Related Experiment Video
Updated: Feb 1, 2026
A Protocol for Lentiviral Transduction and Downstream Analysis of Intestinal Organoids
Published on: April 20, 2015
Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal
Yuki Nakanishi1, Angeles Duran1, Antoine L'Hermitte1
1Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Abstract:
Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-β receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC.
Insights
Reduced protein kinase C (PKC)ζ and PKCλ/ι expression drives aggressive serrated colorectal cancer (CRC). Targeting these pathways with TGF-β inhibitors and anti-PD-L1 offers a promising treatment strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Serrated adenocarcinoma is an aggressive colorectal cancer (CRC) subtype with poor treatment outcomes.
- This pathway involves distinct molecular mechanisms compared to conventional CRC.
- Understanding the role of protein kinase C (PKC) in serrated CRC is crucial.
Purpose of the Study:
- To investigate the role of atypical protein kinase C ζ (PKCζ) and PKCλ/ι in serrated colorectal cancer development.
- To explore the impact of PKCζ and PKCλ/ι deficiency on tumor immunity and progression.
- To identify potential therapeutic strategies for serrated CRC.
Main Methods:
- Analysis of PKCζ and PKCλ/ι expression in human serrated tumors.
- Inactivation of PKCζ and PKCλ/ι encoding genes in mouse intestinal epithelium.
- Assessment of tumor progression, stromal response, and immune cell infiltration in mouse models.
- Evaluation of combination therapy using TGF-β receptor inhibitor and anti-PD-L1 blockade.
Main Results:
- Reduced PKCζ and PKCλ/ι expression observed in human serrated tumors.
- Inactivation of PKC genes in mice led to spontaneous serrated tumorigenesis with immunosuppressive stroma.
- PKCλ/ι deficiency promoted immunogenic cell death and CD8+ T cell infiltration, repressing tumor initiation.
- PKCζ loss impaired interferon and CD8+ T cell responses, facilitating tumorigenesis.
- Combined TGF-β receptor inhibitor and anti-PD-L1 therapy demonstrated synergistic curative effects.
Conclusions:
- PKCζ and PKCλ/ι play critical roles in the immunosurveillance defects of serrated colorectal cancer.
- Targeting PKC signaling and immune checkpoints offers a novel therapeutic avenue for this aggressive CRC subtype.
- These findings provide insights for the detection and treatment of poor-prognosis serrated CRC.
More Related Videos
Related Concept Videos
01:23Anatomy of the Intestines
Small Intestines
The small intestine is an ~7 meter-long tube with an inner diameter of just 2.5 cm. Since most nutrients are absorbed here, the inner lining of the...
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:15Small Intestine
The small intestine is divided into three main sections - the duodenum, jejunum, and ileum. The duodenum, approximately 25 cm long, is nearest the stomach. It acts as a 'mixing bowl,' where chyme (partially digested food) blends with digestive enzymes from the pancreas and liver. The duodenum's unique...
01:09Large Intestine
The ileocecal sphincter, a mucous membrane fold, guards the opening from the ileum to the large intestine. This valve permits material from the small intestine to pass into the large intestine. Attached to the ileocecal valve is the cecum. This small pouch, approximately 6 cm long, has a twisted, coiled tube known as...
01:26Histology of the Large Intestine
The innermost mucosa layer comprises simple columnar epithelium, lamina propria, and muscularis mucosae. This layer is primarily populated with absorptive cells, tasked with water absorption, and goblet cells, responsible for secreting mucus to...
01:27Histology of the Small Intestine
The intestinal lining features transverse folds called circular folds, each housing fingerlike projections known as intestinal villi. These villi are covered by a layer of simple columnar epithelium, also referred to as...