Intratumor heterogeneity in KRAS signaling shapes treatment resistance DOI Creative Commons
Oleksi Petrenko, Varvara Kirillov, Stephen D’Amico

et al.

iScience, Journal Year: 2024, Volume and Issue: 28(2), P. 111662 - 111662

Published: Dec. 22, 2024

KRAS mutations are linked to some of the deadliest forms cancer. Pharmacological studies suggest that co-targeting with feedback/bypass pathways could lead enhanced anti-tumor activity. The underlying premise is cancers display a deep-rooted hypersensitivity inactivation. Here, we investigate role intratumor heterogeneity in pancreatic ductal adenocarcinoma, focusing on oncogenic addiction and treatment resistance. Integrated analysis single-cell bulk RNA sequencing data reveals most tumors mixture cells vastly different degrees dependency. We identify distinct cell populations vary their gene expression patterns pertaining predicted level signaling activity, growth, differentiation commitment within each tumor. Selective targeting mutant suppresses growth tumor high RAS/mitogen-activated protein kinase (MAPK) activity while sparing pre-existing subsets low RAS necessitating alternative treatments. Combination immunotherapy leads durable regression preclinical models.

Language: Английский

Extracellular matrix stiffness regulates colorectal cancer progression via HSF4 DOI Creative Commons
Kangtao Wang,

Siyi Ning,

Shuai Zhang

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Jan. 30, 2025

Abstract Background Colorectal cancer (CRC) has high incidence and mortality rates, with severe prognoses during invasion metastasis stages. Despite advancements in diagnostic therapeutic technologies, the impact of tumour microenvironment, particularly extracellular matrix (ECM) stiffness, on CRC progression is not fully understood. Methods This study included 107 patients. Tumour stiffness was assessed using magnetic resonance elastography (MRE), collagen ratio analysed Masson staining. cell lines were cultured matrices varying followed by transcriptome sequencing to identify stiffness-related genes. An HSF4 knockout model different ECM evaluate effects proliferation, migration, vitro vivo. Results significantly higher than normal tissue positively correlated content TNM staging. High-stiffness regulated functions signalling pathways. High (heat shock transcriptional factor 4) expression strongly associated poor prognosis. increased stages, its inhibited invasion, especially high-stiffness matrices. In vivo experiments confirmed that promoted growth metastasis, independent protein increase. Conclusions reveals promotes proliferation regulating EMT-related pathways through HSF4. could be valuable targets for prognostic assessment intervention CRC.

Language: Английский

Citations

3
Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression DOI Creative Commons
Yi‐Cheng Zhu,

Jiaoshun Chen,

Chen Chen

et al.

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 23, 2025

The tumor microenvironment functions as a dynamic and intricate ecosystem, comprising diverse array of cellular non-cellular components that precisely orchestrate pivotal behaviors, including invasion, metastasis, drug resistance. While unraveling the interplay between behaviors represents tremendous challenge, recent research illuminates crucial biological phenomenon known mechanotransduction. Within microenvironment, mechanical cues like tensile stress, shear stiffness play role by activating mechanosensitive effectors such PIEZO proteins, integrins, Yes-associated protein. This activation initiates cascades intrinsic signaling pathways, effectively linking physical properties tissues to their physiological pathophysiological processes morphogenesis, regeneration, immunity. mechanistic insight offers novel perspective on how within impact behaviors. intricacies are yet be fully elucidated, it exhibits distinct attributes from non-malignant tissues, elevated solid stresses, interstitial hypertension, augmented matrix stiffness, enhanced viscoelasticity. These traits exert notable influences progression treatment responses, enriching our comprehension multifaceted nature microenvironment. Through this innovative review, we aim provide new lens decipher contexts, broadening knowledge these factors promote or inhibit thus offering valuable insights identify potential targets for anti-tumor strategies.

Language: Английский

Citations

1
Learning and actioning general principles of cancer cell drug sensitivity DOI Creative Commons
Francesco Carli, Pierluigi Di Chiaro, Mariangela Morelli

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 15, 2025

High-throughput screening of drug sensitivity cancer cell lines (CCLs) holds the potential to unlock anti-tumor therapies. In this study, we leverage such datasets predict response using line transcriptomics, focusing on models' interpretability and deployment patients' data. We use large language models (LLMs) match mechanisms action (MOA)-related pathways. Genes crucial for prediction are enriched in drug-MOAs, suggesting that our learn molecular determinants response. Furthermore, by only LLM-curated, MOA-genes, enhance predictive accuracy models. To translatability, align RNAseq data from CCLs, used training, those patient samples, inference. validated approach TCGA where best scoring drugs prescribed their type. further experimentally validate effective patients two highly lethal solid tumors, i.e., pancreatic glioblastoma.

Language: Английский

Citations

1
Macrophage diversity in cancer dissemination and metastasis DOI Creative Commons
Alberto Mantovani, Federica Marchesi, Diletta Di Mitri

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(11), P. 1201 - 1214

Published: Oct. 14, 2024

Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous lymphatic pathways metastasis, cancer cell dissemination can occur via transcoelomic perineural routes, which typical ovarian pancreatic cancer, respectively. Macrophages a universal major component tumor microenvironment and, in established tumors, promote growth secondary sites. Here, we review role tumor-associated macrophages (TAMs) emphasizing diversity myeloid cells different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models lung fail capture microenvironments. A better understanding TAM may pave way for tailored diagnostic therapeutic approaches.

Language: Английский

Citations

7
The landscape of cancer-rewired GPCR signaling axes DOI Creative Commons
Chakit Arora, Marin Matic, Luisa Bisceglia

et al.

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(5), P. 100557 - 100557

Published: May 1, 2024

We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities oncology. derived an interaction network receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together upstream partners across subtypes associated specific transcriptional programs patient survival patterns. The expression both receptor-ligand (or enzymes) improved stratification, suggesting a synergistic role for activation GPCR networks modulating phenotypes. Remarkably, we identified many such axes several molecular subtypes, including involving receptor-biosynthetic enzymes neurotransmitters. found that from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, chemokine receptors, targets multiple drugs displaying anti-growth effects large-scale, cell drug screens, which further validated. have made results generated this study freely available through webapp (gpcrcanceraxes.bioinfolab.sns.it).

Language: Английский

Citations

6
Spatial Transcriptomics Reveals Novel Mechanisms Involved in Perineural Invasion in Pancreatic Ductal Adenocarcinomas DOI Open Access
Vanessa Lakis, Noni Chan,

Ruth J. Lyons

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 852 - 852

Published: March 1, 2025

Pancreatic ductal adenocarcinoma (PDAC) has a high incidence of perineural invasion (PNI), pathological feature the cancer nerves. PNI is associated with poor prognosis, local recurrence and pain. It been suggested that interactions between nerves tumor microenvironment (TME) play role in PDAC tumorigenesis. Here, we used Nanostring GeoMx Digital Spatial Profiler to analyze whole transcriptome both nerve cells non-PNI foci from 13 patients. We identified previously reported pathways involved PNI, including Axonal Guidance ROBO-SLIT Signaling. transcriptomics highlighted influencing immune landscape TME similarities injury response. This study revealed endocannabinoid polyamine metabolism may contribute growth Key members these can be targeted, offering potential novel research avenues for exploring new treatment and/or pain management options PDAC.

Language: Английский

Citations

0
Quantifying and interpreting biologically meaningful spatial signatures within tumor microenvironments DOI Creative Commons
Siyu Jing,

He-qi Wang,

Ping Lin

et al.

npj Precision Oncology, Journal Year: 2025, Volume and Issue: 9(1)

Published: March 11, 2025

The tumor microenvironment (TME) plays a crucial role in orchestrating cell behavior and cancer progression. Recent advances spatial profiling technologies have uncovered novel signatures, including univariate distribution patterns, bivariate relationships, higher-order structures. These signatures the potential to revolutionize mechanism treatment. In this review, we summarize current state of signature research, highlighting computational methods uncover spatially relevant biological significance. We discuss impact these on fundamental biology translational address challenges future research directions.

Language: Английский

Citations

0
Sympathetic nerve signaling rewires the tumor microenvironment: a shift in “microenvironmental-ity” DOI Creative Commons
Ariana Sattler, Tetiana Korzun, Kasmira Gupta

et al.

Cancer and Metastasis Reviews, Journal Year: 2025, Volume and Issue: 44(1)

Published: Jan. 20, 2025

Nerve signaling within the tumor microenvironment (TME) plays a critical role in initiation, progression, and metastasis of solid tumors. Due to their highly responsive behavior activation upon injury cancer onset, this review specifically focuses on how sympathetic nerves rewire TME. Within tumors, closely interact with various TME components, combined often shifts tumor-intrinsic physiology toward tumor-supportive phenotypes. In turn, such as myeloid cells, lymphoid extracellular matrix (ECM), endothelial associated fibroblasts (CAFs), Schwann secrete neurotrophic axon guidance factors that influence both outgrowth cell behavior, further exacerbating progression metastasis. Here, we current evidence multidirectional impacts immune non-immune nature these communication processes, exploring interactions may inform future therapeutics impair

Language: Английский

Citations

0
Exploring the biological mechanism and clinical value of perineural invasion in pancreatic cancer DOI
Hao Yuan, Yufeng Zhang, Fengyuan Liu

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217515 - 217515

Published: Jan. 1, 2025

Language: Английский

Citations

0
Comprehensive analysis of mitochondrial-related gene signature for prognosis, tumor immune microenvironment evaluation, and candidate drug development in colon cancer DOI Creative Commons
Hao Wu, Wentao Zhang,

Jingjia Chang

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 20, 2025

Colon adenocarcinoma (COAD), a common digestive system malignancy, involves crucial alterations in mitochondria-related genes influencing tumor growth, metastasis, and immune evasion. Despite limited studies on prognostic models for these COAD, we established mitochondrial-related risk model, including nine based available TCGA MitoCarta 3.0 databases, validated its predictive power. We investigated the microenvironment (TME), cell infiltration, complex communication, mutation burden, drug sensitivity of COAD patients using R language, CellChat, additional bioinformatic tools from single-cell bulk-tissue sequencing data. The model revealed significant differences infiltration between high-risk low-risk groups, with strongest correlation found tissue stem cells macrophages COAD. score exhibited robust TME signature checkpoint molecules. Integrating score, microsatellite status, or TMB through TIDE analysis enhanced accuracy predicting immunotherapy benefits. Predicted efficacy offered options both high- group patients. Our study novel nine-gene signature, providing insights assessment clinical decision-making

Language: Английский

Citations

0