The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity DOI Creative Commons
Vincenzo Salemme, Giorgia Centonze, Lidia Avalle

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: May 17, 2023

Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, this heterogeneity crucial determinant of malignant progression response to treatments. In addition genetic diversity plasticity cells, the tumor microenvironment contributes shaping physical biological surroundings tumor. The activity certain types immune, endothelial or mesenchymal cells in can change effectiveness therapies via plethora different mechanisms. Therefore, deciphering interactions between distinct cell types, their spatial organization specific contribution growth drug sensitivity still major challenge. Dissecting currently an urgent need better define breast biology develop therapeutic strategies targeting as helpful tools for combined personalized treatment. review, we analyze mechanisms by which affects characteristics that ultimately result resistance, outline state art preclinical models emerging technologies will be instrumental unraveling impact on resistance therapies.

Language: Английский

Drug screening at single-organoid resolution via bioprinting and interferometry DOI Creative Commons
Peyton Tebon, Bowen Wang, Alexander L. Markowitz

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 6, 2023

Abstract High throughput drug screening is an established approach to investigate tumor biology and identify therapeutic leads. Traditional platforms use two-dimensional cultures which do not accurately reflect the of human tumors. More clinically relevant model systems such as three-dimensional organoids can be difficult scale screen. Manually seeded coupled destructive endpoint assays allow for characterization treatment response, but capture transitory changes intra-sample heterogeneity underlying observed resistance therapy. We present a pipeline generate bioprinted linked label-free, time-resolved imaging via high-speed live cell interferometry (HSLCI) machine learning-based quantitation individual organoids. Bioprinting cells gives rise 3D structures with unaltered histology gene expression profiles. HSLCI in tandem segmentation classification tools enables accurate, label-free parallel mass measurements thousands demonstrate that this strategy identifies transiently or persistently sensitive resistant specific therapies, information could used guide rapid therapy selection.

Language: Английский

Citations

63
m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization DOI Creative Commons
Ning Wang, Rixin Chen, Minhua Deng

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(2)

Published: Feb. 18, 2023

Abstract The significance of 5-methylcytosine (m 5 C) methylation in human malignancies has become an increasing focus investigation. Here, we show that m C regulators including writers, readers and erasers, are predominantly upregulated urothelial carcinoma the bladder (UCB) derived from Sun Yat-sen University Cancer Center Genome Atlas cohort. In addition, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) as a Aly/REF export factor (ALYREF) nuclear reader, frequently coexpressed UCB. By applying patient-derived organoids model orthotopic xenograft mice model, demonstrate ALYREF enhances proliferation invasion UCB cells C-dependent manner. Integration tanscriptome-wide bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq) Immunoprecipitation (RIP)-seq analysis revealed specifically binds to hypermethylated site RAB, RAS oncogene like 6 (RABL6) thymidine kinase 1 (TK1) mRNA via its K171 domain. controls through promoting RABL6 TK1 for splicing stabilization. Moreover, recognizes NSUN2 , resulting upregulation Clinically, patients with high coexpression ALYREF/RABL6/TK1 axis had poorest overall survival. Our study unveils dependent cross-regulation between reader writer activation oncogenic maintaining stabilization, consequently leading tumor progression, which provides profound insights into therapeutic strategy

Language: Английский

Citations

53
Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis DOI Creative Commons
Tianxing Zhou, Yongjie Xie,

Xupeng Hou

et al.

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

Citations

51
Cancer organoids 2.0: modelling the complexity of the tumour immune microenvironment DOI
Roel Polak, Elisa Zhang, Calvin J. Kuo

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(8), P. 523 - 539

Published: July 8, 2024

Language: Английский

Citations

48
The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity DOI Creative Commons
Vincenzo Salemme, Giorgia Centonze, Lidia Avalle

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: May 17, 2023

Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, this heterogeneity crucial determinant of malignant progression response to treatments. In addition genetic diversity plasticity cells, the tumor microenvironment contributes shaping physical biological surroundings tumor. The activity certain types immune, endothelial or mesenchymal cells in can change effectiveness therapies via plethora different mechanisms. Therefore, deciphering interactions between distinct cell types, their spatial organization specific contribution growth drug sensitivity still major challenge. Dissecting currently an urgent need better define breast biology develop therapeutic strategies targeting as helpful tools for combined personalized treatment. review, we analyze mechanisms by which affects characteristics that ultimately result resistance, outline state art preclinical models emerging technologies will be instrumental unraveling impact on resistance therapies.

Language: Английский

Citations

42