Biology subjects

Patterson, L.

Publications and source records attributed to Patterson, L..

6 recordsLinked to original sources

bioRxiv2026

KRAS-driven metabolic reprogramming of enhanced MFSD2A-mediated lysophosphatidylcholine scavenging promotes survival and progression of pancreatic ductal adenocarcinoma

Oncogenic KRAS drives lipid reprogramming in pancreatic ductal adenocarcinoma (PDAC) to promote disease progression, and these changes are manifest in circulation. Using mass spectrometry, we performed lipidomic analyses on plasmas from a cohort of 93 newly-diagnosed resectable PDAC cases, 43 patients with chronic pancreatitis, and 93 age- and sex-matched healthy controls, the results of which revealed pronounced reductions in circulating lysophosphatidylcholines (LysoPC) as a prominent feature associated with PDAC. Using stable-isotope resolved lipidomics, we further found that PDAC cells exhibit a lipid scavenging phenotype characterized by preferential uptake of extracellular unsaturated LysoPCs to sustain pro-growth signals. Restricting bioavailability of extracellular unsaturated LysoPCs shifted the metabolic phenotype of PDAC cells towards enhanced de novo lipogenesis and autophagy, which was accompanied by suppression of AKT signaling activities and increased susceptibility to apoptosis. Using bulk, single-cell, and spatial transcriptomic datasets together with functional experiments, we identified oncogenic KRAS-mediated upregulation of major facilitator superfamily domain-containing protein 2a (MFSD2A) as a key mediator that facilitates extracellular uptake of LysoPCs in PDAC cells. Loss of MFSD2A expression mimicked LysoPC restriction and resulted in inhibition of AKT signaling and increased propensity of PDAC cells to undergo apoptosis in vitro and suppressed tumor growth in vivo. Therapeutic targeting of the KRAS-MFSD2A-LysoPC axis via repurposing of the synthetic alkyl-lysophospholipid edelfosine promoted potent anti-cancer effects in vitro that were mechanistically attributed to reduced extracellular uptake of LysoPCs, and attenuation of AKT signaling. Collectively, our findings describe a previously unrecognized onco-metabolic program of enhanced LysoPC scavenging mediated by MFSD2A that promotes PDAC progression and that is therapeutically targetable via repurposing edelfosine.

cancer biology↗

bioRxiv2025

Computational Modeling of Motor-Driven Extension of Microtubule Bundles in Axons

In addition to actin assembly at the growth cone, neuronal axons elongate via interactions between microtubules and microtubule-associated proteins including dynein motor proteins and cross-linking proteins. Dynein translocates microtubules toward the growth cone to exert extensile forces for axonal outgrowth. During this process, microtubules are most likely to experience compressive loads, which can result in bending deformation on microtubules called buckling. Such buckled microtubules are impaired in their ability to bear compressive forces and may not contribute significantly to axonal outgrowth. If microtubules are interconnected by cross-linking proteins, they are less likely to be buckled and thus able to resist larger compressive loads. Despite the importance of the buckling and connectivity of microtubules, their effects on the axonal outgrowth have not been investigated to date. In this study, using an agent-based computational model, we created a microtubule bundle to simulate the microtubule system in axons. This bundle increased its length by interactions between dynein-like motors and microtubules against a mechanical load. We found that intermediate cross-linking density resulted in maximal elongation of the bundle, because microtubules were easily buckled at low cross-linking density, whereas the displacement of microtubules was inhibited at high cross-linking density. When individual microtubules were much stiffer, the bundle showed higher elongation even with lower cross-linking density, since stiff microtubules were less likely to be buckled by compressive loads. Our study provides new insights into the mechanisms driving axonal outgrowth.

biophysics↗

bioRxiv2024

Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma

The von Hippel-Lindau (VHL) tumor suppressor is a component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by genetic aberrations is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss leads to constitutive stabilization of E3 ligase targets, including hypoxia inducible factor (HIF), in VHL-associated tumors. HIF stabilization upon VHL loss promotes transactivation of hypoxia responsive genes, which contributes to ccRCC development. However, several HIF-independent VHL targets have also been implicated in the promotion of tumorigenesis. Using proximity labeling to identify proteasomal VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in an oxygen-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, the hyperstabilization of pRb in ccRCC promoted tumorigenesis in vitro and in mouse models. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.

cancer biology↗

bioRxiv2022

The Children's Brain Tumor Network (CBTN) - Accelerating Research in Pediatric Central Nervous System Tumors through Collaboration and Open Science

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Childrens Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTNs 32 member institutions utilize a shared regulatory governance architecture at the Childrens Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4,700 subjects, over 1,500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1,000 tumors and germline material is currently available with data generation for > 5,000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

cancer biology↗

bioRxiv2018

Evolution of Endothelin signaling and diversification of adult pigment pattern in Danio fishes

Fishes of the genus Danio exhibit diverse pigment patterns that serve as useful models for understanding the genes and cell behaviors underlying the evolution of adult form. Among these species, zebrafish D. rerio exhibit several dark stripes of melanophores with sparse iridophores that alternate with light interstripes of dense iridophores and xanthophores. By contrast, the closely related species D. nigrofasciatus has an attenuated pattern with fewer melanophores, stripes and interstripes. Here we demonstrate species differences in iridophore development that presage the fully formed patterns. Using genetic and transgenic approaches we identify the secreted peptide Endothelin-3 (Edn3)--a known melanogenic factor of tetrapods--as contributing to reduced iridophore proliferation and fewer stripes and interstripes in D. nigrofasciatus. We further show the locus encoding this factor is expressed at lower levels in D. nigrofasciatus owing to cis-regulatory differences between species. Finally, we show that functions of two paralogous loci encoding Edn3 have been partitioned between skin and non-skin iridophores. Our findings reveal genetic and cellular mechanisms contributing to pattern differences between these species and suggest a model for evolutionary changes in Edn3 requirements across vertebrates.\n\nAuthor SummaryNeural crest derived pigment cells generate the spectacular variation in skin pigment patterns among vertebrates. Mammals and birds have just a single skin pigment cell, the melanocyte, whereas ectothermic vertebrates have several pigment cells including melanophores, iridophores and xanthophores, that together organize into a diverse array of patterns. In the teleost zebrafish, Danio rerio, an adult pattern of stripes depends on interactions between pigment cell classes and between pigment cells and their tissue environment. The close relative, D. nigrofasciatus has fewer stripes and prior analyses suggested a difference between these species that lies extrinsic to the pigment cells themselves. A candidate for mediating this difference is Endothelin-3 (Edn3), essential for melanocyte development in warm-blooded animals, and required by all three classes of pigment cells in an amphibian. We show that Edn3 specifically promotes iridophore development in Danio, and that differences in Edn3 expression contribute to differences in iridophore complements, and striping, between D. rerio and D. nigrofasciatus. Our study reveals a novel function for Edn3 and provides new insights into how changes in gene expression yield morphogenetic outcomes to effect diversification of adult form.

developmental biology↗

bioRxiv2017

N-(3-Oxododecanoyl)-L-Homoserine Lactone Interactions In The Breast Tumor Microenvironment: Implications For Breast Cancer Viability And Proliferation In Vitro

It is well documented that the tumor microenvironment profoundly impacts the etiology and progression of breast cancer, yet the contribution of the resident microbiome within breast tissue remains poorly understood. Tumor microenvironmental conditions, such as hypoxia and dense tumor stroma, predispose progressive phenotypes and therapy resistance, however the role of bacteria in this interplay remains uncharacterized. We hypothesized that the effect of individual bacterial secreted molecules on breast cancer viability and proliferation would be modulated by these tumor-relevant stressors differentially for cells at varying stages of progression. To test this, we incubated human breast adenocarcinoma cells (MDA-MB-231, MCF-DCIS.com) and non-malignant breast epithelial cells (MCF-10A) with N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a quorum-sensing molecule from Pseudomonas aeruginosa that regulates bacterial stress responses. This molecule was selected because Pseudomonas was recently characterized as a significant fraction of the breast tissue microbiome and OdDHL is documented to impact mammalian cell viability. After OdDHL treatment, we demonstrated the greatest decrease in viability with the more malignant MDAMB-231 cells and an intermediate MCF-DCIS.com (ductal carcinoma in situ) response. The responses were also culture condition (i.e. microenvironment) dependent. These results contrast the MCF-10A response, which demonstrated no change in viability in any culture condition. We further determined that the observed trends in breast cancer viability were due to modulation of proliferation for both cell types, as well as the induction of necrosis for MDA-MB-231 cells in all conditions. Our results provide evidence that bacterial quorum-sensing molecules interact with the host tissue environment to modulate breast cancer viability and proliferation, and that the effect of OdDHL is dependent on both cell type as well as microenvironment. Understanding the interactions between bacterial signaling molecules and the host tissue environment will allow for future studies that determine the contribution of bacteria to the onset, progression, and therapy response of breast cancer.

cancer biology↗