Biology subjects

Kendall, J.

Publications and source records attributed to Kendall, J..

5 recordsLinked to original sources

bioRxiv2023

High-throughput single-nucleus hybrid sequencing reveals genome-transcriptome correlations in cancer

To deepen our understanding of cancer heterogeneity and uncover the dynamic interactions of tumor and host cells, we introduce hybrid BAG-seq: a high-throughput, multi-omic method that simultaneously captures DNA and RNA from tens of thousands of individual single nuclei. This method provides dual molecular layer information: DNA to distinguish tumor from stroma, identify tumor subclones, and detect mutant stromal sub-populations; and RNA to characterize distinct cell types, cell states, and signatures of aberrant expression. Additionally, we developed a suite of analysis tools to illuminate cluster phylogeny and connections between DNA identity and RNA expression. We applied this hybrid protocol to 65,499 single nuclei from samples of five uterine cancer patients, and validated the clustering using RNA-only and DNA-only protocols on 34,651 and 21,432 nuclei, respectively, from the same tissues. Multiple tumor genome or expression clusters were often present within a patient, with different tumor clones projecting into distinct or shared expression states, demonstrating nearly all possible genome-transcriptome correlations across the cohort. While tumor expression profiles were highly unique to each patient, the stromal cell types generally recurred across samples, but certain patients and tissues exhibited unique stromal sub-types characterized by aberrant expression. Moreover, we identified mutant stroma in various cell types from several patients with a significant loss of the X-chromosome. This study reveals the complex landscape of genome and transcriptome interactions at the resolution of single nuclei, providing new insights into mutant stroma and tumor heterogeneity.

genomics↗

bioRxiv2021

Parity-induced changes to mammary epithelial cells control NKT cell expansion and mammary oncogenesis

Pregnancy reprograms the epigenome of mammary epithelial cells (MECs) in a manner that control responses to pregnancy hormone re-exposure and the rate of carcinoma progression. However, the influence of pregnancy on the tissue microenvironment of the mammary gland is less clear. Here, we used single-cell RNA sequencing to comparatively profile the composition of epithelial and non-epithelial cells in mammary tissue from nulliparous and parous female mice. Our analysis revealed an expansion of {gamma}{delta} Natural Killer T (NKT) immune cells following pregnancy, in association with upregulation of immune signal molecules in post-pregnancy MECs. We show that expansion of NKT cells following pregnancy is due to elevated expression of the antigen presenting molecule CD1d protein, which is known to induce NKT activation. Accordingly, loss of CD1d expression on post-pregnancy MECs, or overall lack of activated NKT cells, accompanied the development of mammary oncogenesis in response to cMYC overexpression and loss of Brca1 function. Collectively, our findings illustrate how pregnancy-induced epigenetic changes modulate the communication between MECs and the mammary immune microenvironment, and establish a causal link between pregnancy, the immune microenvironment, and mammary oncogenesis.

developmental biology↗

bioRxiv2020

Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy is typically detrimental to cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to a variety of different culture environments. While chromosomal instability was universally detrimental under normal growth conditions, we discovered that transient CIN reproducibly accelerated the ability of cells to adapt and thrive in the presence of anti-cancer therapeutic agents. Single-cell sequencing revealed that these drug-resistant populations recurrently developed specific whole-chromosome gains and losses. We independently derived one aneuploidy that was frequently recovered in cells exposed to paclitaxel, and we found that this chromosome loss event was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to a variety of systemic therapies in a collection of patient-derived xenografts. In total, our results show that while chromosomal instability generally antagonizes cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure in human tumors.

cancer biology↗

bioRxiv2019

G-Graph: An interactive genomic graph viewer

MotivationEffective and efficient exploration of numeric data and annotations as a function of genomic position requires specialized software. ResultsWe present G-Graph, an interactive genomic scatter plot viewer. G-Graph stacks or tiles multiple data series in one graph using different colors and markers. It displays gene annotation and other metadata, allows easy changes to the appearance of data series, implements stack-based undo functionality, and saves user-selected application views as image and pdf files. G-Graph delivers smooth and rapid scrolling and zooming even for datasets with millions of points and line segments. The primary target user is a researcher examining many copy number profiles to identify potentially deleterious variants. G-Graph runs under Linux, Mac OSX and Windows. Availabilityhttps://github.com/docpaa/mumdex/ or https://mumdex.com/ggraph/ Contactandrewsp@cshl.edu (or paa@drpa.us)

genomics↗

bioRxiv2019

Single chromosome gains can function as metastasis suppressors and metastasis promoters

Most human tumors display chromosome-scale copy number alterations, and high levels of aneuploidy are frequently associated with advanced disease and poor patient prognosis. To examine the relationship between aneuploidy and cancer progression, we generated and analyzed a series of congenic human cell lines that harbor single extra chromosomes. We find that different aneuploidies can have distinct effects on invasive behavior: across 13 different cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, chromosomal instability, which can lead to the development of aneuploidy, uniformly suppressed cellular invasion. By analyzing genomic copy number and survival data from 10,133 cancer patients, we demonstrate that specific aneuploidies are associated with distinct clinical outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different chromosome copy number changes can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, underscoring how genomic plasticity can engender phenotypic plasticity and lead to the acquisition of enhanced metastatic properties.

cancer biology↗