Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer
Thomas Rösner1,2, Carina Rupp1, Christian Lechler1
1TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany.
Gut
|May 12, 2025
Summary
RAS mutations drive cholangiocarcinoma (CCA) development from hepatocytes. Targeting KRAS-downstream pathways like PI3K/AKT and MEK/ERK influences liver cancer differentiation and offers insights into CCA vs. HCC prevalence.
Area of Science:
- Hepatobiliary cancers
- Molecular oncology
- Cancer signaling pathways
Background:
- RAS mutations are common in cholangiocarcinoma (CCA) but rare in hepatocellular carcinoma (HCC).
- The function of RAS-dependent signaling in CCA pathogenesis remains unclear.
Purpose of the Study:
- Investigate RAS-dependent signaling pathways in CCA.
- Determine their role in tumor development and differentiation.
Main Methods:
- Utilized genetically engineered mouse models with liver-specific deletion of Rb and p53, alongside oncogenic Kras activation.
- Examined intrahepatic CCA cell of origin and RAS-dependent pathway roles.
Main Results:
- Kras-mutant intrahepatic CCA in mice originates from hepatocytes.
- Activated downstream pathways include PI3K/AKT and MEK/ERK.
- Inactivating PI3K/AKT promoted well-differentiated tumors; inactivating MEK/ERK induced a hepatocyte-like phenotype via WNT/β-catenin activation.
Conclusions:
- RAS-dependent pathways significantly impact liver cancer differentiation.
- Findings explain the differential prevalence of RAS mutations in CCA versus HCC.
Related Concept Videos
01:07MAPK Signaling Cascades
5.0K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.0K
03:03mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K
02:38The Ras Gene
6.1K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.1K
01:22PI3K/mTOR/AKT Signaling Pathway
3.3K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.3K
02:38Mitogens and the Cell Cycle
6.3K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.3K
01:19Interactions Between Signaling Pathways
6.2K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K