Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.02.20.958132

ASCL1 regulates neurodevelopmental transcription factors and cell cycle genes in glioblastoma

Vue, T. Y.·Kollipara, R.·Borromeo, M. D.·Smith, T.·Mashimo, T.·Burns, D. K.·Bachoo, R. M.·Johnson, J. E.
View original source ↗Export metadata ↓

Abstract

Glioblastomas (GBMs) are incurable brain tumors with a high degree of cellular heterogeneity and genetic mutations. Transcription factors that normally regulate neural progenitors and glial development are aberrantly co-expressed in GBM, conferring cancer stem-like properties to drive tumor progression and therapeutic resistance. However, the functional role of individual transcription factors in GBMs in vivo remains elusive. Here, we demonstrate that the basic-helix-loop-helix (bHLH) transcription factor ASCL1 regulates transcriptional targets that are central to GBM development, including neural stem cell and glial transcription factors, oncogenic signaling molecules, chromatin modifying genes, and cell cycle and mitotic genes. We also show that the loss of ASCL1 significantly reduces the proliferation of GBMs induced in the brain of a genetically relevant glioma mouse model, resulting in extended survival times. RNA-seq analysis of mouse GBM tumors reveal that the loss of ASCL1 is associated with downregulation of cell cycle genes, illustrating an important role for ASCL1 in controlling the proliferation of GBM. TABLE OF CONTENTSO_ST_ABSMain PointsC_ST_ABSO_LIASCL1 is co-expressed with neural stem cell/glial transcription factors in GBM C_LIO_LIASCL1 binds to genes that are important for cell proliferation and cancer in the brain. C_LIO_LILoss of ASCL1 downregulates cell cycle genes and increase survival of glioma mouse model. C_LI Table of Content Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/958132v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@8aa2d7org.highwire.dtl.DTLVardef@1c908edorg.highwire.dtl.DTLVardef@1690085org.highwire.dtl.DTLVardef@a13728_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Vue, T. Y., Kollipara, R., Borromeo, M. D., Smith, T., Mashimo, T., Burns, D. K., Bachoo, R. M., Johnson, J. E.. 2020-02-20. ASCL1 regulates neurodevelopmental transcription factors and cell cycle genes in glioblastoma. https://doi.org/10.1101/2020.02.20.958132

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Ex vivo human tumor slices more accurately predict patient responses to an oncolytic virus than in vivo mouse models

Immunotherapies, including oncolytic viruses (OV), are promising therapies that can enhance anti-tumor immune responses. However, preclinical success of immunotherapies in mouse models has not always translated to clinical benefit in cancer patients. This study compared preclinical efficacy and mechanism of action for ASP9801, a vaccinia virus expressing IL-7 and IL-12, using mouse models of colorectal cancer (CRC) in vivo and in human organotypic tumor slice models ex vivo. The murine surrogate for ASP9801 significantly reduced tumor volumes in treated and abscopal tumors in two different CRC models in vivo (MC38 and RO100). Treatment efficacy was accentuated when combined with anti-PD1 treatment, and single-cell RNA sequencing analysis revealed depletion of tumor cells and increased T cell infiltration and activation in both treated and abscopal tumors. However, human tissue analysis ex vivo (E-slices) using PDX models and patient samples showed that ASP9801 is not effective in CRC, consistent with clinical trial results. On the other hand, ASP9801 was highly effective in GBM, indicating indication-specific efficacy of ASP9801, and how E-slice assays can be used to identify treatment-sensitive indications. This study demonstrates the superiority of E-slices over mouse models for predicting clinical response and its utility in planning clinical trials.

cancer biology↗
bioRxiv2026

Immune-cell depleted diffuse large B-cell lymphomas have reduced expression of MHC class I

Immunotherapy has transformed treatment for many cancers. In the aggressive and genetically heterogeneous diffuse large B-cell lymphoma (DLBCL), CD19 CAR T-cell therapy is highly effective, whereas immune checkpoint blockade has shown limited benefit. Loss of MHC expression is a common mechanism to escape T-cell cytotoxicity, and loss of MHC class I (MHC-I) and II are frequent in DLBCL. We applied imaging mass cytometry to diagnostic biopsies from younger, high-risk DLBCL patients to map the tumor microenvironment (TME) spatial architecture in relation to tumor cell MHC expression, mutational status, transcriptomic and proteomic profiles. Neighborhood analyses identified four TME subtypes: immune-cell depleted and three immune-infiltrated types (mixed, CD4 T cell-rich, CD8 T-cell/macrophage-rich). Depleted cases had shorter overall survival (p = 0.033) and increased expression of proteins involved in DNA replication and proliferation markers compared to infiltrated cases. Tumor cell MHC-I expression was heterogeneous. Cases with low frequency of MHC-I-pos tumor cells were enriched for the depleted TME type. MHC-I-pos tumor cells were surrounded by CD4 and CD8 T cells and M1 macrophages, whereas MHC-I-neg tumor cells were closer to other MHC-I-neg tumor cells. These findings suggest that TME-based classification incorporating tumor cell MHC-I status may improve individualized immunotherapy selection.

cancer biology↗
bioRxiv2026

Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis

Cell-cell interactions shape the fate of mutant cells during cancer initiation but how these interactions evolve during progression to pathologically recognizable lesions remain poorly understood. Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in Trp53/Rb1-mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.

cancer biology↗