Biology subjects

Bosma-Moody, A.

Publications and source records attributed to Bosma-Moody, A..

7 recordsLinked to original sources

bioRxiv2022

Mutational footprint of platinum chemotherapy in a secondary thyroid cancer

Although papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor with a generally excellent prognosis, a patient developed a clinically aggressive PTC eleven years after receiving platinum chemotherapy for ovarian endometrioid adenocarcinoma. Germline and somatic analyses of multi-temporal and multi-regional molecular profiles indicated that ovarian and thyroid tumors did not share common genetic alterations. PTC tumors had driver events associated with aggressive PTC behavior, an RBPMS-NTRK3 fusion and a TERT promoter mutation. Spatial and temporal genomic heterogeneity analysis indicated a close link between anatomical locations and molecular patterns of PTC. Mutational signature analyses demonstrated a molecular footprint of platinum exposure, and that aggressive molecular drivers of PTC were linked to prior platinum-associated mutagenesis. This case provides a direct association between platinum chemotherapy exposure and secondary solid tumor evolution, in specific aggressive thyroid carcinoma, and suggests that uniform clinical assessments for secondary PTC after platinum chemotherapy may warrant further evaluation.

genomics↗

bioRxiv2020

Integrative Molecular Characterization of Sarcomatoid and Rhabdoid Renal Cell Carcinoma Reveals Determinants of Poor Prognosis and Response to Immune Checkpoint Inhibitors

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1-3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

cancer biology↗

bioRxiv2020

Transcriptional mediators of treatment resistance in lethal prostate cancer

Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-{beta} signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

genomics↗

bioRxiv2019

Distribution and strength of interlaminar synaptic connectivity in mouse primary visual cortex revealed by two-photon optogenetic stimulation

The most common synaptic connections between neurons in different cortical layers form the basis of the canonical cortical microcircuit. Understanding of cortical function will require further development and application of methods to efficiently characterize synaptic connections within and outside of the canonical pathway. Accordingly, we measured synaptic inputs onto superficial excitatory neurons in response to sequential two-photon optogenetic stimulation of neurons in deeper layers. Layer 4 excitatory neurons and somatostatin-neurons within layer 2/3 represented the most common sources of input. Although connections from excitatory and somatostatin-neurons in layer 5 were less common, the amplitudes of synaptic responses were equally strong. We examined synaptic strength across all connections, as well as the relationships between the strength of connections diverging from a common presynaptic neuron or converging to a single target. While the overall distribution indicates synaptic weight is concentrated to a few connections, strong excitatory connections are distributed across cells.

neuroscience↗

bioRxiv2019

Multimodal cell type correspondence by intersectional mFISH in intact tissues

Defining a complete set of cell types within the cortex requires reconciling disparate results achieved through diverging methodologies. To address this correspondence problem, multiple methodologies must be applied to the same cells across multiple single-cell experiments. Here we present a new approach applying spatial transcriptomics using multiplexed fluorescence in situ hybridization, (mFISH) to brain tissue previously interrogated through two photon optogenetic mapping of synaptic connectivity. This approach can resolve the anatomical, transcriptomic, connectomic, electrophysiological, and morphological characteristics of single cells within the mouse cortex.

neuroscience↗

bioRxiv2018

Sparse recurrent excitatory connectivity in the cortical microcircuit of the adult mouse and human

Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, the Allen Institute is engaged in a pipeline project using multipatch electrophysiology, supplemented with 2-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell types and layers we sampled, with the most sparse connections in layers 5 and 6. Almost all mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons; however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits.

neuroscience↗

bioRxiv2017

A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality

Modern genetic approaches are powerful in providing access to diverse types of neurons within the mammalian brain and greatly facilitating the study of their function. We here report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically-defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

neuroscience↗