AI Article Synopsis
- - The study investigates how cancer cells in colonic organoids are influenced by both genetic mutations (oncogenes) and their surrounding environment, particularly focusing on the roles of different cell types like fibroblasts and macrophages.
- - Researchers conducted a detailed analysis that showed a stepwise differentiation process among cancer stem cells, highlighting that specific combinations of mutations and external signals determine whether these cells become regenerative (revCSCs) or hyper-proliferative (proCSCs).
- - Findings suggest that the loss of the APC gene and mutations in KRAS disrupt normal communication between stromal and epithelial cells, leading to a dominance of oncogenic signals that hinder typical cell differentiation processes.
Article Abstract
Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU) revival colonic stem cells (revCSCs) to oncogene-driven LRIG1 hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRAS or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRAS collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.cell.2023.11.004 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Ectopic Salivary Duct Cyst in the Median Mandible: A Case Report with Radiological, Immunohistochemical and Genetic Studies.
Int J Surg Pathol
January 2025
Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama, Japan.
Median mandibular cyst is defined as an odontogenic cyst in a rare midline location. In spite of this definition, there have been two reports of a peculiar lesion, so-called "ciliated" median mandibular cyst associated with vital teeth, the origin of which cannot be explained in terms of odontogenic epithelium multipotentiality. We describe a thorough profile of an additional example.
View Article and Find Full Text PDFCrypt density and recruited enhancers underlie intestinal tumour initiation.
Nature
January 2025
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs). Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny.
View Article and Find Full Text PDFKRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma.
JAMA Netw Open
January 2025
Huntsman Cancer Institute, University of Utah Health Care, Salt Lake City.
Importance: Despite the high prevalence of KRAS alterations in pancreatic ductal adenocarcinoma (PDAC), the clinical impact of common KRAS mutations with different cytotoxic regimens is unknown. This evidence is important to inform current treatment and provide a benchmark for emergent targeted KRAS therapies in metastatic PDAC.
Objective: To assess the clinical implications of common KRAS G12 mutations in PDAC and to compare outcomes of standard-of-care multiagent therapies across these common mutations.
Impact of Sotorasib, a KRAS G12C Inhibitor, on the Pharmacokinetics and Therapeutic Window of Digoxin, a P-Glycoprotein Substrate.
Clin Pharmacol Drug Dev
January 2025
Clinical Pharmacology Modeling and Simulation, Amgen Inc., Thousand Oaks, CA, USA.
Sotorasib is a small-molecule Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C inhibitor indicated for the treatment of KRAS G12C-driven cancers. KRAS G12C is a common mutation in solid tumors, including non-small cell lung cancer. In vitro studies suggested that sotorasib is a weak inhibitor of P-glycoprotein transporter.
View Article and Find Full Text PDFMolecular heterogeneity and MYC dysregulation in triple-negative breast cancer: genomic advances and therapeutic implications.
3 Biotech
January 2025
School of Health Sciences and Technology (SoHST), UPES, Dehradun, Uttarakhand 248007 India.
Triple-negative breast cancer (TNBC) is characterized by a diverse range of molecular features that have been extensively studied. MYC plays a critical role in regulating metabolism, differentiation, proliferation, cell growth, and apoptosis. Dysregulation of MYC is associated with poor prognosis and contributes to the development and progression of breast cancer.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!