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Updated: Dec 28, 2025
08:16
Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
Published on: February 11, 2019
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Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor
Prasenjit Dey1, Jun Li2, Jianhua Zhang2
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discovery
|February 13, 2020
Summary
Oncogenic KRAS in pancreatic cancer drives communication between cancer cells and Th2 immune cells. This interaction promotes tumor growth and glycolysis via the MYC pathway, offering new therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment.
- Oncogenic KRAS mutations are a key driver in PDAC progression.
- Interactions between cancer cells and immune cells significantly influence tumor behavior.
Purpose of the Study:
- To investigate the role of oncogenic KRAS in mediating protumorigenic signaling between PDAC cells and host cells.
- To elucidate the molecular mechanisms by which KRAS mutations influence the tumor microenvironment.
- To identify potential therapeutic targets within the identified signaling pathways.
Main Methods:
- Analysis of cell-autonomous expression of type I cytokine receptor complexes in KRAS-mutated cancer cells.
- Investigating cytokine signaling (IL4, IL13) from Th2 cells to cancer cells.
- Utilizing transcriptomic, chromatin occupancy, and metabolomic studies.
- Examining the JAK1-STAT6 signaling pathway and MYC transcriptional regulation.
Main Results:
- KRAS mutation drives cancer cell expression of IL2rγ-IL4rα and IL2rγ-IL13rα1 receptors.
- Th2 cells in the microenvironment provide IL4 and IL13 cytokines, activating these receptors.
- Activated STAT6 signaling leads to MYC upregulation, which in turn drives glycolysis.
- A KRAS*-driven heterotypic signaling circuit promotes protumorigenic interactions.
Conclusions:
- Paracrine signaling between KRAS-mutated PDAC cells and Th2 cells is crucial for metabolic reprogramming.
- Type II cytokines from Th2 cells stimulate MYC-driven glycolysis in cancer cells.
- This signaling circuit represents a potential therapeutic strategy for PDAC.
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