Biology subjects

Linn, S.

Publications and source records attributed to Linn, S..

3 recordsLinked to original sources

bioRxiv2023

Breast cancer risk SNPs converge on estrogen receptor binding sites commonly shared between breast tumors to locally alter estrogen signalling output

Estrogen Receptor alpha (ER) is the main driver and prime drug target in luminal breast. ER chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ER chromatin action, along with its biological implications. Here, we use a large set of ER ChIP-seq data from 70 ER+ breast cancers to explore inter-patient heterogeneity in ER DNA binding, to reveal a striking inter-tumor heterogeneity of ER action. Interestingly, commonly-shared ER sites showed the highest estrogen-driven enhancer activity and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ER-occupied enhancers were enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ER and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ER-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ER landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

genomics↗

bioRxiv2023

Deconstructing the contributions of heterogeneity to combination treatment of hormone sensitive breast cancer

Combination therapies are fundamental to cancer treatments, including in breast cancer the most common invasive malignancy in women. Breast cancer treatment is determined based on molecular subtypes, and since 2016, combination palbociclib and fulvestrant has been used to treat hormone receptor-positive breast cancer. However, the impact of heterogeneity of the tumour landscape and tumour composition dynamics on scheduling decisions remains poorly understood. To elucidate the contributions of variability at multiple scales to treatment outcomes in hormone receptor-positive breast cancer, we developed a simple mathematical model of two unique estrogen receptor positive (ER+) breast cancer cell types and their response to combination treatment with palbociclib and fulvestrant. We used this model to understand how the initial fraction of either cell type may impact the fraction remaining after treatment and examined how heterogeneity in pharmacokinetics and pharmacodynamics result in a large distribution of outcomes. Our results suggest that the pharmacokinetics and pharmacodynamics of fulvestrant were the major drivers of final tumour size and composition. We then leveraged our model to guide therapeutic scheduling of combination palbociclib and fulvestrant, demonstrating the use of mathematical modelling to improve our understanding of cancer biology and treatments.

cancer biology↗

bioRxiv2020

Miniaturized head-mounted device for whole cortex mesoscale imaging in freely behaving mice

The advent of genetically encoded calcium indicators, along with surgical preparations such as thinned skulls or refractive index matched skulls, have enabled mesoscale cortical activity imaging in head-fixed mice. Such imaging studies have revealed complex patterns of coordinated activity across the cortex during spontaneous behaviors, goal-directed behavior, locomotion, motor learning, and perceptual decision making. However, neural activity during unrestrained behavior significantly differs from neural activity in head-fixed animals. Whole-cortex imaging in freely behaving mice will enable the study of neural activity in a larger, more complex repertoire of behaviors not possible in head-fixed animals. Here we present the "Mesoscope," a wide-field miniaturized, head-mounted fluorescence microscope compatible with transparent polymer skulls recently developed by our group. With a field of view of 8 mm x 10 mm and weighing less than 4 g, the Mesoscope can image most of the mouse dorsal cortex with resolution ranging from 39 to 56 {micro}m. Stroboscopic illumination with blue and green LEDs allows for the measurement of both fluorescence changes due to calcium activity and reflectance signals to capture hemodynamic changes. We have used the Mesoscope to successfully record mesoscale calcium activity across the dorsal cortex during sensory-evoked stimuli, open field behaviors, and social interactions. Finally, combining the mesoscale imaging with electrophysiology enabled us to measure dynamics in extracellular glutamate release in the cortex during the transition from wakefulness to natural sleep.

neuroscience↗