Fosl1 is a transcriptional effector of BRAFV600E-driven intestinal tumorigenesis
The serrated neoplasia pathway is an alternate route to colorectal cancer (CRC) development where <i>BRAF</i> <sup>V600E</sup> is the most common initiating genetic alteration. BRAF<sup>V600E</sup>-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 BRAF<sup>V600E</sup>-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 <i>BRAF</i> <sup>V600E</sup>-like serrated morphology and transcriptional profile. These findings reveal a mechanism through which oncogenic BRAF-driven ERK signaling reprograms transcription to drive serrated neoplasia.
Authors
- Camilla M. Reehorst (ORCID: https://orcid.org/0000-0002-8039-3582)
- Erwin F. Wagner (ORCID: https://orcid.org/0000-0001-7872-0196)
- Faiza Basheer (ORCID: https://orcid.org/0000-0003-4850-2205)
- Larry Croft (ORCID: https://orcid.org/0000-0002-4588-6170)
- Eugene M. Tulchinsky (ORCID: https://orcid.org/0000-0001-8684-0315)
- Amardeep S. Dhillon (ORCID: https://orcid.org/0000-0002-6065-663X)
- Laura J. Jenkins (ORCID: https://orcid.org/0000-0001-9218-8669)
- John M. Mariadason (ORCID: https://orcid.org/0000-0001-9123-7684)
- Natalia Vukelic (ORCID: https://orcid.org/0000-0003-0123-5701)
- Joshua Badshah
- Fiona Chionh (ORCID: https://orcid.org/0000-0002-9392-5816)
- Zakia Alam (ORCID: https://orcid.org/0000-0002-9426-4538)
- Rebecca Nightingale
- Troy Dumenil (ORCID: https://orcid.org/0000-0002-3032-8360)
- Niall C. Tebbutt (ORCID: https://orcid.org/0000-0003-2613-5168)
- Latifa Bakiri (ORCID: https://orcid.org/0000-0002-6300-2420)
- Vicki Whitehall (ORCID: https://orcid.org/0000-0002-8285-2391)
- Mark F. Richardson (ORCID: https://orcid.org/0000-0002-1650-0064)
- Ian Y. Luk (ORCID: https://orcid.org/0000-0001-7229-0543)
- Analia Lesmana
- Cheng Liu (ORCID: https://orcid.org/0000-0002-4957-0771)
Institutions
- Deakin University (AU)
- The University of Melbourne (AU)
- La Trobe University (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Olivia Newton-John Cancer Wellness & Research Centre (AU)
- Mater Adult Hospital (AU)
- Nazarbayev University (KZ)
Publication Details
- Journal
- iScience
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1016/j.isci.2025.113875
- Citations
- 1
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.81