Publications: MPI-CBG

^* joint first author ^# joint corresponding author

2024

Srustidhar Das^✳︎, S Martina Parigi^✳︎, Xinxin Luo^✳︎, Jennifer Fransson, Bianca C Kern, Ali Okhovat, Oscar E Diaz, Chiara Sorini, Paulo Czarnewski, Anna T Webb, Rodrigo A Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J Villablanca
Liver X receptor unlinks intestinal regeneration and tumorigenesis.
Nature, Art. No. doi: 10.1038/s41586-024-08247-6 (2024)
Open Access DOI

Uncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.

2023

Scharaw, S.^#, Sola Carvajal, A., Belevich, I., Webb, A. T., Das, S., Andersson, S., Pentinmikko, N., Villablanca, E. J., Goldenring, J. R., Jokitalo, E., Coffey, R. J., & Katajisto, P.^# (2023).
Golgi organization is a determinant of stem cell function in the small intestine.
bioRxiv, 2023.2003.2023.533814.
https://doi.org/10.1101/2023.03.23.533814
PMID: 36993731

2022

Pentinmikko, N., Lozano, R., Scharaw, S.*, Andersson, S., Englund, J. I., Castillo-Azofeifa, D., Gallagher, A., Broberg, M., Song, K. Y., Sola Carvajal, A., Speidel, A. T., Sundstrom, M., Allbritton, N., Stevens, M. M., Klein, O. D., Teixeira, A., & Katajisto, P^#. (2022).
Cellular shape reinforces niche to stem cell signaling in the small intestine.
Science Advances, 8(41), eabm1847.
https://doi.org/10.1126/sciadv.abm1847
PMID: 36240269

2021

Flanagan, D. J., Pentinmikko, N., Luopajarvi, K., Willis, N. J., Gilroy, K., Raven, A. P., McGarry, L., Englund, J. I., Webb, A. T., Scharaw, S., Nasreddin, N., Hodder, M. C., Ridgway, R. A., Minnee, E., Sphyris, N., Gilchrist, E., Najumudeen, A. K., Romagnolo, B., Perret, C., . . . Katajisto, P.^# & Sansom, O. J.^# (2021).
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.
Nature, 594(7863), 430-435.
https://doi.org/10.1038/s41586-021-03525-z
PMID: 34079124

2016

Scharaw, S., Iskar, M., Ori, A., Boncompain, G., Laketa, V., Poser, I., Lundberg, E., Perez, F., Beck, M., Bork, P., & Pepperkok, R. (2016).
The endosomal transcriptional regulator RNF11 integrates degradation and transport of EGFR.
Journal of Cell Biology, 215(4), 543-558. https://doi.org/10.1083/jcb.201601090 (Highlighted as journal cover and selected for a spotlight article in The Journal of Cell Biology, 2016.
https://doi.org/10.1083/jcb.201611014
PMID: 27872256

Scharaw, S., Iskar, M., Ori, A., Boncompain, G., Laketa, V., Poser, I., Lundberg, E., Perez, F., Beck, M., Bork, P., & Pepperkok, R. (2016).
Maintenance of EGFR plasma membrane levels involves cargo-specific COPII components of the early secretory pathway machinery.
Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27