Related Experiment Video
Updated: Jul 16, 2026
09:29
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Oncogenic KRAS Promotes Extracellular DNA Clearance to Drive Immunosuppression in Colorectal Cancer
1Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Research
|July 15, 2026
Summary
Mutant KRAS reduces colorectal tumor-derived DNA (tDNA) by upregulating CD9, which promotes endocytosis. CD9 knockdown increases extracellular tDNA, enhancing anti-PD-1 therapy efficacy by reprogramming macrophages.
Area of Science:
- Cancer biology
- Molecular oncology
- Immunology
Background:
- Cellular turnover releases tumor-derived DNA (tDNA) into circulation (ctDNA), offering insights for noninvasive cancer detection and monitoring.
- tDNA influences the tumor microenvironment (TME), impacting cancer progression, oncogenesis, and metastasis.
- Mechanisms controlling tDNA accumulation and functional impacts within the TME are not fully understood.
Purpose of the Study:
- To investigate the role of mutant KRAS in regulating colorectal tDNA levels.
- To explore the functional consequences of tDNA modulation on the tumor microenvironment and therapeutic response.
Main Methods:
- Investigated the effect of mutant KRAS on colorectal tDNA levels.
- Examined the role of CD9 in tDNA endocytosis and membrane tension.
- Assessed the impact of CD9 knockdown on extracellular tDNA and tumor-associated macrophages (TAMs).
- Evaluated the sensitization of tumors to PD-1 blockade following CD9 manipulation.
Main Results:
- Mutant KRAS upregulates CD9, leading to reduced extracellular colorectal tDNA via enhanced endocytosis.
- CD9 knockdown increases extracellular tDNA accumulation in the TME.
- Increased extracellular tDNA reprograms TAMs, potentially enhancing anti-tumor immunity.
- Modulating tDNA levels via CD9 affects tumor sensitivity to PD-1 blockade.
Conclusions:
- Mutant KRAS plays a novel role in controlling tDNA turnover within the TME.
- tDNA accumulation influences immune evasion and can be therapeutically modulated.
- CD9 is identified as a key mediator of tDNA endocytosis and a potential therapeutic target.
Related Concept Videos
01:33Cancer-Critical Genes I: Proto-oncogenes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:33Cancer-Critical Genes I: Proto-oncogenes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...