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1.
Cell Rep ; 43(6): 114270, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38787726

ABSTRACT

Stem cells play pivotal roles in maintaining intestinal homeostasis, orchestrating regeneration, and in key steps of colorectal cancer (CRC) initiation and progression. Intriguingly, adult stem cells are reduced during many of these processes. On the contrary, primitive fetal programs, commonly detected in development, emerge during tissue repair, CRC metastasis, and therapy resistance. Recent findings indicate a dynamic continuum between adult and fetal stem cell programs. We discuss critical mechanisms facilitating the plasticity between stem cell states and highlight the heterogeneity observed upon the appearance of fetal-like states. We focus on therapeutic opportunities that arise by targeting fetal-like CRC cells and how those concepts can be translated into the clinic.


Subject(s)
Colorectal Neoplasms , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/therapy , Humans , Animals , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Fetal Stem Cells/metabolism
2.
Nat Commun ; 14(1): 2353, 2023 04 24.
Article in English | MEDLINE | ID: mdl-37095087

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Peritoneal Neoplasms , Mice , Animals , Peritoneum/metabolism , Peritoneal Neoplasms/pathology , Hyaluronic Acid , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , Cell Line, Tumor , Neoplasm Metastasis/pathology , Gene Expression Regulation, Neoplastic , Tumor Microenvironment , Pancreatic Neoplasms
3.
Cancers (Basel) ; 14(17)2022 Aug 31.
Article in English | MEDLINE | ID: mdl-36077793

ABSTRACT

Colorectal cancer (CRC) is among the deadliest cancers worldwide, with metastasis being the main cause of patient mortality. During CRC progression the complex tumor ecosystem changes in its composition at virtually every stage. However, clonal dynamics and associated niche-dependencies at these stages are unknown. Hence, it is of importance to utilize models that faithfully recapitulate human CRC to define its clonal dynamics. We used an optical barcoding approach in mouse-derived organoids (MDOs) that revealed niche-dependent clonal selection. Our findings highlight that clonal selection is controlled by a site-specific niche, which critically contributes to cancer heterogeneity and has implications for therapeutic intervention.

4.
Nat Commun ; 11(1): 3883, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32753598

ABSTRACT

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.


Subject(s)
Brain Neoplasms/drug therapy , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Drug Resistance, Neoplasm/genetics , Gene Rearrangement , Glioma/drug therapy , Neoplasm Recurrence, Local/genetics , Temozolomide/pharmacology , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Aged , Animals , Brain Neoplasms/genetics , Cell Line, Tumor , DNA Adducts/drug effects , DNA Adducts/metabolism , DNA Methylation , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , Female , Gene Expression Regulation, Neoplastic , Glioma/genetics , Humans , Male , Mice , Middle Aged , Neoplasm Recurrence, Local/prevention & control , Promoter Regions, Genetic/genetics , RNA-Seq , Temozolomide/therapeutic use , Tumor Suppressor Proteins/metabolism , Up-Regulation , Whole Genome Sequencing , Xenograft Model Antitumor Assays , Young Adult
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