Biology subjects

Sparks, J. L.

Publications and source records attributed to Sparks, J. L..

5 recordsLinked to original sources

bioRxiv2020

Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach

Colorectal cancer (CRC) and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic (PVE) model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could "reawaken" after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer.

systems biology↗

bioRxiv2018

Mechanism of replication-coupled DNA-protein crosslink proteolysis by SPRTN and the proteasome

DNA-protein crosslinks (DPCs) are bulky DNA lesions that interfere with DNA metabolism and therefore threaten genomic integrity. Recent studies implicate the metalloprotease SPRTN in S-phase removal of DPCs, but how SPRTN activity is coupled to DNA replication is unknown. Using Xenopus egg extracts that recapitulate replication-coupled DPC proteolysis, we show that DPCs can be degraded by SPRTN or the proteasome, which act as independent DPC proteases. Proteasome recruitment requires DPC polyubiquitylation, which is triggered by single-stranded DNA, a byproduct of DNA replication. In contrast, SPRTN-mediated DPC degradation is independent of DPC polyubiquitylation but requires polymerase extension of a nascent strand to the lesion. Thus, SPRTN and proteasome activities are coupled to DNA replication by distinct mechanisms and together promote replication across immovable protein barriers.\n\nHighlightsO_LIThe proteasome, in addition to SPRTN, degrades DPCs during DNA replication\nC_LIO_LIProteasome-dependent DPC degradation requires DPC ubiquitylation\nC_LIO_LIDPC ubiquitylation is triggered by ssDNA and does not require the replisome\nC_LIO_LISPRTN-dependent DPC degradation is a post-replicative process\nC_LI

molecular biology↗

bioRxiv2018

The CMG helicase bypasses DNA protein cross-links to facilitate their repair

Covalent and non-covalent nucleoprotein complexes impede replication fork progression and thereby threaten genome integrity. Using Xenopus laevis egg extracts, we previously showed that when a replication fork encounters a covalent DNA-protein cross-link (DPC) on the leading strand template, the DPC is degraded to a short peptide, allowing its bypass by translesion synthesis polymerases. Strikingly, we show here that when DPC proteolysis is blocked, the replicative DNA helicase (CMG), which travels on the leading strand template, still bypasses the intact DPC. The DNA helicase RTEL1 facilitates bypass, apparently by translocating along the lagging strand template and generating single-stranded DNA downstream of the DPC. Remarkably, RTEL1 is required for efficient DPC proteolysis, suggesting that CMG bypass of a DPC normally precedes its proteolysis. RTEL1 also promotes fork progression past non-covalent protein-DNA complexes. Our data suggest a unified model for the replisomes response to nucleoprotein barriers.

biochemistry↗

bioRxiv2016

MultiCellDS: a standard and a community for sharing multicellular data

Cell biology is increasingly focused on cellular heterogeneity and multicellular systems. To make the fullest use of experimental, clinical, and computational efforts, we need standardized data formats, community-curated \"public data libraries\", and tools to combine and analyze shared data. To address these needs, our multidisciplinary community created MultiCellDS (MultiCellular Data Standard): an extensible standard, a library of digital cell lines and tissue snapshots, and support software. With the help of experimentalists, clinicians, modelers, and data and library scientists, we can grow this seed into a community-owned ecosystem of shared data and tools, to the benefit of basic science, engineering, and human health.

systems biology↗

bioRxiv2016

MultiCellDS: a community-developed standard for curating microenvironment-dependent multicellular data

Exchanging and understanding scientific data and their context represents a significant barrier to advancing research, especially with respect to information siloing. Maintaining information provenance and providing data curation and quality control help overcome common concerns and barriers to the effective sharing of scientific data. To address these problems in and the unique challenges of multicellular systems, we assembled a panel composed of investigators from several disciplines to create the MultiCellular Data Standard (MultiCellDS) with a use-case driven development process. The standard includes (1) digital cell lines, which are analogous to traditional biological cell lines, to record metadata, cellular microenvironment, and cellular phenotype variables of a biological cell line, (2) digital snapshots to consistently record simulation, experimental, and clinical data for multicellular systems, and (3) collections that can logically group digital cell lines and snapshots. We have created a MultiCellular DataBase (MultiCellDB) to store digital snapshots and the 200+ digital cell lines we have generated. MultiCellDS, by having a fixed standard, enables discoverability, extensibility, maintainability, searchability, and sustainability of data, creating biological applicability and clinical utility that permits us to identify upcoming challenges to uplift biology and strategies and therapies for improving human health.

systems biology↗