Biology subjects

Kucukkose, E.

Publications and source records attributed to Kucukkose, E..

2 recordsLinked to original sources

bioRxiv2023

Stromal localization of inactive CD8+ T cells in metastatic mismatch repair deficient colorectal cancer

BackgroundThe determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC. MethodsWe profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of stromal and immune cells in primary CRC tumors with or without metastatic capacity. We validated our findings in a second independent cohort using immunohistochemistry. ResultsHigh-plex imaging mass cytometry and hierarchical clustering based on microenvironmental markers separated primary MSI-H CRC tumors with and without metastatic capacity. Primary tumors with metastatic capacity displayed a high stromal content and low influx of CD8+ T cells, which expressed significantly lower levels of markers reflecting proliferation (Ki67) and antigen-experience (CD45RO) compared to CD8+ T cells in non-metastatic tumors. CD8+ T cells showed intra-epithelial localization in non-metastatic tumors, but stromal localization in metastatic tumors, which was validated in a second cohort. ConclusionWe conclude that localization of phenotypically distinct CD8+ T cells within stroma may predict metastasis formation in MSI-H CRC.

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↗