Biology subjects

Freie, B.

Publications and source records attributed to Freie, B..

5 recordsLinked to original sources

bioRxiv2025

MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma

MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy. Significance StatementThis report investigates mechanisms underlying the dependence of MYC-amplified pancreatic cancer cells on the MYC network member MondoA which, as a heterodimer with MLX, is a nutrient-sensing transcription factor. We show this dependency is linked to genomic crosstalk between MYC, components of the proximal MYC network, and the master regulator of the integrated stress response, ATF4. Moreover, we find that small molecule inhibitors of MondoA-MLX transcriptional activity abrogate survival of MYC-amplified PDAC lines and patient derived organoids. The significance of this work relates to its focus on a unique vulnerability intrinsic to MYC, an oncogenic driver associated with a wide range of cancers, which is considered to be "undruggable".

cancer biology↗

bioRxiv2024

MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues

The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network. TeaserMAX inactivation deregulates multiple transcription factors to induce neuroendocrine cancers

cancer biology↗

bioRxiv2023

A Germline Point Mutation in the MYC-FBW7 Phosphodegron Initiates Hematopoietic Malignancies

Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently contain point mutations in the MYC phospho-degron, including at threonine-58 (T58), where phosphorylation permits binding by the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in [~]60% of adult homozygous T58A mice. We find that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and upregulate a subset of Myc target genes important in maintaining stem/progenitor cell balance. Genomic occupancy by MYC-T58A was increased at all promoters, compared to WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation in Myc is sufficient to produce a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.

cancer biology↗

bioRxiv2020

Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness

MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of atypical Polycomb PRC1.6, E2F and MYC-MAX targets. Similarly, MGA depletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA, E2F6 and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes PRC1.6 subunits. Lastly, we report that MGA loss has also a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F targets mediated by an atypical Polycomb complex containing MGA-MAX dimers.

cancer biology↗

bioRxiv2019

Max deletion destabilizes MYC protein and abrogates Eμ-Myc lymphomagenesis

Although MAX is widely regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is not well defined. We show that B-cell specific deletion of Max has a surprisingly modest effect on B-cell development but completely abrogates E{micro}-Myc driven lymphomagenesis. In both contexts, MAX loss leads to a significant reduction in MYC protein levels. This outcome is associated with the downregulation of numerous transcriptional targets of MAX including a subset that regulate MYC stability. Reduction in MYC protein levels is also observed in multiple cell lines treated with a MYC-MAX dimerization inhibitor. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal lymphoid development.

cancer biology↗