{"messages":[{"status":"ok","category":"all"}],"collection":[{"title":"RNF43 mutations facilitate mucinous colorectal cancer metastasis via formation of a tumour-intrinsic niche","authors":"Bugter, J. M.; El Bouazzaoui, L.; Kucukkose, E.; Hong, Y.; Sprangers, J.; Jordens, I.; Fenderico, N.; Gonzalez, D. M.; van Boxtel, R.; Suijkerbuijk, S. J. E.; Tejpar, S.; Snippert, H. J. G.; Kranenburg, O.; Maurice, M. M.","author_corresponding":"Madelon M. Maurice","author_corresponding_institution":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands","doi":"10.1101/2022.12.22.521159","date":"2022-12-23","version":"1","type":"new results","license":"cc_by_nc_nd","category":"cancer biology","jatsxml":"https://www.biorxiv.org/content/early/2022/12/23/2022.12.22.521159.source.xml","abstract":"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.","funder":[{"name":"St Mark's Hospital","id":"https://ror.org/05am5g719","id-type":"ROR","award":"019.233EN.017024.005.00991815604"},{"name":"Glangwili General Hospital","id":"https://ror.org/01cs14q41","id-type":"ROR","award":"11491/2018-1"},{"name":"Higashi Nagoya National Hospital","id":"https://ror.org/05x2sza30","id-type":"ROR","award":"A21139A26825A28223A29055CTRQQR-2021/100006DRCQQR-May21/100002"}],"published":"NA","server":"bioRxiv"},{"title":"RNF43 mutations facilitate colorectal cancer metastasis via formation of a tumour-intrinsic niche","authors":"Bugter, J. M.; El Bouazzaoui, L.; Kucukkose, E.; Hong, Y.; Sprangers, J.; Jordens, I.; Fenderico, N.; Gonzalez, D. M.; van Boxtel, R.; Suijkerbuijk, S. J. E.; Tejpar, S.; Snippert, H. J. G.; Kranenburg, O.; Maurice, M. M.","author_corresponding":"Madelon M. Maurice","author_corresponding_institution":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands","doi":"10.1101/2022.12.22.521159","date":"2023-04-15","version":"2","type":"new results","license":"cc_by_nc_nd","category":"cancer biology","jatsxml":"https://www.biorxiv.org/content/early/2023/04/15/2022.12.22.521159.source.xml","abstract":"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.","funder":[{"name":"St Mark's Hospital","id":"https://ror.org/05am5g719","id-type":"ROR","award":"019.233EN.017024.005.00991815604"},{"name":"Glangwili General Hospital","id":"https://ror.org/01cs14q41","id-type":"ROR","award":"11491/2018-1"},{"name":"Higashi Nagoya National Hospital","id":"https://ror.org/05x2sza30","id-type":"ROR","award":"A21139A26825A28223A29055CTRQQR-2021/100006DRCQQR-May21/100002"}],"published":"NA","server":"bioRxiv"},{"title":"Mutation-induced phenotypic plasticity drives formation of a pro-metastatic tumour-intrinsic niche","authors":"Bugter, J. M.; El Bouazzaoui, L.; Kucukkose, E.; Mills, M. L.; Hong, Y.; Sprangers, J.; Jordens, I.; Kokkinidi, D.; Plugge, S.; Venhuizen, A.; Bosman, S.; Hageman, J.; Fenderico, N.; Gilroy, K.; Montiel Gonzalez, D.; van Boxtel, R.; Suijkerbuijk, S. J. E.; Tejpar, S.; Campbell, A. D.; Sansom, O. J.; Snippert, H. J. G.; Kranenburg, O.; Maurice, M. M.","author_corresponding":"Madelon M. Maurice","author_corresponding_institution":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands","doi":"10.1101/2022.12.22.521159","date":"2026-08-20","version":"3","type":"new results","license":"cc_by_nc_nd","category":"cancer biology","jatsxml":"https://www.biorxiv.org/content/early/2026/08/20/2022.12.22.521159.source.xml","abstract":"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.","funder":[{"name":"St Mark's Hospital","id":"https://ror.org/05am5g719","id-type":"ROR","award":"019.233EN.017024.005.00991815604"},{"name":"Glangwili General Hospital","id":"https://ror.org/01cs14q41","id-type":"ROR","award":"11491/2018-1"},{"name":"Higashi Nagoya National Hospital","id":"https://ror.org/05x2sza30","id-type":"ROR","award":"A21139A26825A28223A29055CTRQQR-2021/100006DRCQQR-May21/100002"}],"published":"NA","server":"bioRxiv"}]}