Quick note for RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
Paper: RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
doi: 10.1038/s41598-017-15704-y
I would like to start with my rough drawing since it can help me recognize by heart now.
The concept of this paper relies on Wnt signaling that contributes to the growth of colorectal tumors.
Mutation of genes in Wnt pathway that related to CRC is beta-catenin, APC and RNF43 and these type of mutations are found 90% of CRC. My understanding, this paper points out the microenvironment supporting the tumor growth. Not only Wnt ligand but also R-spondin is the ligand that can activate the Wnt signaling pathway. Wnt binds to the Fz directly whereas R-spondin (RSPO) quantitatively control RNF43. RSPO binds to RNF43 which leads to proteasomal degradation, therefore, controlling the availability of Fz on the membrane.
It was shown that RSPO3 antagonism worked effectively with RSPO gene fusion type (RSPO-PTPRK) in CRC. Therefore, the team wanted to investigate more whether the RSPO3 could be used with the CRC which has either beta-catenin, APC and RNF43 mutation, as mentioned above, all these mutations were majorly found in CRC.
In my point of view, there are two concepts now for the wnt signaling that promote the cancer growth;
1. autocrine effect, like the one that studied in pancreatic adenocarcinoma
2. paracrine effect which relied on either niche cell that supporting the tumor growth, like in this study.
In this study, there are two basic drugs that mostly being used to cure all types of cancers; taxane (microtubule forming inhibitor) and irinotecan (topo-I inhibitor)
Another new candidate drug is RSPO antagonist, more specific is anti-RSPO3 (antibody)
To study the microenvironment that affecting on tumor growth, the team used the patient-derived tumor xenografts (PDTX) model and corresponding targeted drug that affected the microenvironment. In this study is anti-RSPO3.
In this study also showed the combinatorial therapy since there were previous reports demonstrating that combination of Wnt-inhibitor with taxane therapy effectively inhibit other types of tumor growth.
Fusion type of CRC; PTPRK-RSPO3 (minority type of CRC) -- combinatorial therapy between taxane + anti-RSPO3 significantly inhibited tumor growth.
Majority type of CRC mutations -- combination of taxane with anti-Rspo3 significantly inhibited tumor growth, however, there were two PDXs which did not respond well to the treatment. OMP-C8-9 was picked to investigate more on cancer stem cell self-renewal properties.
Quick reminder;
Wnt control the balance between cell differentiation and cell growth, more activation more growth, if no activation, cell starts to differentiate.
LGR5 is the cellular marker for the stem cell.
ZNRF3 is the negative regulator for Fz receptor and the amount is controlled by the R-spondin (RSPO).
Assay to determine the number of cancer initiated cells (first panel figure A.); all data showed that Wnt signaling activation was decreased when the mice were treated with anti-Rspo3+taxane, less CSC (less LGR5), less growth, less beta-catenin (more ZRNF3), more cell-differentiate (more PTPRO).
doi: 10.1038/s41598-017-15704-y
I would like to start with my rough drawing since it can help me recognize by heart now.
The concept of this paper relies on Wnt signaling that contributes to the growth of colorectal tumors.
Mutation of genes in Wnt pathway that related to CRC is beta-catenin, APC and RNF43 and these type of mutations are found 90% of CRC. My understanding, this paper points out the microenvironment supporting the tumor growth. Not only Wnt ligand but also R-spondin is the ligand that can activate the Wnt signaling pathway. Wnt binds to the Fz directly whereas R-spondin (RSPO) quantitatively control RNF43. RSPO binds to RNF43 which leads to proteasomal degradation, therefore, controlling the availability of Fz on the membrane.
It was shown that RSPO3 antagonism worked effectively with RSPO gene fusion type (RSPO-PTPRK) in CRC. Therefore, the team wanted to investigate more whether the RSPO3 could be used with the CRC which has either beta-catenin, APC and RNF43 mutation, as mentioned above, all these mutations were majorly found in CRC.
In my point of view, there are two concepts now for the wnt signaling that promote the cancer growth;
1. autocrine effect, like the one that studied in pancreatic adenocarcinoma
2. paracrine effect which relied on either niche cell that supporting the tumor growth, like in this study.
In this study, there are two basic drugs that mostly being used to cure all types of cancers; taxane (microtubule forming inhibitor) and irinotecan (topo-I inhibitor)
Another new candidate drug is RSPO antagonist, more specific is anti-RSPO3 (antibody)
To study the microenvironment that affecting on tumor growth, the team used the patient-derived tumor xenografts (PDTX) model and corresponding targeted drug that affected the microenvironment. In this study is anti-RSPO3.
In this study also showed the combinatorial therapy since there were previous reports demonstrating that combination of Wnt-inhibitor with taxane therapy effectively inhibit other types of tumor growth.
Fusion type of CRC; PTPRK-RSPO3 (minority type of CRC) -- combinatorial therapy between taxane + anti-RSPO3 significantly inhibited tumor growth.
Majority type of CRC mutations -- combination of taxane with anti-Rspo3 significantly inhibited tumor growth, however, there were two PDXs which did not respond well to the treatment. OMP-C8-9 was picked to investigate more on cancer stem cell self-renewal properties.
Quick reminder;
Wnt control the balance between cell differentiation and cell growth, more activation more growth, if no activation, cell starts to differentiate.
LGR5 is the cellular marker for the stem cell.
ZNRF3 is the negative regulator for Fz receptor and the amount is controlled by the R-spondin (RSPO).
Assay to determine the number of cancer initiated cells (first panel figure A.); all data showed that Wnt signaling activation was decreased when the mice were treated with anti-Rspo3+taxane, less CSC (less LGR5), less growth, less beta-catenin (more ZRNF3), more cell-differentiate (more PTPRO).
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