Biology subjects

Boe, R. H.

Publications and source records attributed to Boe, R. H..

5 recordsLinked to original sources

bioRxiv2025

Heterogeneous therapy-resistant cancer cells have distinct and exploitable drug sensitivity profiles

Resistance to targeted therapies is a significant clinical problem, but eliminating resistant cancer cells has proven difficult. One potential reason for this difficulty is heterogeneity in the resistant population: even genetically homogeneous cancer cell populations can give rise to many resistant subtypes, each potentially with specific second-line drug vulnerabilities. Using high-throughput drug screening of genetically-identical resistant clones with varying transcriptomes and morphologies, we show that each clone had a distinct drug sensitivity profile. These results suggested that there are drugs that are effective against only subsets of resistant populations but in combination eliminate a large proportion of the resistant population. Using the individual clone sensitivity profiles, we prospectively identified combinations that were highly effective at eliminating most of the resistant population. Our results demonstrate the effectiveness of "subpopulation-directed synergy", showing that considering population heterogeneity can reveal therapeutic opportunities otherwise masked by population averages, offering new strategies to combat therapy resistance.

systems biology↗

bioRxiv2025

SpaceBar enables clone tracing in spatial transcriptomic data

We report a cellular barcoding strategy, SpaceBar, that enables simultaneous clone tracing and spatial transcriptomics profiling. Our approach uses a library of 96 synthetic barcode sequences that can be robustly detected by imaging based spatial transcriptomics (seqFISH), delivered such that each cell is labeled with a combination of barcodes. We used these barcodes to label melanoma cells in a tumor xenograft model and profiled both clone identity and spatial gene expression in situ. We developed a gene scoring metric that quantifies how strongly gene expression is driven by intrinsic cellular cues or extrinsic environmental signals. Our framework distinguishes between clonal dynamics and environmentally-driven transcriptional regulation in complex tissue contexts.

genomics↗

bioRxiv2024

AP-1 Mediates Cellular Adaptation and Memory Formation During Therapy Resistance

Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that melanoma cells can form and maintain cellular memories during the acquisition of therapy resistance that exhibit characteristics of cellular learning and are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that resistance was not purely selective. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility showed concomitant persistence. A two-color AP-1 reporter system showed that these memories are encoded in cis, constituting an example of activating cis epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance.

systems biology↗

bioRxiv2024

Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance

Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.

systems biology↗

bioRxiv2021

Allelic correlation is a marker of tradeoffs between barriers to transmission of expression variability and signal responsiveness in genetic networks

Accurately functioning genetic networks should be responsive to signals but prevent transmission of stochastic bursts of expression. Existing data in mammalian cells suggests that such transcriptional "noise" is transmitted by some genes and not others, suggesting that noise transmission is tunable, perhaps at the expense of other signal processing capabilities.However, systematic claims about noise transmission in genetic networks have been limited by the inability to directly measure noise transmission. Here we build a mathematical framework capable of modeling allelic correlation and noise transmission. We find that allelic correlation and noise transmission correspond across a broad range of model parameters and network architectures. We further find that limiting noise transmission comes with the trade-off of being unresponsive to signals, and that within the parameter regimes that are responsive to signals, there is a further trade-off between response time and basal noise transmission. Using a published allele specific single cell RNA-sequencing dataset, we found that genes with high allelic odds ratios are enriched for cell-type specific functions, and that within multiple signaling pathways, factors which are upstream in the pathway have higher allelic odds ratios than downstream factors. Overall, our findings suggest that some degree of noise transmission is required to be responsive to signals, but that minimization of noise transmission can be accomplished by trading-off for a slower response time.

systems biology↗