Biology subjects

Wilde, B. R.

Publications and source records attributed to Wilde, B. R..

4 recordsLinked to original sources

bioRxiv2025

PPARG governs adipogenic differentiation and cell state plasticity in well-differentiated and dedifferentiated liposarcoma

Well-differentiated and dedifferentiated liposarcoma (WD/DD LPS) represent a pathological continuum, often coexisting within the same tumor. While the dedifferentiated component is clinically aggressive, marked by rapid growth and metastatic potential, the evolutionary relationship between WD and DD LPS remains unknown. To investigate this, we performed single-nucleus RNA sequencing on matched WD and DD tumor regions. Both compartments shared a predominant population of undifferentiated mesenchymal cells, but only WD regions contained cells expressing adipocytic differentiation markers and PPARG target genes. Given the central role of PPARG in coordinating lipid metabolism and mitochondrial biogenesis during adipogenesis, these findings suggest that loss of this program may underlie the poorly differentiated, proliferative phenotype of DD LPS. Functional studies confirmed that PPARG activation in DD LPS cells induces lipid accumulation, reduces proliferation, and impairs tumor growth in vivo. These support a model in which impaired adipogenic differentiation underlies DD LPS pathology and identify PPARG as a potential therapeutic target to promote differentiation and suppress tumor progression. TeaserPPARG reprograms DD liposarcoma toward adipogenesis, reducing proliferation and tumor growth

cancer biology↗

bioRxiv2022

FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer

The tricarboxylic citric acid cycle enzyme fumarate hydratase (FH) is a tumor suppressor. When lost in cells, its substrate fumarate accumulates to mM levels and drives oncogenic signaling and transformation. Germline alterations lead to an autosomal dominant condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to various benign tumors and an aggressive form of kidney cancer. FH alterations of unclear significance are frequently observed with germline testing; thus, there is an unmet need to classify FH variants by their cancer-associated risk, allowing for screening, early diagnosis and treatment. Here we quantify catalytic efficiency of 74 FH variants of uncertain significance. Over half were enzymatically inactive which is strong evidence of pathogenicity. We generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks purine biosynthesis, rendering FH-deficient cells reliant on purine salvage to maintain purine nucleotide pools. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. Together, these findings suggest pathogenicity of many patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors. Statement of SignificanceThis study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers.

cancer biology↗

bioRxiv2022

TXNIP loss expands Myc-dependent transcriptional programs by increasing Myc genomic binding

c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To achieve this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters and represses the expression of Thioredoxin Interacting Protein (TXNIP), which is a potent negative regulator of glucose uptake. A Mychigh/TXNIPlow gene signature is clinically significant as it correlates with poor clinical prognosis in Triple-Negative Breast Cancer (TNBC) but not in other subtypes of breast cancer. To better understand how TXNIP function contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show here that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Mycs intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the metabolic signals that control TXNIP expression.

cancer biology↗

bioRxiv2018

Cellular acidosis triggers MondoA transcriptional activity by driving mitochondrial ATP production

MondoA and its transcriptional target thioredoxin-interacting protein (TXNIP) constitute a regulatory loop that senses glycolytic flux and controls glucose availability. Cellular stress also triggers MondoA activity and TXNIP expression. To understand how MondoA integrates glucose and stress signals, we studied its activation by acidosis. We found that acidosis drives mitochondrial ATP (mtATP) synthesis. The subsequent export of mtATP from mitochondria via adenine-nucleotide transporter and voltage-dependent anion channel, and the enzymatic activity of mitochondria-bound hexokinase results in the production of glucose-6-phosphate (G6P), a known activator of MondoA transcriptional activity. MondoA localizes to the outer-mitochondrial membrane (OMM), and in response to G6P, shuttles to the nucleus and activates transcription. Our data suggests that MondoA is a required feature of a glucose- and mtATP-dependent, OMM-localized signaling center. We propose MondoA functions as a coincidence detector and its ability to sense glucose and cellular stress is coupled to the concerted production of G6P.

cancer biology↗