Fosl1 is a transcriptional effector of BRAFV600E-driven intestinal tumorigenesis
Alam Z. Nightingale R. Lesmana A. Liu C. Jenkins L.J. Richardson M.F. Croft L. Luk I.Y. Reehorst C.M. Chionh F. Vukelic N. Basheer F. Tulchinsky E. Badshah J. Dumenil T. Bakiri L. Wagner E.F. Tebbutt N.C. Whitehall V. Mariadason J.M. Dhillon A.S.
21 November 2025Elsevier Inc.
iScience
2025#28Issue 11
The serrated neoplasia pathway is an alternate route to colorectal cancer (CRC) development where BRAFV600E is the most common initiating genetic alteration. BRAFV600E-driven tumorigenesis requires gene expression changes mediated by activation of the ERK MAPK signaling pathway. However, the key effectors of this process are elusive. Here, we identify the ERK-regulated transcription factor Fosl1, one such effector. We show that Fosl1 is dispensable for the initiation of BRAFV600E-driven serrated neoplasia in mice but promotes progression of the disease by regulating the expression of genes involved in inflammation, immunity, cell cycle control, fetal-like programming, and gastric metaplasia. Notably, transgenic Fosl1 expression alone was sufficient to induce tumors with a BRAFV600E-like serrated morphology and transcriptional profile. These findings reveal a mechanism through which oncogenic BRAF-driven ERK signaling reprograms transcription to drive serrated neoplasia.
Biological sciences , Cancer , Molecular mechanism of gene regulation
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Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
Mater Pathology, Mater Hospital Brisbane, South Brisbane, QLD, Australia
School of Life and Environment Sciences, Deakin University, Geelong, VIC, Australia
Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC, Australia
Nazarbayev University School of Medicine, Nur-Sultan, Kazakhstan
Laboratory of Gene and Disease, Department of Medicine, Medical University of Vienna (MUW), Vienna, Austria
Laboratory of Gene and Disease, Department of Dermatology, Medical University of Vienna (MUW), Vienna, Austria
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine
QIMR Berghofer Medical Research Institute
Mater Pathology
School of Life and Environment Sciences
Institute for Mental and Physical Health and Clinical Translation
Nazarbayev University School of Medicine
Laboratory of Gene and Disease
Laboratory of Gene and Disease
Department of Medicine
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