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Pancreatic Cancer is one of the most fatal cancers with a projected increase in mortality rate by 2030 (Rahib et al., 2014). 95% of this cancer comprised of Adenocarcinoma (PDAC) while neuroendocrine tumors (PNET) and other exocrine tumors account for the remaining 5% (Muthalagu et al., 2020). The survival rate of PDAC is significantly lower (3%-5%) compared to PNET (30%-50%). Therefore, it is important to further understand the biology behind these tumors.
PDAC develops due to the occurrence of different genetic alterations, which includes KRAS mutation activation.
However, an experiment carried out by Jackson et al. (2001) demonstrated that KRAS activation alone is not sufficient for PDAC development (Muthalagu et al., 2020). Although this activation alone results in the development of low-grade pancreatic Intraepithelial Neoplasms (PanIN) (Hingorani et al., 2003), which could spontaneously progress to PDAC following the acquisition of additional mutations (Aguirre, 2003) (Muthalagu et al., 2020).
Just like KRAS, there are alternative oncogenes that encode proteins serving as potentially rate-limiting RAS effectors in PDAC progression (Mueller et al., 2018); these oncogenes include MYC.
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MYC overexpression is commonly noticed in PDAC, even at a low-level amplification rate. This indicates that a minute change in MYC expression is sufficient to contribute to the development and progression of PDAC (Schleger et al., 2002).
This paper (Muthalagu et al., 2020) investigated the level of MYC deregulation required for pancreatic tumor development. It demonstrated that modest deregulation of MYC is sufficient for the development of PNET and the progression of PDAC metastasis if combined with KRAS activation. This combined action suppresses the type-1 Interferon (IFN) pathway; as targeted suppression of the MYC-MIZ1 complex reinstates IFN-related gene expression, consequently restoring B-cell and NK cell-mediated immuno-surveillance.
Rosa26DM-Isl-MYC mice were used in this study to determine the level of MYC deregulation needed to develop pancreatic tumors.
RT-PCR was performed to demonstrate Cre-dependent MYC expression and compare it with murine MYC expression.
| Mouse Type | MYC Expression |
|---|---|
| Rosa26DM-Isl-MYC (2 copies) | Increased expression |
| Murine MYC (2 copies) | Low expression |
Endogenous activation of Lsl-KrasG12D drove high expression of MYC compared to Rosa26DM-Isl-MYC, and the expression became even higher upon combined activation of both alleles.
Rosa26DM-Isl-MYC mice (M) were interbred with pancreas-specific pdx1-Cre mice (C) both with and without KrasG12D allele (K). The median time for pdx1-Cre-positive mice carrying one copy of MYC (MC) to develop pancreatic cancer requiring euthanasia was 297 days, while those carrying 2 copies of MYC (M2C) took 180 days before euthanasia was required (Muthalagu et al., 2020).
However, the combination of Lsl-KrasG12D and a copy of Rosa26DM-Isl-MYC (KMC) resulted in accelerated need for euthanasia within a median of 50 days. Also, MC and M2C mice developed PNET and showed no evidence of PanIN lesions, unlike KC-mice that mostly developed PanIN, which could later progress to PDAC (Hingorani et al., 2003). But on the contrary, the inclusion of Lsl-KrasG12D allele masked the PNET phenotype in KMC-mice; hence, tumors arising from KMC-mice are predominantly PDAC phenotype.
Likewise, following the substitution of pdx1-Cre allele (C) with inactive pdx1-Cre-Er allele (CER) and treatment with Tamoxifen (which activates CER); KMCER mice also developed PDAC and reached a median experimental endpoint of 128 days, while M2CER mice developed PNET at 275 days post-induction of Tamoxifen. Contrarily, the majority of MCER mice didn't develop disease symptoms within a median endpoint of 400 days post-induction. The periodic tissue-sampling of KMCER mice showed tumor progression from PanIN to PDAC (Muthalagu et al., 2020).
To facilitate imaging of the tumor population, mice with IRFP allele were generated following the interbreeding of KMCER mice with mice carrying Hprt-Lsl-IRFP Cre-reporter allele. This allele revealed both liver and diaphragmatic metastasis; where the liver metastasis are of PNET phenotype and the diaphragmatic metastasis are mainly PDAC phenotype. Hence, activation of MYC and KRAS in fully developed adult tissue can drive tumor metastasis. These experiments also attest to the role of MYC expression activation in pancreatic (PNET-PDAC) tumorigenesis and in PDAC, especially when combined with KRAS.
The results of this study demonstrate that MYC deregulation plays a crucial role in pancreatic tumor development, especially when combined with KRAS activation. Modest deregulation of MYC is sufficient to lead to the development of PNET and the progression of PDAC metastasis. The combination of MYC and KRAS activation accelerates the onset of pancreatic cancer and leads to a predominantly PDAC phenotype.
Furthermore, the study highlights the importance of the type-1 Interferon (IFN) pathway in the immuno-surveillance against pancreatic tumors. Targeted suppression of the MYC-MIZ1 complex reinstates IFN-related gene expression, potentially enhancing B-cell and NK cell-mediated immuno-surveillance, which is crucial in combating these aggressive tumors.
In conclusion, this study provides valuable insights into the role of MYC deregulation in pancreatic tumor development and metastasis. Modest MYC deregulation, when combined with KRAS activation, can lead to the development of aggressive PDAC. The findings also suggest potential therapeutic strategies targeting the MYC-MIZ1 complex to restore the IFN pathway and enhance immune surveillance against pancreatic tumors.
MYC Deregulation in Pancreatic Tumor Development. (2024, Jan 22). Retrieved from https://studymoose.com/document/myc-deregulation-in-pancreatic-tumor-development
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