Cancer Spheroids and Organoids as Novel Tools for Research and Therapy: State of the Art and Challenges to Guide Precision Medicine

Cells, Journal Year: 2023, Volume and Issue: 12(7), P. 1001 - 1001

Published: March 24, 2023

Spheroids and organoids are important novel players in medical life science research. They gradually replacing two-dimensional (2D) cell cultures. Indeed, three-dimensional (3D) cultures closer to the vivo reality open promising perspectives for academic research, drug screening, personalized medicine. A large variety of cells tissues, including tumor cells, can be starting material generation 3D cultures, primary stem or lines. panoply methods has been developed generate structures, spontaneous forced aggregation, air–liquid interface conditions, low attachment supports, magnetic levitation, scaffold-based technologies. The choice most appropriate method depends on (i) origin tissue, (ii) presence absence a disease, (iii) intended application. This review summarizes approaches cancer spheroids organoids, their advantages limitations. We also highlight some challenges unresolved issues field discuss possible therapeutic applications.

Language: Английский

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Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Theranostics, Journal Year: 2023, Volume and Issue: 13(5), P. 1520 - 1544

Published: Jan. 1, 2023

Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on forms of various regulating mechanisms to enhance therapeutic effect, including blockade interaction between PD-1, downregulation expression degradation mature PD-L1. Thereinto, describe variety materials been designed target PD-L1, antibodies, nanoparticle, peptide, aptamer, RNA, small molecule. Additionally, list drugs regulation capacity used in clinical ongoing studies explore other alternatives besides anti-PD-L1 monoclonal antibodies. Moreover, discuss associated opportunities cancer combination therapy modalities such as chemotherapy, radiotherapy, photodynamic (PDT) photothermal (PTT), these conventional or emerging capable increasing cells by altering microenvironment (TME), would display synergistic effect. At last, give brief summary outlook regarding research status future prospect immunotherapy.

Language: Английский

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Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria

Cell Research, Journal Year: 2023, Volume and Issue: 33(3), P. 215 - 228

Published: Jan. 10, 2023

Abstract Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated subcellular redistribution PD-L1. In our immunotherapy cohort nab-paclitaxel, tumor samples responders showed significant distribution PD-L1 at mitochondria, while non-responders increased accumulation on cell membrane instead mitochondria. Our results also revealed the pattern regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited mitochondria for degradation via mitophagy pathway. Importantly, ATAD3A expression disrupt proteostasis restraining PINK1-dependent mitophagy. Clinically, tumors exhibiting high detected before treatment had markedly shorter progression-free survival compared those ATAD3A-low tumors. Preclinical further demonstrated reset favorable antitumor microenvironment and efficacy therapy paclitaxel. summary, indicate serves not only as resistant factor through preventing mitochondrial distribution, but promising target increasing responses chemoimmunotherapy.

Language: Английский

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The opportunities and challenges in immunotherapy: Insights from the regulation of PD-L1 in cancer cells

Cancer Letters, Journal Year: 2023, Volume and Issue: 569, P. 216318 - 216318

Published: July 15, 2023

The immunosuppressive molecule programmed death-ligand 1 (PD-L1) is frequently upregulated in human cancers. Binding of PD-L1 to its receptor, death-1 (PD-1), on activated T cells facilitates cancer evade the host immune system. Antibody-based PD-1/PD-L1 inhibitors can inhibit interaction allowing reactivate cytotoxic eradicate advanced cells. However, majority patients fail respond anti-PD-1/PD-L1 therapies and molecular mechanisms for this remain poorly understood. Recent studies show that expression level tumor affect clinical efficacy checkpoint therapies. Thus, furthering our understanding regulatory will be critical improve response rates Here we review recent studies, primarily focusing regulate at transcriptional, post-transcriptional protein level, with purpose drive development more targeted effective

Language: Английский

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Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: May 4, 2023

Chemoresistance is the main reason for poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there an urgent need to screen out new targets and compounds reverse chemotherapeutic resistance.We established a bio-bank human PDAC organoid models, covering representative range tumor subtypes. We screened library 1304 FDA-approved identify candidates efficiently overcoming chemotherapy resistance. The effects were evaluated with CellTiter-Glo-3D assay, apoptosis assay in vivo patient-derived xenograft (PDX), (PDO) LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays luciferase conducted elucidate mechanism.High-throughput drug screening chemotherapy-resistant PDOs identified irbesartan, angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance ability kill cells. In vitro validation using PDO, PDX KPC models showed that irbesartan sensitized tumors chemotherapy. Mechanistically, we found decreased c-Jun expression by inhibiting Hippo/YAP1 pathway further overcame resistance PDAC. also explored c-Jun, potential target can transcriptionally upregulate key genes involved stemness maintenance (SOX9/SOX2/OCT4) metabolism (FTH1/FTL/TFRC). More importantly, observed patients high levels demonstrated responses current standard regimen (gemcitabine plus nab-paclitaxel). Moreover, had significant survival benefits from treatment two-center retrospective clinical cohorts exhibited better response combination chemotherapy.Irbesartan be used improve therapeutic efficacy expression. Irbesartan effectively inhibited suppressing Hippo/YAP1/c-Jun/stemness/iron axis. Based on our findings, are designing investigator-initiated phase II trial safety gemcitabine/nab-paclitaxel advanced III/IV staged hopeful will observe patient benefits.

Language: Английский

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Current and future immunotherapeutic approaches in pancreatic cancer treatment

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: June 4, 2024

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type tumor have remained grim long time. Currently, it extremely challenging to prevent or detect early enough effective treatment because patients rarely exhibit symptoms there are no reliable indicators detection. Most advanced spreading that difficult treat, treatments like chemotherapy radiotherapy can only slightly prolong their life by few months. Immunotherapy has revolutionized pancreatic cancer, yet its effectiveness limited tumor's immunosuppressive hard-to-reach microenvironment. First, article explains microenvironment highlights wide range immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered chimeric antigen [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced cells, immune checkpoint inhibitors, immunomodulators, vaccines, strategies targeting myeloid in context contemporary knowledge future trends. Lastly, discusses main challenges ahead immunotherapy.

Language: Английский

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Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Jan. 2, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this major cause therapy resistance poor prognosis. In recent years, research has advanced our understanding signaling mechanism which TIME interact with evolution immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs “cold” “hot” to comprehensive approach immunophenotyping that considers all cells components. This key improving clinical efficacy treatments. review, elaborate on various PDAC, mechanisms underlying their interactions, latest into A deep these network will contribute effective combination TIME-based therapeutic approaches, checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid CAF reprogramming, stromal normalization. By selecting appropriate integrated based precise immunophenotyping, significant advances future treatment are possible.

Language: Английский

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Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance

Autophagy, Journal Year: 2024, Volume and Issue: 20(6), P. 1314 - 1334

Published: Jan. 4, 2024

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance cancer immunotherapy unclear. The present study revealed inhibition suppresses vivo immune-deficient xenografts. This deletion compromises anti-tumor immunity efficacy both vitro by upregulating CD274/PDL1 levels an immune-competent mouse model. A block reduced production IL6 (interleukin 6), disrupting high desmoplastic TME decreasing USP14 expression at transcription level cells. We further identify as post-translational factor responsible downregulating CD274 removing K63 linked-ubiquitination K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, accurately targeting CAFs, inhibited autophagy, improving immunochemotherapy to combat cancer.

Language: Английский

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Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment

Cellular Oncology, Journal Year: 2022, Volume and Issue: 46(1), P. 17 - 48

Published: Nov. 11, 2022

Language: Английский

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Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment

Cancers, Journal Year: 2022, Volume and Issue: 14(4), P. 985 - 985

Published: Feb. 16, 2022

Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth patients present with potentially curable tumors. The available curative intent surgery followed by adjuvant chemotherapy. However, even for that eligible surgery, 5-year OS remains below 10%. Hence, there an urgent need find new therapeutic regimens. In first part this review, we discuss tumor staging method and impact on corresponding current standard-of-care treatments PDAC. We also consider key clinical trials over last 20 years have improved patient survival. second part, provide overview major components cell types involved in PDAC, well their respective roles interactions each other. A deeper knowledge taking place TME may lead discovery potential targets. Finally, promising strategies targeting specific combinations thereof. Overall, review provides challenges future perspectives pancreatic cancer.

Language: Английский

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