Quick note for Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma
Paper: Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma
doi: 10.1073/pnas.1307218110. Epub 2013 Jul 11
I like the picture that the team showed the cytotoxicity assay toward PDAC cell lines by using Wnt secretion inhibitor; LGK974. LGK974 inhibits the wnt-secretion by inhibiting the enzyme called "porcupine" which add the palmitoleic acid to the wnt as an indispensable signal for its secretion.
What I have learned in this publication is molecular subtyping is a very important procedure for the cancer treatment since each molecular subtype will differently response to the treatment.
The main idea for this paper is that;
1. PDAC cell lines have a different molecular genotypic signature.
2. There is more than 1 factor that supporting the growth of PDAC cell lines.
3. The growth of RNF43 malfunctioned PDAC cell lines relies on the Wnt pathway (by understanding this characteristic, we can apply the wnt inhibitor to this patient that have this genotypic signature)
4. PDAC cell lines that contain dysfunctional of RNF43 have very good response toward PORN inhibitor.
5. There is the observation that some PDAC cell lines which contain malfunction of RNF43 but they did not respond well to LGK974, it means there might be the other mechanism that helps these cells grow regardless to wnt.
6.Therefore, it is very important to classify the patients in order to get the most benefits out from using PORN inhibitor treatment.
The picture shows the viability assay toward LGK974 inhibitor; 3 cell-lines (label red) respond well and when RNF43 exons were sequenced, the cells contained malfunctioned mutation of RNF43.
We can apply synthetic lethality concept to this study? Drug target RNF43 --> if the tumor growth is found out to depend on Wnt --> giving Wnt-inhibitor would kill the tumor cell with this genotype.
Another observation --> the cell-lines can feed themselves with wnt ligand (autocrine) for their growth.
Little bit knowledge of Wnt to understand this paper (all about wnt can be found in the wnt homepage -- very informative and super useful homepage)
Wnt bind to Frizzled receptor and can activate through three different pw.
Degradation complex:
AXIN1, APC, GSK3,CKI --> working as complex to phosphorylate b-catenin and signaling it to ubiquitinylation --> no activation of wnt signaling
Wnt target gene:
ZNRF3 -- negative feedback to control the Frizzled receptor
RNF43 -- negative feedback to control the Frizzled receptor
AXIN2
Myc (support on growth)
My understanding, in this case, is once the wnt has been inactivated the related cell would differentiate (wnt signaling involves so many cellular physiology; cell differentiation, cell growth, cell adhesion or cellular polarity, etc. -- depending on the cell types)
doi: 10.1073/pnas.1307218110. Epub 2013 Jul 11
I like the picture that the team showed the cytotoxicity assay toward PDAC cell lines by using Wnt secretion inhibitor; LGK974. LGK974 inhibits the wnt-secretion by inhibiting the enzyme called "porcupine" which add the palmitoleic acid to the wnt as an indispensable signal for its secretion.
What I have learned in this publication is molecular subtyping is a very important procedure for the cancer treatment since each molecular subtype will differently response to the treatment.
The main idea for this paper is that;
1. PDAC cell lines have a different molecular genotypic signature.
2. There is more than 1 factor that supporting the growth of PDAC cell lines.
3. The growth of RNF43 malfunctioned PDAC cell lines relies on the Wnt pathway (by understanding this characteristic, we can apply the wnt inhibitor to this patient that have this genotypic signature)
4. PDAC cell lines that contain dysfunctional of RNF43 have very good response toward PORN inhibitor.
5. There is the observation that some PDAC cell lines which contain malfunction of RNF43 but they did not respond well to LGK974, it means there might be the other mechanism that helps these cells grow regardless to wnt.
6.Therefore, it is very important to classify the patients in order to get the most benefits out from using PORN inhibitor treatment.
The picture shows the viability assay toward LGK974 inhibitor; 3 cell-lines (label red) respond well and when RNF43 exons were sequenced, the cells contained malfunctioned mutation of RNF43.
We can apply synthetic lethality concept to this study? Drug target RNF43 --> if the tumor growth is found out to depend on Wnt --> giving Wnt-inhibitor would kill the tumor cell with this genotype.
Another observation --> the cell-lines can feed themselves with wnt ligand (autocrine) for their growth.
Little bit knowledge of Wnt to understand this paper (all about wnt can be found in the wnt homepage -- very informative and super useful homepage)
Wnt bind to Frizzled receptor and can activate through three different pw.
Degradation complex:
AXIN1, APC, GSK3,CKI --> working as complex to phosphorylate b-catenin and signaling it to ubiquitinylation --> no activation of wnt signaling
Wnt target gene:
ZNRF3 -- negative feedback to control the Frizzled receptor
RNF43 -- negative feedback to control the Frizzled receptor
AXIN2
Myc (support on growth)
My understanding, in this case, is once the wnt has been inactivated the related cell would differentiate (wnt signaling involves so many cellular physiology; cell differentiation, cell growth, cell adhesion or cellular polarity, etc. -- depending on the cell types)
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