Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma DOI Creative Commons
Aristeidis Papargyriou,

Mulham Najajreh,

David P. Cook

et al.

Nature Biomedical Engineering, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance mortality rates. However, such morphological phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the landscape seen murine human PDAC, pronounced molecular is governed defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), different phenotypes represent distinct tumour-cell states unique biological features vivo. We also phenotype-specific therapeutic vulnerabilities modes treatment-induced phenotype reprogramming be maps. Our methodology analyses PDAC may guide development phenotype-targeted treatment strategies.

Language: Английский

Current and future immunotherapeutic approaches in pancreatic cancer treatment DOI Creative Commons
Pooya Farhangnia, Hossein Khorramdelazad, Hamid Nickho

et al.

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

Citations

34
Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept DOI Creative Commons
Wenyu Luo, Ti Wen, Xiujuan Qu

et al.

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

Citations

24
The nuclear factor ID3 endows macrophages with a potent anti-tumour activity DOI Creative Commons
Zihou Deng, Pierre-Louis Loyher, Tomi Lazarov

et al.

Nature, Journal Year: 2024, Volume and Issue: 626(8000), P. 864 - 873

Published: Feb. 7, 2024

Macrophage activation is controlled by a balance between activating and inhibitory receptors

Language: Английский

Citations

23
Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer DOI Creative Commons

Suhail Yousuf,

Mengjie Qiu,

Lena Voith von Voithenberg

et al.

Gastroenterology, Journal Year: 2023, Volume and Issue: 165(4), P. 891 - 908.e14

Published: May 30, 2023

As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant therapeutic interventions, including poor response immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment PDAC is urgently needed. We aimed unveil detailed view micromilieu using spatially resolved multimodal single-cell approach.We applied RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry profile compartment treatment-naïve tumors matched adjacent normal tissue, as well systemic circulation. determined prognostic associations signatures performed meta-analysis lung on level.We provided fine map landscape PDAC. substantiated exhausted phenotype CD8 T cells immunosuppressive features myeloid cells, highlighted subsets with potentially underappreciated roles that diverged from populations within areas, particularly CD4 cell natural killer are terminally acquire regulatory phenotype. Differential analysis phenotypes revealed presence extraordinarily subtypes PDAC, along distinctive checkpoint composition.Our study sheds light multilayered dysfunction presents holistic adenocarcinoma, providing comprehensive resource for functional studies exploration therapeutically actionable targets

Language: Английский

Citations

38
Escape from T-cell–targeting immunotherapies in acute myeloid leukemia DOI
Jayakumar Vadakekolathu, Sergio Rutella

Blood, Journal Year: 2023, Volume and Issue: 143(26), P. 2689 - 2700

Published: July 19, 2023

Language: Английский

Citations

30
Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC DOI Creative Commons
Xu Zhou,

Jingyu An,

Roma Kurilov

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(9), P. 1362 - 1381

Published: Sept. 7, 2023

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) multiplexed immunofluorescence 122) on chemo-naive postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) define impact neoadjuvant chemotherapy. Transcriptome analysis combined high-resolution mapping whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX samples. The persistence

Language: Английский

Citations

29
Oncogenic KRAS induces arginine auxotrophy and confers a therapeutic vulnerability to SLC7A1 inhibition in non-small cell lung cancer DOI
Xiameng Gai, Yingluo Liu, Xiaojing Lan

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(12), P. 1963 - 1977

Published: March 19, 2024

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation underlying mechanism by which oncogenic signaling mediates reprogramming could help identify targetable vulnerabilities. In this study, we discovered that activation KRAS non-small cell lung (NSCLC) silenced expression argininosuccinate synthase 1 (ASS1), a enzyme catalyzes production arginine from aspartate and citrulline, thereby diverted utilization pyrimidine synthesis high demand for DNA replication. Specifically, facilitated hypoacetylated state promoter region ASS1 gene histone deacetylase 3-dependent manner, turn impeded recruitment c-MYC transcription. suppression KRAS-mutant NSCLC impaired biosynthesis rendered dependency on transmembrane transporter SLC7A1 import extracellular arginine. Depletion both patient-derived organoid xenograft models inhibited KRAS-driven growth. Together, these findings uncover role rewiring metabolism SLC7A1-mediated uptake as therapeutic vulnerability treating NSCLC.

Language: Английский

Citations

14
Single-cell resolution characterization of myeloid-derived cell states with implication in cancer outcome DOI Creative Commons
Gabriela Rapozo Guimarães, Giovanna Resk Maklouf, Cristiane Esteves Teixeira

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 7, 2024

Abstract Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment responses due to their remarkable plasticity tumorigenic behaviors. Here, we integrate single-cell RNA-sequencing data from different types, identifying 29 MDC subpopulations within the tumor microenvironment. Our analysis reveals abnormally expanded across various tumors distinguishes cell states that have often been grouped together, such as TREM2+ FOLR2+ subpopulations. Using deconvolution approaches, identify five independent prognostic markers, including co-expressing TREM2 PD-1, FOLR2 PDL-2. Additionally, alone does not reliably predict prognosis, other macrophages show varied associations with depending on local cues. Validation in cohorts confirms FOLR2-expressing correlate poor clinical outcomes ovarian triple-negative breast cancers. This comprehensive atlas offers valuable insights a foundation for futher analyses, advancing strategies treating solid

Language: Английский

Citations

12
Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response DOI Creative Commons
Chen Lior, Debra Barki, Coral Halperin

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114236 - 114236

Published: May 1, 2024

The tumor microenvironment (TME) presents cells with challenges such as variable pH, hypoxia, and free radicals, triggering stress responses that affect cancer progression. In this study, we examine the response landscape in four carcinomas—breast, pancreas, ovary, prostate—across five pathways: heat shock, oxidative stress, DNA damage, unfolded protein stress. Using a combination of experimental computational methods, create an atlas across various types carcinomas. We find vary within TME are especially active near cells. Focusing on non-immune stroma find, types, NRF2 distinctly activated immune-regulatory cancer-associated fibroblasts unique subset pericytes. Our study thus provides interactome cancer, offering ways to intersect survival pathways tumor, advance therapy.

Language: Английский

Citations

11
An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer DOI Creative Commons
Veronica Ruta, Chiara Naro, Marco Pieraccioli

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(2), P. 101411 - 101411

Published: Feb. 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. PDAC presents with molecularly distinct subtypes, the basal-like one being associated enhanced chemoresistance. Splicing dysregulation contributes to PDAC; however, its involvement in subtype specification remains elusive. Herein, we uncover a subtype-specific splicing signature prognosis and factor Quaking (QKI) as determinant of signature. Single-cell sequencing analyses highlight QKI marker phenotype. represses events classical while promoting shorter survival. favors plastic, quasi-mesenchymal phenotype that supports migration chemoresistance organoids cell lines, expression elevated high-grade primary tumors metastatic lesions. These studies identify defines subtypes indicate promotes an undifferentiated, plastic phenotype, which renders cells chemoresistant adaptable environmental changes.

Language: Английский

Citations

10