Biology subjects

Tourdot, R. W.

Publications and source records attributed to Tourdot, R. W..

4 recordsLinked to original sources

bioRxiv2024

Haplotype-resolved karyotype construction from Hi-C data using refLinker

Genomic characterization has revealed widespread structural complexity in cancer karyotypes, however shotgun sequencing cannot resolve genomic rearrangements with chromosome-length continuity. Here, we describe a two-tiered approach to determine the segmental composition of rearranged chromosomes with haplotype resolution. First, we present refLinker, a new method for robust determination of chromosomal haplotypes using cancer Hi-C data. Second, we use haplotype-specific Hi-C contacts to determine the segmental structure of rearranged chromosomes. By contrast with existing methods for diploid haplotype inference, our approach is robust to the confounding effects of large-scale DNA deletions, duplications, and high-level amplification in cancer sequencing. Using this approach, we examine haplotype-specific expression changes on rearranged homologs and provide direct evidence for long-range transcriptional activation and repression associated with rearrangements of the inactive X chromosome (Xi). Together, these results reveal the significant transcriptional consequences of somatic Xi rearrangements, highlighting refLinkers broad utility for studying the functional consequences of chromosomal rearrangements.

genomics↗

bioRxiv2023

A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

cancer biology↗

bioRxiv2021

ECM dimensionality tunes actin tension to modulate the endoplasmic reticulum and spheroid phenotype

Primary tissue organoids and cell spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a three dimensional laminin-rich extracellular matrix supports the polarized, stress resilient spheroid phenotype of mammary epithelial cells. Cells within a three dimensional laminin-rich extracellular matrix decreased and redistributed the actin crosslinker filamin to reduce their cortical actin tension. Cells with low cortical actin tension had increased plasma membrane protrusions that promoted negative plasma membrane curvature and fostered protein associations with the plasma membrane, consistent with efficient protein secretion. By contrast, cells engaging a laminin-rich extracellular matrix in two dimensions had high filamin-dependent cortical actin tension, exhibited compromised endoplasmic reticulum function including increased expression of PKR-like Endoplasmic Reticulum Kinase signaling effectors, and had compromised protein secretion. Cells with low filamin-mediated cortical actin tension and reduced endoplasmic reticulum stress response signaling secreted, and assembled, a polarized endogenous basement membrane and survived better, and their spheroids were more resistant to exogenous stress. The findings implicate filamin-dependent cortical actin tension in endoplasmic reticulum function and highlight a role for mechanics in organoid homeostasis.

cell biology↗

bioRxiv2019

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes with chromothripsis, another catastrophic mutational process. Here, we explain this association by identifying a mutational cascade downstream of chromosome bridge formation that generates increasing amounts of chromothripsis. We uncover a new role for actomyosin forces in bridge breakage and mutagenesis. Chromothripsis then accumulates starting with aberrant interphase replication of bridge DNA, followed by an unexpected burst of mitotic DNA replication, generating extensive DNA damage. Bridge formation also disrupts the centromeric epigenetic mark, leading to micronucleus formation that itself promotes chromothripsis. We show that this mutational cascade generates the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.

cancer biology↗