Biology subjects

Beane, J.

Publications and source records attributed to Beane, J..

10 recordsLinked to original sources

bioRxiv2026

Non-Genetic Mechanisms of Fractional Resistance to Abemaciclib in Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma is a rare mesenchymal malignancy driven by amplification of chromosome 12q13-15, which includes the oncogenes CDK4 and MDM2. CDK4 amplification provides a rationale for targeted therapy with CDK4/6 inhibitors, and abemaciclib has shown the most durable activity reported to date in this disease. Clinical responses, however, are incomplete and often transient, and the cellular features that allow tumor cells to continue proliferating during treatment are not well understood. To address this gap, we performed multiplexed single-cell imaging to quantify 17 cell-cycle regulators in both dedifferentiated liposarcoma cell line Lipo246 and surgically resected primary human cells exposed to abemaciclib. Both models contained a subpopulation of cells that retained phosphorylated retinoblastoma protein, a marker of cell proliferation, at the highest abemaciclib doses. These fractionally resistant cells were defined by selective enrichment of cyclin-dependent kinase 2 (CDK2), cyclin B1, and phosphorylated ribosomal protein S6 (pS6), and showed enhanced sensitivity to the CDK2 inhibitor, tagtociclib. Together, these findings reveal nongenetic cell cycle plasticity as a mechanism of escape from CDK4/6 inhibition in dedifferentiated liposarcoma and nominate CDK2 and the PI3K-mTOR pathway as candidate targets for combination therapy.

cancer biology↗

bioRxiv2025

Upregulation of GREB1 in colorectal cancer ovarian metastases may be a potential therapeutic target

IntroductionClassification of ovarian metastases (OM) in colorectal cancer (CRC) as peritoneal metastasis (PM) remains controversial. OM demonstrate resistance to systemic therapy, suggesting distinct molecular tumorigenesis. Gene expression profiling and transcriptomic analysis were performed to distinguish OM, PM, and primary CRC (pCRC) and identify potential therapeutic targets. MethodsRNA sequencing data were obtained from the Total Cancer Care database. After filtering out low-expressed genes, raw counts of retained genes were normalized in trimmed mean of M-values and then log2-transformed. Genes with a |Log2FC|>0.58 and adjusted p-value <0.05 were considered dysregulated. In silico motif enrichment analysis of estrogen receptor 1 (ESR1) on growth regulating estrogen receptor binding 1 (GREB1) was conducted. ResultsThere were 115 patients with tissue from OM (n=6), PM (n=4), and pCRC (n=105). Among upregulated genes, LAMC3, SCUBE1, and GREB1 had the highest differential expression in OM compared to PM, and PEG3, C7, and GREB1 had the highest differential expression in OM compared to pCRC (all p<0.001). GREB1 was upregulated in OM compared to PM and pCRC. There are two estrogen response element (ERE) sites within the promoter region of GREB1. ESR1 transcription factor was shown to bind to these ERE (p<0.001). ConclusionsTranscriptomic analysis demonstrated clear molecular distinction between OM, PM and pCRC. We identified upregulation of GREB1 in OM compared to PM and pCRC. GREB1 contains both ERE and ESR1 in the upstream promoter regions implying potential upstream transcription regulation mediated by ESR1. GREB1 may represent a novel, hormonal target in treatment of OM in CRC.

cancer biology↗

bioRxiv2025

An atlas of gene programs in non-small cell lung cancer delineates novel patterns of lineage vacillation, plasticity, and aggressiveness

Combinations of molecular programs can be altered in cancer cells and contribute to tumor initiation and aggressiveness. We developed a novel framework called a Gene Program Association Study (GPAS) to create an atlas of gene co-expression modules in cancer cells from 127 primary non-small-cell-lung cancers (NSCLCs) and determine their association with clinical and histopathological features. Lung adenocarcinoma (LUAD) displayed "lineage vacillation" defined by extensive heterogeneity of modules from different alveolar cell types. Modules associated with late-stage LUAD were found in cells from early-stage tumors suggesting that aggressive phenotypes can be observed before clinical progression. Basal- and squamous-like intermediate cells were observed in the transition to invasive mucinous LUAD. In lung squamous cell carcinoma, a novel subtype was identified with lower levels of canonical squamous modules and higher levels of fibrinogen. Overall, this atlas elucidated the combinations of molecular programs in cancer cells that contribute to heterogeneity and aggressiveness in NSCLC. Statement of SignificanceWe performed a Gene Program Association Study (GPAS) to create an atlas of gene modules in cancer cells from NSCLCs. This atlas revealed extensive lineage vacillation, combinations of modules that defined late-stage disease, novel routes of lineage plasticity, and novel subtypes in lung adenocarcinoma or lung squamous cell carcinoma.

bioinformatics↗

bioRxiv2025

TWIST1 mediated transcriptional activation of SPON2 drives colorectal peritoneal metastasis through activation of cancer-associated fibroblast signaling network

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality in the United States. Peritoneal metastasis (PM), a malignant dissemination within the peritoneal cavity, affects approximately 20% of CRC patients and accounts for 25-35% of stage IV cases. CRC PM is associated with dismal outcomes, with a median overall survival of only 16 months on systemic chemotherapy and an almost 0% five-year survival rate, largely due to frequent treatment resistance and limited therapeutic options. Despite advances in understanding CRC metastasis, the molecular mechanisms driving CRC PM remain poorly defined. CRC heterogeneity is classified into four Consensus Molecular Subtypes (CMS1-4), with CRC PM tumors predominantly exhibiting the CMS4 signature--characterized by stromal enrichment, high mesenchymal gene expression, and enhanced cellular plasticity--features linked to aggressive disease progression and resistance to standard chemotherapy. In this study, we identify TWIST1, a basic helix-loop-helix transcription factor, as significantly upregulated in CRC PM. We establish TWIST1-SPON2 as a novel transcriptional axis driving CRC PM tumorigenesis, mediating tumor-stroma interactions between tumor epithelium and cancer-associated fibroblasts (CAFs). Additionally, we identify SPP1, secreted by CAFs, as an upstream regulator of the TWIST1-SPON2 cascade via AKT activation in tumor cells. This newly defined SPP1-TWIST1-SPON2 signaling circuit plays a pivotal role in shaping the tumor microenvironment and promoting CRC PM progression. The findings establish the SPP1-TWIST1-SPON2 axis as a potential biomarker and a promising therapeutic target in CRC PM. Keyword: Colorectal cancer, peritoneal metastasis, epithelial-mesenchymal transition, cancer-associated fibroblast

cancer biology↗

bioRxiv2024

FourierMIL: Fourier filtering-based multiple instance learning for whole slide image analysis

Recent advancements in computer vision, driven by convolutional neural network, multilayer perceptron and transformer architectures, have significantly improved the analysis on natural images. Despite their potential, the application of these architectures in digital pathology, specifically for analyzing gigapixel-resolution whole-slide images (WSIs), remains challenging due to the extensive and variable sizes of these images. Here we present a multiple instance learning framework that leverages the discrete Fourier transform and learns from WSIs. Dubbed as FourierMIL, our framework is designed to capture both global and local dependencies within WSIs. To validate the efficacy of our model, we conducted extensive experiments on a prevalent computational pathology challenge: tumor classification. Our results demonstrate that FourierMIL outperforms existing state-of-the-art methods, marking a significant advancement in the field of digital pathology and highlighting the potential of attention-free architectures in managing the complexities related to WSI analysis. The code will be released for public access upon the manuscripts acceptance.

bioinformatics↗

bioRxiv2024

Identification of a gene expression signature of vascular invasion and recurrence in stage I lung adenocarcinoma via bulk and spatial transcriptomics

Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection specimens and cannot be accurately predicted prior to surgery. Thus, new biomarkers are needed to identify this aggressive subset of stage I LUAD tumors. To assess molecular and microenvironment features associated with angioinvasive LUAD we profiled 162 resected stage I tumors with and without VI by RNA-seq and explored spatial patterns of gene expression in a subset of 15 samples by high-resolution spatial transcriptomics (stRNA-seq). Despite the small size of invaded blood vessels, we identified a gene expression signature of VI from the bulk RNA-seq discovery cohort (n=103) and found that it was associated with VI foci, desmoplastic stroma, and high-grade patterns in our stRNA-seq data. We observed a stronger association with high-grade patterns from VI+ compared with VI- tumors. Using the discovery cohort, we developed a transcriptomic predictor of VI, that in an independent validation cohort (n=60) was associated with VI (AUROC=0.86; p=5.42x10-6) and predictive of recurrence-free survival (HR=1.98; p=0.024), even in VI- LUAD (HR=2.76; p=0.003). To determine our VI predictors robustness to intra-tumor heterogeneity we used RNA-seq data from multi-region sampling of stage I LUAD cases in TRACERx, where the predictor scores showed high correlation (R=0.87, p<2.2x10-16) between two randomly sampled regions of the same tumor. Our study suggests that VI-associated gene expression changes are detectable beyond the site of intravasation and can be used to predict the presence of VI. This may enable the prediction of angioinvasive LUAD from biopsy specimens, allowing for more tailored medical and surgical management of stage I LUAD.

cancer biology↗

bioRxiv2022

Interrogating the Precancerous Evolution of Pathway Dysfunction in Lung Squamous Cell Carcinoma Using XTABLE

Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE, an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two and multiple group comparisons, interrogation of genes of interests and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.

bioinformatics↗

bioRxiv2020

Single-cell characterization of subsolid and solid lesions in the lung adenocarcinoma spectrum

Determining the clinical significance of CT scan-detected subsolid pulmonary nodules requires an understanding of the molecular and cellular features that may foreshadow disease progression. We studied the alterations at the transcriptome level in both immune and non-immune cells, utilizing single-cell RNA sequencing, to compare the microenvironment of subsolid, solid, and non-involved lung tissues from surgical resection specimens. This evaluation of early spectrum lung adenocarcinoma reveals a significant decrease in the cytolytic activities of natural killer and natural killer T cells, accompanied by a reduction of effector T cells as well as an increase of CD4+ regulatory T cells in subsolid lesions. Characterization of non-immune cells revealed that both cancer-associated alveolar type 2 cells and fibroblasts contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid lesions through ligand-receptor interactions. These findings suggest a decrement of immune surveillance in subsolid lesions.

cancer biology↗

bioRxiv2018

Characterizing smoking-induced transcriptional heterogeneity in the human bronchial epithelium at single-cell resolution

The human bronchial epithelium is composed of multiple, distinct cell types that cooperate to perform functions, such as mucociliary clearance, that defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, the precise effects of this exposure on specific cell types are not well-understood. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never- and six current smokers. Unsupervised analyses identified thirteen cell clusters defined by unique combinations of nineteen distinct gene sets. Expression of a set of toxin metabolism genes localized to ciliated cells from smokers. Smoking-induced airway remodeling was characterized by a loss of club cells and extensive goblet cell hyperplasia. Finally, we identified a novel peri-goblet epithelial subpopulation in smokers that expressed a marker of bronchial premalignant lesions. Our data demonstrates that smoke exposure drives a complex landscape of cellular and molecular alterations in the human bronchial epithelium that may contribute to the onset of smoking-associated lung diseases.

genomics↗

bioRxiv2018

Molecular Subtyping reveals Immune Alterations associated with Progression of Bronchial Premalignant Lesions

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at highest risk for progression to invasive cancer. Profiling endobronchial biopsies of PMLs obtained from high-risk smokers by RNA-Seq identified four PML subtypes with differences in epithelial and immune processes. One molecular subtype (Proliferative) is enriched with dysplastic lesions and exhibits up-regulation of metabolic and cell cycle pathways and down-regulation of ciliary processes. RNA-Seq profiles from normal-appearing uninvolved large airway brushings could identify subjects with Proliferative lesions with high specificity. Expression of interferon signaling and antigen processing/presentation pathways are decreased in progressive/persistent Proliferative lesions and immunofluorescence indicates a depletion of innate and adaptive immune cells in these lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggests that immunoprevention strategies may be effective in intercepting the progression of PMLs to lung cancer.

cancer biology↗