p53 and NF 1 loss plays distinct but complementary roles in glioma initiation and progression

Abstract

Malignant glioma is one of the deadliest types of cancer. Understanding how the cell of origin progressively evolves toward malignancy in greater detail could provide mechanistic insights and lead to novel concepts for tumor prevention and therapy. Previously we have identified oligodendrocyte precursor cell (OPC) as the cell of origin for glioma following the concurrent deletion of p53 and NF1 using a mouse genetic mosaic system that can reveal mutant cells prior to malignancy. In the current study, we set out to deconstruct the gliomagenic process in two aspects. First, we determined how the individual loss of p53 or NF1 contributes to aberrant behaviors of OPCs. Second, we determined how signaling aberrations in OPCs progressively change from pre-malignant to transformed stages. We found that while the deletion of NF1 leads to mutant OPC expansion through increased proliferation and decreased differentiation, the deletion of p53 impairs OPC senescence. Signaling analysis showed that, while PI3K and MEK pathways go through stepwise over-activation, mTOR signaling remains at the basal level in pre-transforming mutant OPCs but is abruptly up-regulated in tumor OPCs. Finally, inhibiting mTOR via pharmacological or genetic methods, led to a significant blockade of gliomagenesis but had little impact on pre-transforming mutant OPCs, suggesting that mTOR is necessary for final transformation but not early progression. In summary, our findings show that deconstructing the tumorigenic process reveals specific aberrations caused by individual gene mutations and altered signaling events at precise timing during tumor progression, which may shed light on tumor-prevention strategies.

Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

“…On the other hand, the MADMs system is more suitable for dual-lineage analysis of the fate of one mutant and one WT cell from the same progenitor cell (Zong et al, 2005). Although previous applications of MADMs were focused on cell-autonomous gene functions in cancer (Gonzalez et al, 2018;Liu et al, 2011;Muzumdar et al, 2007), this study took advantage of its lineage-tracing capability to uncover tumor-TME relationships. The fact that such complexity of interactions could be unveiled from an ostensibly ''simple'' cancer further emphasizes the importance of untangling the inner works of the TME in more complex tumors.…”

Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns

“…The strict correlation between the activation or lack of activation of the HPV16 enhancer and cell-specific subsets of NF-1 proteins argues for the pivotal role of NF-1 binding sites in the epithelial cell-specific function of the viral enhancer (Apt et al, 1993). NF-1 and p53 play an important role in glioma initiation and progression (Gonzalez et al, 2018). In HPV16 genome NF-1 binding sites were found methylated in high grade disease, in cervical cancer methylation percentages of E6 and E7 CpG were elevated (Kottaridi et al, 2019).…”

A Genome-wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis

“…Most prominently, tumor formation and the delineation of cancer cell of origin at single cell level upon the introduction of mutations in tumor suppressor genes and/or loss of heterozygosity has been studied (Gonzalez et al 2018;Liu et al 2011;Muzumdar et al 2016;Muzumdar et al 2007;Yao et al 2020).…”

“…Cells that are homozygous mutant for a candidate tumor suppressor gene are uniquely labeled and can be followed dynamically in vivo to study tumor progression and metastasis and/or to assay for the effects of therapeutic agents. As such, MADM has been used for the analysis of tumor formation and the delineation of cancer cell of origin at single cell level in the brain and distinct organs (Gonzalez et al 2018;Liu et al 2011;Muzumdar et al 2016;Muzumdar et al 2007;Yao et al 2020). MADM could in principle be exploited to systematically study the loss of any tumor suppressor in the entire genome and for identifying the cellular origins of a wide variety of cancers.…”