Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA753131 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15382900.fastq.gz | Fastqsanger.gz | |||
| SRR15382891.fastq.gz | Fastqsanger.gz | |||
| SRR15382892.fastq.gz | Fastqsanger.gz | |||
| SRR15382893.fastq.gz | Fastqsanger.gz | |||
| SRR15382894.fastq.gz | Fastqsanger.gz |
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Project description:Colon cancer is initiated by stem cells that escape the strict control. In most colon tumors this process is driven through aberrant activation of Wnt signaling by mutations that occur in components acting downstream of the receptor complex and that unfetter tumor cells from the need for Wnt ligands. Here we describe a special type of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells auto-secrete Wnt ligands to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt- dependent colon cancer, that might be responsive to Wnt secretion inhibitors.
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Project description:Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.
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Project description:The recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the long-standing understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we lower the levels of Wnt signaling in SW480 and SW620 colon cancer cell lines via interference with two different steps in Wnt signaling that lie upstream or downstream of the effector protein ß-catenin. We find that these Wnt-reduced lines exhibit a more aggressive disease phenotype, including increased mobility in vitro and localized invasion in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion. We identify a set of upregulated genes common among the Wnt perturbations, and find that elevated expression of these genes is strongly predictive of poor patient outcomes in early-invasive colon cancer. These genes may have clinical applications as either patient biomarkers or new drug targets to be used in concert with existing therapies.
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Project description:Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancers (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiologic Wnt activity, we have performed comprehensive transcriptome and proteome profiling in human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9 induced APC loss. We could catalogue two non-overlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal colon stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.
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