Biology subjects

Bristow, C.

Publications and source records attributed to Bristow, C..

6 recordsLinked to original sources

bioRxiv2026

Chromatin Landscape of Cancer Cell Lines Identifies Enhancer Subtypes

Epigenetic aberrations are a hallmark of cancer; however, systematic chromatin state maps of cancer cells are unavailable. We generated and analyzed 803 histone mark profiles in 142 cancer cell lines and 114 human tumors belonging to 9 solid tumor types. Irrespective of their cell-of-origin, cancer cells segregate from normal tissues based on their enhancer patterns, suggesting enhancer deregulation is a fundamental epigenetic feature in cancer. Enhancer based clustering defined 5 distinct subgroups of cancer cells (EpiC1-5) with unique developmental trajectories, molecular features and dependencies. Importantly, we define a set of core TFs that are critical for EpiC-specific enhancer patterns and survival. Notably, EpiC4 represented a predominantly epigenetic, pan-cancer subtype that displays poor survival, activation and dependence on a FN1-CAV1-SRC-PI3K-AKT signaling network. Together, these data uncover enhancer heterogeneity in pan-cancer systems with identification of a novel enhancer-based subtype and identify potential new therapeutic targets associated with unique epigenetic features.

cancer biology↗

bioRxiv2025

Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer

MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.

cancer biology↗

bioRxiv2024

Diffusion within the synaptonemal complex can account for signal transduction along meiotic chromosomes

Meiotic chromosomes efficiently transduce information along their length to regulate the distribution of genetic exchanges within and between chromosomes. However, the mode of signal transduction remains unknown. Recently, a conserved chromosomal interface, the synaptonemal complex, was shown to be a biomolecular condensate, offering an attractive mechanism for signal transduction: diffusion of signaling molecules within the synaptonemal complex to allow transmission of information along each pair of chromosomes. Here, we test the feasibility of this mechanism in live C. elegans gonads. Single-molecule tracking shows that a component of the synaptonemal complex (SYP-3) and a conserved regulator of exchanges (ZHP-3) both diffuse within the synaptonemal complex. However, ZHP-3 diffuses 4- and 9-fold faster than SYP-3 before and after crossovers formation, respectively. We use these measurements to parameterize a physical model for signal transduction. We find that ZHP-3, but not SYP-3, explores the lengths of chromosomes on the time scale of crossover maturation, consistent with a role in the spatial regulation of exchanges. Given the conservation of ZHP-3 paralogs across eukaryotes, we propose that diffusion within the synaptonemal complex may be a conserved mechanism of meiotic regulation. More broadly, our work explores how diffusion contained within condensates regulates crucial cellular functions.

cell biology↗

bioRxiv2022

Meiotic DNA exchanges are promoted by proximity to the synaptonemal complex

During meiosis, programmed double strand DNA breaks are repaired to form exchanges between the parental chromosomes called crossovers. Chromosomes lacking a crossover fail to segregate accurately into the gametes, leading to aneuploidy. Crossover formation requires the promotion of exchanges, rather than non-exchanges, as repair products. However, the mechanism underlying this meiosis-specific preference is not fully understood. Here, we study the regulation of meiotic sister chromatid exchanges in Caenorhabditis elegans by direct visualization. We find that a conserved chromosomal interface that promotes exchanges between the parental chromosomes, the synaptonemal complex, also promotes exchanges between the sister chromatids. In both cases, exchanges depend on recruitment of the same set of pro-exchange factors to repair sites. Surprisingly, while the synaptonemal complex usually assembles between the two DNA molecules undergoing an exchange, its activity does not rely on a specific chromosome conformation and it can also promote sister exchanges when assembling next to the sisters. This suggests that the synaptonemal complex regulates exchanges by establishing a nuclear domain conducive to nearby coalescence of exchange-promoting factors.

cell biology↗

bioRxiv2021

Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets for tumor maintenance. This is especially challenging in the context of PDAC, in which activating mutations of KRAS oncogene (KRAS*) dominate the genetic landscape. By using an inducible KrasG12D-driven p53 deficient PDAC mouse model (iKras model), we demonstrate that RAF-MEK-MAPK signaling is the major effector for oncogenic Kras-mediated tumor maintenance. However, MEK inhibition has minimal therapeutic effect as single agent for PDAC both in vitro and in vivo. Although MEK inhibition partially downregulates the transcription of glycolysis genes, it surprisingly fails to suppress the glycolysis flux in PDAC cell, which is a major metabolism effector of oncogenic KRAS. Accordingly, In vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MAPK inhibition. Furthermore, inhibition of glucose metabolism with low dose 2-deoxyglucose (2DG) in combination with MEK inhibitor dramatically induces apoptosis in KrasG12D-driven PDAC cell in vitro, inhibits xenograft tumor growth and prolongs the overall survival of genetically engineered mouse PDAC model. Molecular and metabolism analyses indicate that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combinatory inhibition of glycolysis and MAPK pathway may serve as an alternative approach to target KRAS-driven PDAC.

cancer biology↗

bioRxiv2018

Multiplexed pooled library screening with Cpf1

RNA interference and CRISPR/Cas9-based pooled library screens have revolutionized the field of functional genomics. However, currently available pooled library screens face a trade-off between library effectiveness and library complexity. We developed a multiplexed, high-throughput screening strategy based on an optimized AsCpf1 nuclease that minimizes library size without sacrificing gene targeting efficiency. Our AsCpf1-based multiplexed library performed similarly well compared to currently available CRISPR/Cas9 libraries, but with a single polycistronic crRNA clone targeting each gene. With this strategy, we constructed the smallest whole-genome knock-out library available, \"Mini-human\" for the human genome, which is one-fourth the size of the smallest CRISPR library currently available.

systems biology↗