bims-tuchim 2021-12-05 papers

Transl Res. 2021 Nov 26. pii: S1931-5244(21)00281-4. [Epub ahead of print]

The Biomimetic Extracellular Matrix: a Therapeutic Tool for Breast Cancer Research.

Marta Tamayo-Angorrilla, Julia López de Andrés, Gema Jiménez, Juan Antonio Marchal.

BACKGROUND: A deeper knowledge of the functional versatility and dynamic nature of the ECM has improved the understanding of cancer biology. Translational Significance: This work provides an in-depth view of the importance of the ECM to develop more mimetic breast cancer models, which aim to recreate the components and architecture of tumor microenvironment. Special focus is placed on decellularized matrices derived from tissue and cell culture, both in procurement and applications, as they have achieved great success in cancer research and pharmaceutical sector. Abstract: The extracellular matrix (ECM) is increasingly recognized as a master regulator of cell behavior and response to breast cancer (BC) treatment. During BC progression, the mammary gland ECM is remodeled and altered in the composition and organization. Accumulated evidence suggests that changes in the composition and mechanics of ECM, orchestrated by tumor-stromal interactions along with ECM remodeling enzymes, are actively involved in BC progression and metastasis. Understanding how specific ECM components modulate the tumorigenic process has led to an increased interest in the development of biomaterial-based biomimetic ECM models to recapitulate key tumor characteristics. The decellularized ECMs (dECMs) have emerged as a promising in vitro 3D tumor model, whose recent advances in the processing and application could become the biomaterial by excellence for BC research and the pharmaceutical industry. This review offers a detailed view of the contribution of ECM in BC progression, and highlights the application of dECM-based biomaterials as promising personalized tumor models that more accurately mimic the tumorigenic mechanisms of BC and the response to treatment. This will allow the design of targeted therapeutic approaches adapted to the specific characteristics of each tumor that will have a great impact on the precision medicine applied to BC patients.

Keywords: 5FU, 5-fluorouaracil; BC, Breast Cancer; BCCs, Breast Cancer cells; BCSC, Breast cancer stem cells; CAFs, Cancer-associated fibroblasts; CLS, Capillary-like structures; CSC, Cancer Stem Cells; Col I, Collagen type I; DAPI, 4’,6-diamidino-2-phenylindole; DCIS, Ductal carcinoma in situ; DOX, Doxorubicin; ECSs, Embryonic stem cells; EGF, Epidermal Growth Factor; EGFR, Epidermal growth factor receptor; EMT, Epithelial-Mesenchymal Transition; ERK, Extracellular signal-regulated kinases; FAP, Fibroblast activation protein; FN, Fibronectin; GAG, Glycosaminoglycan; GPC, Glypican; GelMA, Methacrylate gelatin; HA, Hyaluronan; HASPc, Heparan sultafe Proteoglycans; ICH, Immunohistochemical; LM, Laminin; LOX, Lysyl Oxidase; MDR1, Multidrug resistance protein; MHC-I, Major histocompatibility class I complex; MMPs, Matrix metalloproteinase; MSCs, Mesenchymal stem cells; PAM, Polyacrylamide; PDGF, Platelet-derived growth factor; PEG MAL, Polyethylene glycol maleimide; PEG, Polyethylene glycol; PEG-PC, Polyethylene glycol phosphocholine; PG, Proteoglycans; PGA, Poly-glycolic acid; PI3K, Phosphoinositide 3-kinase; PLA, Poly-lactic acid; PLGA, Poly lactic-co-glycolic acid; POSTN, Periostine; PTX, Paclitaxel; SC, Stem Cell; SDC1, Sydencan-1; SDC2, Syndecan-2; SDS, Sodium deoxysulfate; SEM, Scanning electron microscopy; SLES, Sodium lauryl Ether Sulphate; SLPR, Small Leucine-rich proteoglycan; SPARC, Secreted Protein Acidic and Rich in Cysteine; SSP1, Phosphoprotein 1; TACS, Tumor Associated Collagen Signatures; TAMs, Tumor-associated macrophages; TGF-β, Transforming growth factor-beta; THBS, Thrombospondine; TME, Tumor Microenvironment; TNC, Tenascin; Upa, Urokinase plasminogen; VEGF, Endothelial growth factor; Wnt, Wingless; dECMs, Decellularized Extracellular Matrix; extracellular matrix (ECM), decellularized ECM, desmoplasia, biomaterials, decellularized3D models, breast cancer, Abbreviations, ECM, Extracellular Matrix; hDAM, Human adipose tissue; rBM, Reconstituted basement membrane

DOI: https://doi.org/10.1016/j.trsl.2021.11.008

Anticancer Res. 2021 Dec;41(12): 5973-5985

The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death.

Jan-Philipp Ruff, Anna-Laura Kretz, Marko Kornmann, Doris Henne-Bruns, Johannes Lemke, Benno Traub.

BACKGROUND/AIM: This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells.
MATERIALS AND METHODS: To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis.
RESULTS: Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach.
CONCLUSION: This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.

Keywords: Atuveciclib; CDK9; TRAIL; apoptosis; pancreatic cancer; pancreatic ductal adenocarcinoma

DOI: https://doi.org/10.21873/anticanres.15416

Front Immunol. 2021 ;12 767939

Exploiting the STAT3 Nexus in Cancer-Associated Fibroblasts to Improve Cancer Therapy.

Amr Allam, Marina Yakou, Lokman Pang, Matthias Ernst, Jennifer Huynh.

The tumor microenvironment (TME) is composed of a heterogenous population of cells that exist alongside the extracellular matrix and soluble components. These components can shape an environment that is conducive to tumor growth and metastatic spread. It is well-established that stromal cancer-associated fibroblasts (CAFs) in the TME play a pivotal role in creating and maintaining a growth-permissive environment for tumor cells. A growing body of work has uncovered that tumor cells recruit and educate CAFs to remodel the TME, however, the mechanisms by which this occurs remain incompletely understood. Recent studies suggest that the signal transducer and activator of transcription 3 (STAT3) is a key transcription factor that regulates the function of CAFs, and their crosstalk with tumor and immune cells within the TME. CAF-intrinsic STAT3 activity within the TME correlates with tumor progression, immune suppression and eventually the establishment of metastases. In this review, we will focus on the roles of STAT3 in regulating CAF function and their crosstalk with other cells constituting the TME and discuss the utility of targeting STAT3 within the TME for therapeutic benefit.

Keywords: STAT (signal transducer and activator of transcription); cancer associated fibroblasts (CAF); cytokines; tumor development; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2021.767939

Cancer Discov. 2021 Dec 03.

BRD4-cJUN-CCL2-TNFα Axis Maintains Basal-Like Pancreatic Cancer Subtype Identity.

BRD4-cJUN-CCL2-TNFα axis disruption in basal-like pancreatic cancer restores a favorable phenotype.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-171

Oncogene. 2021 Dec 03.

Tumor-associated macrophages promote PD-L1 expression in tumor cells by regulating PKM2 nuclear translocation in pancreatic ductal adenocarcinoma.

Qing Xia, Jing Jia, Chupeng Hu, Jinying Lu, Jiajin Li, Haiyan Xu, Jianchen Fang, Dongju Feng, Liwei Wang, Yun Chen.

In many types of cancer, tumor cells prefer to use glycolysis as a major energy acquisition method. Here, we found that the 18fluoro-deoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based markers were positively associated with the expression of programmed cell death ligand 1 (PD-L1), pyruvate kinase M2 (PKM2), both of which indicate poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. In this study, we confirmed that transforming growth factor-beta1 (TGF-β1) secreted by tumor-associated macrophages (TAMs) was a key factor contributing to the expression of PD-L1 in PDAC cells by inducing the nuclear translocation of PKM2. Using co-immunoprecipitation and chromatin immunoprecipitation assays, we demonstrated that the interaction between PKM2 and signal transducer and activator of transcription 1 (STAT1) was enhanced by TGF-β1 stimulation, which facilitated the transactivation of PD-L1 by the binding of PKM2 and STAT1 to its promoter. In vivo, PKM2 knockdown decreased PD-L1 expression in PDAC cells and inhibited tumor growth partly by promoting natural killer cell activation and function, and the combination of PD-1/PD-L1 blockade with PKM2 knockdown limited tumor growth. In conclusion, PKM2 significantly contributes to TAM-induced PD-L1 overexpression and immunosuppression, providing a novel target for immunotherapies for PDAC.

DOI: https://doi.org/10.1038/s41388-021-02133-5

Cell. 2021 Nov 26. pii: S0092-8674(21)01331-3. [Epub ahead of print]

An NK-like CAR T cell transition in CAR T cell dysfunction.

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

Keywords: CAR T cell; ID3; NK-like T cell; SOX4; T cell dysfunction; T cell exhaustion; cancer; cell transfer therapy; immunology; immunotherapy; pancreatic cancer; single-cell RNA-seq

DOI: https://doi.org/10.1016/j.cell.2021.11.016

Front Immunol. 2021 ;12 781032

The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer.

Ghazal Mohseni, Juan Li, Abakundana Nsenga Ariston Gabriel, Lutao Du, Yun-Shan Wang, Chuanxin Wang.

The activation of stimulator of interferon genes (STING) signalling pathway has been suggested to promote the immune responses against malignancy. STING is activated in response to the detection of cytosolic DNA and can induce type I interferons and link innate immunity with the adaptive immune system. Due to accretive evidence demonstrating that the STING pathway regulates the immune cells of the tumor microenvironment (TME), STING as a cancer biotherapy has attracted considerable attention. Pancreatic cancer, with a highly immunosuppressive TME, remains fatal cancer. STING has been applied to the treatment of pancreatic cancer through distinct strategies. This review reveals the role of STING signalling on pancreatic tumors and other diseases related to the pancreas. We then discuss new advances of STING in either monotherapy or combination methods for pancreatic cancer immunotherapy.

Keywords: cGAS-STING pathway; cytosolic DNA; immunotherapy; pancreatic cancer; type I interferon (IFN)

DOI: https://doi.org/10.3389/fimmu.2021.781032

Elife. 2021 Nov 29. pii: e73020. [Epub ahead of print]10

Quantitative analysis of tumour spheroid structure.

Alexander P Browning, Jesse A Sharp, Ryan J Murphy, Gency Gunasingh, Brodie Lawson, Kevin Burrage, Nikolas K Haass, Matthew Simpson.

Tumour spheroids are common in vitro experimental models of avascular tumour growth. Compared with traditional two-dimensional culture, tumour spheroids more closely mimic the avascular tumour microenvironment where spatial differences in nutrient availability strongly influence growth. We show that spheroids initiated using significantly different numbers of cells grow to similar limiting sizes, suggesting that avascular tumours have a limiting structure; in agreement with untested predictions of classical mathematical models of tumour spheroids. We develop a novel mathematical and statistical framework to study the structure of tumour spheroids seeded from cells transduced with fluorescent cell cycle indicators, enabling us to discriminate between arrested and cycling cells and identify an arrested region. Our analysis shows that transient spheroid structure is independent of initial spheroid size, and the limiting structure can be independent of seeding density. Standard experimental protocols compare spheroid size as a function of time; however, our analysis suggests that comparing spheroid structure as a function of overall size produces results that are relatively insensitive to variability in spheroid size. Our experimental observations are made using two melanoma cell lines, but our modelling framework applies across a wide range of spheroid culture conditions and cell lines.

Keywords: cancer biology; computational biology; human; systems biology

DOI: https://doi.org/10.7554/eLife.73020

Nat Cell Biol. 2021 Dec 02.

A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers.

A Fatehullah, Y Terakado, S Sagiraju, T L Tan, T Sheng, S H Tan, K Murakami, Y Swathi, N Ang, R Rajarethinam, T Ming, P Tan, B Lee, N Barker.

Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.

DOI: https://doi.org/10.1038/s41556-021-00793-9