Overcoming therapy resistance in pancreatic cancer: New insights and future directions

Biochemical Pharmacology, Год журнала: 2024, Номер 229, С. 116492 - 116492

Опубликована: Авг. 15, 2024

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this mostly due therapy failure. Limited treatment options resistance standard-of-care (SoC) therapies makes PDAC one types with poorest prognosis survival rates [1,2]. tumors are renowned for their poor response therapeutic interventions including targeted therapies, chemotherapy radiotherapy. Herein, we review hallmarks in current strategies aiming tackle escape mechanisms re-sensitize cells therapy. We will further provide insights on recent advances field drug discovery, nanomedicine, disease models that setting ground future research.

Язык: Английский

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The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

Cancers, Год журнала: 2022, Номер 14(13), С. 3293 - 3293

Опубликована: Июль 5, 2022

Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause cancer-related mortality worldwide. Abundant desmoplastic stroma histological hallmark pancreatic ductal adenocarcinoma. Emerging evidence suggests promising therapeutic effect several stroma-modifying therapies that target stromal elements in microenvironment. The also unveils multifaceted roles cancer-associated fibroblasts (CAFs) manipulating progression, immunity, chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics multiplexed tissue imaging techniques, have provided more profound knowledge CAF heterogeneity real-world specimens from patients, as well genetically engineered mouse models. In this review, we describe recent advances understanding molecular pathology bases at multilayered levels heterogeneity, namely, (1) variations cellular non-cellular members, subtypes extracellular matrix (ECM) proteins; (2) geographical relation to cell–cell interactions signaling pathways niche spatial locoregional or organ levels; (3) intertumoral individual levels. This review further discusses clinicopathological significance potential opportunities for stroma-targeted against malignancy.

Язык: Английский

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USP51/ZEB1/ACTA2 axis promotes mesenchymal phenotype in gastric cancer and is associated with low cohesion characteristics

Pharmacological Research, Год журнала: 2023, Номер 188, С. 106644 - 106644

Опубликована: Янв. 2, 2023

poorly cohesive (PC) gastric cancer (GC) (PC-GC) is a distinct histological subtype of GC and defined as tumor consisting isolated or small clusters cells with differentiated metastatic characteristics. According to multiple studies, PC-GC intrinsically heterogeneous, mesenchymal variants being the most aggressive. However, date, molecular mechanisms associated are still not fully understood. This study investigated role USP51/ZEB1/ACTA2 axis in promoting metastasis. Single-cell sequencing revealed that E-box binding homeobox 1 (ZEB1) expression was significantly increased subpopulation low-adherent an independent prognostic factor patients. Furthermore, bulk transcriptome analysis significant positive correlation between Ubiquitin Specific Peptidase 51 (USP51), ZEB1, Actin Alpha 2 (ACTA2), our data further confirmed all three were highly co-localized tissues. findings vitro vivo experiments, USP51 able maintain ZEB1 promote ACTA2 transcription, thereby activating phenotype Moreover, could recruit activate stromal cells, including M2-like macrophages fibroblasts, through cells. Clinical suggested overexpression predicts patients have difficulty benefiting from immunotherapy immune-exclusion Collectively, this shed light on key mechanism by which elevated induces Epithelial-mesenchymal transition (EMT) hence facilitating cell proliferation, survival, dissemination. In view, may serve candidate therapeutic target against

Язык: Английский

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Targeted mechanical forces enhance the effects of tumor immunotherapy by regulating immune cells in the tumor microenvironment

Cancer Biology and Medicine, Год журнала: 2023, Номер 20(1), С. 44 - 55

Опубликована: Янв. 12, 2023

Mechanical forces in the tumor microenvironment (TME) are associated with growth, proliferation, and drug resistance. Strong mechanical tumors alter metabolism behavior of cancer cells, thus promoting progression metastasis. signals transformed into biochemical signals, which activate tumorigenic signaling pathways through transduction. Cancer immunotherapy has recently made exciting progress, ushering a new era “chemo-free” treatments. However, not achieved satisfactory results variety tumors, because complex microenvironment. Herein, we discuss effects on immune highlight emerging therapeutic strategies for targeting immunotherapy.

Язык: Английский

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Collagen VI sustains cell stemness and chemotherapy resistance in glioblastoma

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(8)

Опубликована: Июль 28, 2023

Abstract Microenvironmental factors are known fundamental regulators of the phenotype and aggressiveness glioblastoma (GBM), most lethal brain tumor, characterized by fast progression marked resistance to treatments. In this context, extracellular matrix (ECM) is heavily influence behavior cancer cells from several origins, contributing stem cell niches, influencing tumor invasiveness response chemotherapy, mediating survival signaling cascades, modulating inflammatory recruitment. Here, we show that collagen VI (COL6), an ECM protein widely expressed in both normal pathological tissues, has a distinctive distribution within GBM mass, strongly correlated with aggressive phenotypically immature cells. Our data demonstrate COL6 sustains stem-like properties supports maintenance transcriptional program promoting proliferation survival. particular, identified specific subset COL6-transcriptionally co-regulated genes, required for replicative stress DNA damage, supporting concept essential stimulus activation through ATM/ATR axis. Altogether, these findings indicate plays pivotal role biology, exerting pleiotropic action across different hallmarks, including phenotypic identity gene transcription, as well treatments, thus providing valuable information understanding complex microenvironmental cues underlying malignancy.

Язык: Английский

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Spatial profiling of endoplasmic reticulum stress markers in tumor associated cells predicts patient outcomes in pancreatic cancer

Neoplasia, Год журнала: 2025, Номер 60, С. 101115 - 101115

Опубликована: Янв. 15, 2025

Язык: Английский

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Breaking the stromal barrier in pancreatic cancer: Advances and challenges

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2023, Номер 1879(1), С. 189065 - 189065

Опубликована: Дек. 30, 2023

Язык: Английский

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Cold Atmospheric Plasma Does Not Affect Stellate Cells Phenotype in Pancreatic Cancer Tissue in Ovo

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(4), С. 1954 - 1954

Опубликована: Фев. 10, 2022

Pancreatic ductal adenocarcinoma (PDAC) is a challenging neoplastic disease, mainly due to the development of resistance radio- and chemotherapy. Cold atmospheric plasma (CAP) an alternative technology that can eliminate cancer cells through oxidative damage, as shown in vitro, ovo, vivo. However, how CAP affects pancreatic stellate (PSCs), key players invasion metastasis PDAC, poorly understood. This study aims determine effect anti-PDAC treatment on PSCs tissue developed ovo using mono- co-cultures RLT-PSC (PSCs) Mia PaCa-2 (PDAC). We measured reduction upon mRNA expression PSC activation markers extracellular matrix (ECM) remodelling factors via qRT-PCR. Protein selected was confirmed immunohistochemistry. inhibited growth co-cultured tissue, but its effectiveness reduced latter, which correlates with ki67 levels. did not alter ECM markers. No changes MMP2 MMP9 were observed RLT-PSCs, small cells. Our findings support ability PDAC cells, without altering PSCs.

Язык: Английский

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Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer

Cancer Immunology Research, Год журнала: 2022, Номер 11(1), С. 72 - 92

Опубликована: Дек. 7, 2022

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology disease. Here, we identified galectin 4 (gal 4) as a cancer cell-produced protein that was deposited into ECM PDAC tumors and detected high-circulating levels gal in patients with PDAC. In orthotopic transplantation experiments, observed increased infiltration T cells prolonged survival immunocompetent mice transplanted reduced expression 4. Increased not immunodeficient RAG1-/- mice, demonstrating effect mediated adaptive immune system. By performing single-cell RNA-sequencing, found myeloid compartment cancer-associated fibroblast (CAF) subtypes were altered tumors. Reduced associated higher proportion myofibroblastic CAFs numbers inflammatory CAFs. We also proportions M1 macrophages, cells, antigen-presenting dendritic expression. Using coculture system, induced apoptosis binding N-glycosylation residues on CD3ε/δ. Hence, show involved evasion identify promising drug target for overcoming immunosuppression

Язык: Английский

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Hyperthermia-induced stellate cell deactivation to enhance dual chemo and pH-responsive photothermal therapy for pancreatic cancers

Nanoscale, Год журнала: 2022, Номер 14(42), С. 15735 - 15748

Опубликована: Янв. 1, 2022

Lipid nanoparticles loaded with dual gemcitabine and pH-sensitive photothermal drug generate local hyperthermia, assist in deactivating pancreatic stellate cells, enhance penetration significantly boost chemo-phototherapy outcomes.

Язык: Английский

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