak, Edwin C M Mariman.
      Weight regain after successful weight loss resulting from lifestyle interventions is a major challenge in the management of overweight and obesity. Knowledge of the causal mechanisms for weight regain can help researchers and clinicians to find effective strategies to tackle weight regain and reduce obesity-associated metabolic and cardiovascular complications. This Review summarizes the current understanding of a number of potential physiological mechanisms underlying weight regain after weight loss, including: the role of adipose tissue immune cells; hormonal and neuronal factors affecting hunger, satiety and reward; resting energy expenditure and adaptive thermogenesis; and lipid metabolism (lipolysis and lipid oxidation). We describe and discuss obesity-associated changes in these mechanisms, their persistence during weight loss and weight regain and their association with weight regain. Interventions to prevent or limit weight regain based on these factors, such as diet, exercise, pharmacotherapy and biomedical strategies, and current knowledge on the effectiveness of these interventions are also reviewed.
    DOI:  https://doi.org/10.1038/s41574-023-00887-4
  26. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041381. [Epub ahead of print]
    Patient-Derived-Xenografts in Mice: A Preclinical Platform for Cancer Research.
    Emiliano Cocco, Elisa de Stanchina.
      The use of patient-derived xenografts (PDXs) has dramatically improved drug development programs. PDXs (1) reproduce the pathological features and the genomic profile of the parental tumors more precisely than other preclinical models, and (2) more faithfully predict therapy response. However, PDXs have limitations. These include the inability to completely capture tumor heterogeneity and the role of the immune system, the low engraftment efficiency of certain tumor types, and the consequences of the human-host interactions. Recently, the use of novel mouse strains and specialized engraftment techniques has enabled the generation of "humanized" PDXs, partially overcoming such limitations. Importantly, establishing, characterizing, and maintaining PDXs is costly and requires a significant regulatory, administrative, clinical, and laboratory infrastructure. In this review, we will retrace the historical milestones that led to the implementation of PDXs for cancer research, review the most recent innovations in the field, and discuss future avenues to tackle deficiencies that still exist.
    DOI:  https://doi.org/10.1101/cshperspect.a041381
  27. Cell. 2023 Sep 14. pii: S0092-8674(23)00902-9. [Epub ahead of print]186(19): 4216-4234.e33
    Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.
    Franziska Blaeschke, Yan Yi Chen, Ryan Apathy, Bence Daniel, Andy Y Chen, Peixin Amy Chen, Katalin Sandor, Wenxi Zhang, Zhongmei Li, Cody T Mowery, Tori N Yamamoto, William A Nyberg, Angela To, Ruby Yu, Raymund Bueno, Min Cheol Kim, Ralf Schmidt, Daniel B Goodman, Tobias Feuchtinger, Justin Eyquem, Chun Jimmie Ye, Julia Carnevale, Ansuman T Satpathy, Eric Shifrut, Theodore L Roth, Alexander Marson.
      Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions.
    Keywords:  CRISPR; chimeric antigen receptor; chronic stimulation; human T cells; immunotherapy; knockins; pooled screens; synthetic surface receptor; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2023.08.013
  28. Biochim Biophys Acta Mol Cell Res. 2023 Sep 13. pii: S0167-4889(23)00158-1. [Epub ahead of print] 119585
    Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane.
    Paulo F V Bizerra, Eduardo H Gilglioni, H L Li, Simei Go, Ronald P J Oude Elferink, Arthur J Verhoeven, Jung-Chin Chang.
      Cyclic AMP is produced in cells by two different types of adenylyl cyclases: at the plasma membrane by the transmembrane adenylyl cyclases (tmACs, ADCY1~ADCY9) and in the cytosol by the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). By employing high-resolution extracellular flux analysis in HepG2 cells to study glycogen breakdown in real time, we showed that cAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells and the downstream cAMP effectors. While the canonical tmAC-cAMP-PKA signaling promotes glycogenolysis, we demonstrate here that the non-canonical sAC-cAMP-Epac1 signaling suppresses glycogenolysis. Mechanistically, suppression of sAC-cAMP-Epac1 leads to Ser-15 phosphorylation and thereby activation of the liver-form glycogen phosphorylase to promote glycogenolysis. Our findings highlight the importance of cAMP microdomain organization for distinct metabolic regulation and establish sAC as a novel regulator of glycogen metabolism.
    Keywords:  Cyclic AMP; Exchange protein directly activated by cAMP (Epac); Glycogen breakdown; Glycogenolysis; Soluble adenylyl cyclase; cAMP signaling microdomains
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119585
  29. Oncotarget. 2023 Sep 15. 14 811-818
    Real time ex vivo chemosensitivity assay for pancreatic adenocarcinoma.
    Dae Won Kim, Francisca Beato, Youngchul Kim, Alexandra F Tassielli, Ruifan Dai, Jason W Denbo, Pamela J Hodul, Mokenge P Malafa, Jason B Fleming.
      BACKGROUND: Patient-derived organoids (PDOs) and xenografts (PDXs) have been extensively studied for drug-screening. However, their usage is limited due to lengthy establishment time, high engraftment failure rates and different tumor microenvironment from original tumors. To overcome the limitations, we developed real time-live tissue sensitivity assay (RT-LTSA) using fresh tumor samples.METHODS: Tissue slices from resected pancreatic cancer samples were placed in 96-well plates, and the slices were treated with chemotherapeutic agents. The correlation between the chemo-sensitivity of tissue slices and each patient's clinical outcome was analyzed.
    RESULTS: The viability and tumor microenvironment of the tissue slices are well-preserved over 5 days. The drug sensitivity assay results are available within 5 days after tissue collection. While all 4 patients who received RT-LTSA sensitive adjuvant regimens did not develop recurrence, 7 of 8 patients who received resistant adjuvant regimens developed recurrence. We observed significantly improved disease-free survival in the patients who received RT-LTSA sensitive adjuvant regimens (median: not reached versus 10.6 months, P = 0.02) compared with the patient who received resistant regimens. A significant negative correlation between RT-LTSA value and relapse-free survival was observed (Somer's D: -0.58; P = 0.016).
    CONCLUSIONS: RT-LTSA which maintains the tumor microenvironment and architecture as found in patients may reflect clinical outcome and could be used as a personalized strategy for pancreatic adenocarcinoma. Further, studies are warranted to verify the findings.
    Keywords:  chemotherapy; pancreatic cancer; sensitivity assay
    DOI:  https://doi.org/10.18632/oncotarget.28508
  30. Nat Nanotechnol. 2023 Sep 11.
    Oxyhaemoglobin saturation NIR-IIb imaging for assessing cancer metabolism and predicting the response to immunotherapy.
    Zhiguo Fang, Chenlei Wang, Jingrun Yang, Zhizheng Song, Chunyu Xie, Yu Ji, Zhongliang Wang, Xiaohui Du, Qiang Zheng, Chunying Chen, Zhiyuan Hu, Yeteng Zhong.
      In vivo quantitative assessment of oxyhaemoglobin saturation (sO2) status in tumour-associated vessels could provide insights into cancer metabolism and behaviour. Here we develop a non-invasive in vivo sO2 imaging technique to visualize the sO2 levels of healthy and tumour tissue based on photoluminescence bioimaging in the near-infrared IIb (NIR-IIb; 1,500-1,700 nm) window. Real-time dynamic sO2 imaging with a high frame rate (33 Hz) reveals the cerebral arteries and veins through intact mouse scalp/skull, and this imaging is consistent with the haemodynamic analysis results. Utilizing our non-invasive sO2 imaging, the tumour-associated-vessel sO2 levels of various cancer models are evaluated. A positive correlation between the tumour-associated-vessel sO2 levels and the basal oxygen consumption rate of corresponding cancer cells at the early stages of tumorigenesis suggests that cancer cells modulate the tumour metabolic microenvironment. We also find that a positive therapeutic response to the checkpoint blockade cancer immunotherapy could lead to a dramatic decrease of the tumour-associated-vessel sO2 levels. Two-plex dynamic NIR-IIb imaging can be used to simultaneously observe tumour-vessel sO2 and PD-L1, allowing a more accurate prediction of immunotherapy response.
    DOI:  https://doi.org/10.1038/s41565-023-01501-4
  31. Nat Methods. 2023 Sep 14.
    Community-developed checklists for publishing images and image analyses.
    Christopher Schmied, Michael S Nelson, Sergiy Avilov, Gert-Jan Bakker, Cristina Bertocchi, Johanna Bischof, Ulrike Boehm, Jan Brocher, Mariana T Carvalho, Catalin Chiritescu, Jana Christopher, Beth A Cimini, Eduardo Conde-Sousa, Michael Ebner, Rupert Ecker, Kevin Eliceiri, Julia Fernandez-Rodriguez, Nathalie Gaudreault, Laurent Gelman, David Grunwald, Tingting Gu, Nadia Halidi, Mathias Hammer, Matthew Hartley, Marie Held, Florian Jug, Varun Kapoor, Ayse Aslihan Koksoy, Judith Lacoste, Sylvia Le Dévédec, Sylvie Le Guyader, Penghuan Liu, Gabriel G Martins, Aastha Mathur, Kota Miura, Paula Montero Llopis, Roland Nitschke, Alison North, Adam C Parslow, Alex Payne-Dwyer, Laure Plantard, Rizwan Ali, Britta Schroth-Diez, Lucas Schütz, Ryan T Scott, Arne Seitz, Olaf Selchow, Ved P Sharma, Martin Spitaler, Sathya Srinivasan, Caterina Strambio-De-Castillia, Douglas Taatjes, Christian Tischer, Helena Klara Jambor.
      Images document scientific discoveries and are prevalent in modern biomedical research. Microscopy imaging in particular is currently undergoing rapid technological advancements. However, for scientists wishing to publish obtained images and image-analysis results, there are currently no unified guidelines for best practices. Consequently, microscopy images and image data in publications may be unclear or difficult to interpret. Here, we present community-developed checklists for preparing light microscopy images and describing image analyses for publications. These checklists offer authors, readers and publishers key recommendations for image formatting and annotation, color selection, data availability and reporting image-analysis workflows. The goal of our guidelines is to increase the clarity and reproducibility of image figures and thereby to heighten the quality and explanatory power of microscopy data.
    DOI:  https://doi.org/10.1038/s41592-023-01987-9
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