Biology subjects

Shannon, E.

Publications and source records attributed to Shannon, E..

6 recordsLinked to original sources

bioRxiv2025

Conserved Neuronal-like and Secretory Programs Define the Spatial Architecture of Gastroenteropancreatic Neuroendocrine Tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (pNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program (si-cNMF1/p-cNMF1), and a secretory neuroendocrine program (si-cNMF2/p-cNMF2). Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in pNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that si/p-cNMF1-high regions localized to high cell density, immune-rich tumor areas, whereas si/p-cNMF2-high regions occupied stromal and vascularized niches and co-occured with fibroblast and endothelial compartments enriched for TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enrichedfor pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.

cancer biology↗

bioRxiv2025

Evaluation of single-cell RNA profiling technologies using FFPE, fresh, and frozen ccRCC tumor specimens

The application of single-cell transcriptomic approaches has deepened our understanding of tumor heterogeneity, immune dynamics, and molecular programs underlying therapy response. The recent development of fixation-compatible single-cell platforms, such as 10x Genomics Flex, offers the opportunity to profile archived formalin-fixed, paraffin-embedded (FFPE) specimens, expanding access to clinically valuable samples. However, most benchmarking studies of recent single-cell RNA sequencing (scRNA-seq) technologies have relied on peripheral blood mononuclear cells, limiting their relevance to human tissues. Here, we compared three 10x single-cell RNA profiling methods, fresh tumor scRNA-seq, flash-frozen single-nucleus Multiome, and FFPE single-nucleus Flex (snFlex), using clear cell renal cell carcinoma (ccRCC) biopsies. Across methods, we observed broadly consistent cell type-specific transcriptional profiles among major ccRCC cell populations. Despite lower gene and UMI counts, snFlex reliably identified fine-grained states within CD8+ T cells, tumor-associated macrophages, and tumor compartments, comparable to those detected by scRNA-seq. Together, these findings highlight the distinct advantages of each technology depending on sample preservation type and study design, providing practical guidance for single-cell RNA profiling technology selection in translational studies using human tumor biopsies.

cancer biology↗

bioRxiv2025

Epigenetic dysregulation of metabolic programs mediates liposarcoma cell plasticity

Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) holds valuable insights into dysfunctional differentiation given its well- and dedifferentiated histologic subtypes (WDLPS, DDLPS). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human LPS samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 loss was associated with worse overall survival in LPS patients. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS led to a block in differentiation that could not be fully overcome with the addition of exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease.

cancer biology↗

bioRxiv2024

Single-cell epigenetic profiling reveals an interferon response-high program associated with BAP1 deficiency in kidney cancer

Renal cell carcinoma (RCC) is characterized by recurrent somatic mutations in epigenetic regulators, which stratify patients into clinically significant subgroups with distinct prognoses and treatment responses. However, the cell type-specific epigenetic landscape of RCC--broadly and in the context of these mutations--is incompletely understood. To investigate these open questions, we integrated single nucleus ATAC sequencing data from RCC tumors across four independent cohorts. In clear cell RCC tumors, we identified four shared malignant epigenetic programs related to angiogenesis, proximal tubule-like features, interferon (IFN) signaling, and one that lacked distinct genomic regions with increased accessibility. Among the mutated epigenetic regulators, BAP1 mutation exhibited the most significant impact on chromatin accessibility in tumor cells, and the associated epigenetic changes were linked to IFN response. We identify multiple potential sources of elevated IFN signaling in these lesions, such as increased immune infiltration and increased accessibility and expression of an IFN-associated ERV, ERV3-16A3_LTR. We find that the expression of ERV3-16A3_LTR may itself be a negative prognostic biomarker in ccRCC. Our findings highlight the convergence of malignant epigenetic programs across ccRCC tumors and suggest that BAP1 loss, potentially through ERV3-16A3_LTR dysregulation, is associated with an IFN response-high epigenetic program.

cancer biology↗

bioRxiv2022

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors (NETs) are rare cancers that may arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP) NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation and fate determination stages. While tumor and lymphoid compartments sparsely expressed immunosuppressive targets, infiltrating myeloid cells were enriched for alternative immunotherapy pathways including VSIR, Tim3/Gal9, and SIGLEC10. Finally, analysis of paired primary and metastatic tissue specimens from small intestinal NETs demonstrated transcriptional transformation between the primary tumor and its distant metastasis. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

cancer biology↗

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↗