Biology subjects

Sprangers, J.

Publications and source records attributed to Sprangers, J..

3 recordsLinked to original sources

bioRxiv2024

WNT7B drives a program for pancreatic cancer subtype switching and progression

Hyperactivation of WNT signaling is a well-established hallmark of cancer. Various epithelial cancers express high levels of WNT7B and WNT10A that are not commonly expressed during tissue homeostasis, but rather associate with tissue development and regeneration. Although increased WNT7B/10A expression correlates with aggressive disease and lower patient survival rates, the mechanism by which these WNTs influence cancer progression remains unknown. Here, we use patient-derived organoids to show that tumor-intrinsic expression of WNT7B/10A drives survival and growth of advanced pancreatic ductal adenocarcinoma (PDAC). Bulk and single-cell profiling reveal that WNT7B drives proliferation and promotes expression of a poor prognosis basal-like state by preventing expression of a more differentiated, classical PDAC signature. By generating WNT7B reporter organoids, we show that heterogeneously distributed WNT-high PDAC cells are shifted towards a more basal-like phenotype and stably co-exist with WNT-low/negative lineages. Furthermore, hybrid co-cultures of WNT7B-proficient and -knockout PDAC organoids demonstrate that WNT-sending cells drive survival and proliferation of neighboring WNT-negative cells within the cancer epithelium via short range, cell contact-dependent signaling. In summary, our work uncovers a prominent role of WNT7B/10A in driving PDAC subtype heterogeneity and argues that WNT inhibition may be applied to force a class switch to a more differentiated, less aggressive cancer subtype that correlates with improved therapeutical response.

cancer biology↗

bioRxiv2023

Intestinal LKB1 loss drives a pre-malignant program along the serrated cancer pathway

Background & AimsHeterozygous inactivating mutations of Serine Threonine Kinase 11 (STK11)/Liver Kinase B1 (LKB1) are causative to the Peutz-Jeghers syndrome (PJS), a hereditary disease characterized by gastrointestinal hamartomatous polyposis and increased cancer susceptibility. While LKB1 loss-induced polyp formation has been ascribed to non-epithelial tissues, how LKB1 deficiency increases cancer risk of patients by altering the phenotypical landscape and hierarchical organization of epithelial tissues remains poorly understood. MethodsUsing CRISPR/Cas9, we generated heterozygous and homozygous Lkb1-deficient mouse small intestinal and human colon organoids. These organoids were characterized by an integrated approach that combines imaging, bulk and single-cell RNA sequencing and growth factor dependency assays. Our findings were validated in human PJS-derived tissues using immunohistochemistry and linked to colorectal cancer profiles using the TCGA cancer database. ResultsOur results reveal that heterozygous Lkb1 loss is sufficient to push intestinal cells into a premalignant transcriptional program associated with serrated colorectal cancer, which is further amplified by loss-of-heterozygosity. This altered epithelial growth state associates with persistent features of regeneration and enhanced EGFR ligand and receptor expression, conferring niche-independent growth properties to Lkb1-deficient organoids. Moreover, our newly generated LKB1-mutant signature is enriched in sporadic serrated colorectal cancer, and synergistic cooperation of Lkb1-deficiency with mutant Kras was experimentally confirmed by assessing organoid growth properties and transcriptomes. ConclusionsHeterozygous loss of LKB1 pushes intestinal cells into a chronic regenerative state which is amplified upon loss-of-heterozygosity. Lkb1-deficiency thereby generates fertile ground for serrated colorectal cancer formation in the intestine, potentially explaining the increased cancer risk observed in PJS.

cancer biology↗

bioRxiv2022

RNF43 mutations facilitate mucinous colorectal cancer metastasis via formation of a tumour-intrinsic niche

Colorectal cancer (CRC) progression is characterised by a remarkable increase in plasticity and cellular heterogeneity. The ability of cells to shift states and adopt mixed lineage potential exacerbates during metastasis and associates with poor patient survival. How these atypical differentiated states emerge and drive cancer progression however has remained unclear. Here, we investigate this issue for BRAF-mutant CRC that commonly arise via the serrated pathway and are linked to poor prognosis via incompletely understood progression steps. Using patient-derived organoids, gene editing and murine tumour models, we show that mutations in RNF43, a regulator of WNT receptor abundance, endow BRAF-mutant CRC with metastatic capacity by driving a non-dividing tumour-intrinsic niche cell (TINC) state that provides growth factor self-sufficiency to the cancer tissue. TINCs are enriched in RNF43-mutant, mucinous and metastatic samples of human CRC, and ablation of TINCs lead to re-acquired external growth factor dependency during CRC organoid outgrowth. Together, our findings uncover a mechanism by which tumours leverage cellular plasticity to mediate self-organised stem- and niche-cell interactions. Our results argue that formation of a tumour-intrinsic niche is a prerequisite for BRAF-mutant CRC seeding to distant organs and that interference with niche formation may help avoid metastatic relapse.

cancer biology↗