Biology subjects

Heselmeyer-Haddad, K.

Publications and source records attributed to Heselmeyer-Haddad, K..

5 recordsLinked to original sources

bioRxiv2025

Dual inhibition of EGFR and PI3Kinase signaling in EGFR amplified triple negative breast cancer cells induces apoptosis and reduces tumor growth

EGFR family receptor tyrosine kinase signaling is commonly dysregulated in cancer by amplification or activating mutations. Although studies have investigated dual EGFR/PI3K inhibition in breast cancer, they have not determined biomarkers which predict success. We present evidence of a patient subset with EGFR amplification and PI3Kinase pathway mutations in breast cancer which can be synergistically targeted by dual EGFR/PI3K inhibition. This study identified that EGFR amplification occurs in approximately 1-5% of breast cancer patients with shorter overall survival compared to unamplified patients. Up to 71% of EGFR amplified tumors have activating mutations in the PI3K pathway. Dual EGFR/PI3K inhibition more dramatically reduced mTOR and AKT signaling in BT20 and MDA-MB-468 cells which both have EGFR amplification and PI3K pathway activating mutations, compared to control cells. Dual inhibition synergistically reduced cell viability and increased apoptosis in MDA-MB-468 and BT20 compared to control. Single agent therapy in a BT20 xenograft model reduced tumor volume, however only the combination statistically significantly reduced tumor volume compared to control. We conclude that EGFR amplification with co-incident PI3K pathway mutations are driver mutations in a subset of breast cancers and present a subgroup of breast cancers that are more likely to respond to dual targeted therapy.

cancer biology↗

bioRxiv2025

Genome reorganization and its functional impact during breast cancer progression

Cancer progression involves extensive alterations in epigenetic and gene expression programs, but the accompanying changes in higher-order genome organization remain less well understood. Using high-resolution Micro-C mapping in the MCF10 cell model of breast cancer, we profiled chromatin compartments, topologically associated domains, and chromatin loops. We find large-scale compartmental shifts occur predominantly in early stages of cancer development, with more fine-scale structural changes in TADs and looping accumulating during the later transition to metastasis. Relating these chromatin features to gene expression and enhancer-associated histone marks revealed that many differentially expressed genes are physically connected to distal regulatory elements. While enhancer-promoter contact frequency and distal enhancer activity correlated with gene expression, strong changes in chromatin looping were relatively infrequent during progression, suggesting that alterations in chromatin contacts are not globally necessary but may facilitate gene regulation at a subset of genes. These results elucidate the connection between gene regulation and genome remodeling in a cell-based cancer progression model.

genomics↗

bioRxiv2021

TP53 loss initiates chromosomal instability in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). While the direct causes of CIN are errors during DNA replication and/or chromosome segregation, mutations in genes encoding DNA replication and mitotic factors are rare in HGSOC. Thus, the drivers of CIN remain undefined. We therefore asked whether the oncogenic lesions that are frequently observed in HGSOC are capable of driving CIN via indirect mechanisms. To address this question, we genetically manipulated non-transformed hTERT-immortalized human fallopian tube epithelial cells to model homologous recombination deficiency (HRD) and oncogenic signalling in HGSOC. Using CRISPR/Cas9-mediated gene editing, we sequentially mutagenized the tumour suppressors TP53 and BRCA1, followed by overexpression of the MYC oncogene. Single-cell shallow-depth whole-genome sequencing revealed that loss of p53 function was sufficient to lead to the emergence of heterogenous karyotypes harbouring whole chromosome and chromosome arm aneuploidies, a phenomenon exacerbated by subsequent loss of BRCA1 function. In addition, whole-genome doubling events were observed in independent p53/BRCA1-deficient subclones. Global transcriptomics showed that TP53 mutation was also sufficient to deregulate gene expression modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function, suggesting that p53-deficiency induces cell cycle distortions that could precipitate CIN. Again, loss of BRCA1 function and MYC overexpression exacerbated these patterns of transcriptional deregulation. Thus, our observations support a model whereby the initial loss of the key tumour suppressor TP53 is sufficient to deregulate gene expression networks governing multiple cell cycle controls, and that this in turn is sufficient to drive CIN in pre-malignant fallopian tube epithelial cells. SUMMARY STATEMENTHigh-grade serous ovarian cancer is defined by TP53 mutation and chromosomal instability, the cause of which remains poorly understood. We developed a novel model system that implicates cell cycle deregulation upon p53-loss as cause of CIN.

cancer biology↗

bioRxiv2020

Tumor heterogeneity assessed by sequencing and fluorescence in situ hybridization (FISH) data

Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation (SV) events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate. In the present work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization (miFISH) to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. We demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence, and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data. Availabilitygithub.com/CMUSchwartzLab/FISH_deconvolution Contactrussells@andrew.cmu.edu

bioinformatics↗

bioRxiv2019

Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin

Most carcinomas have characteristic chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is unknown. As aneuploidies directly affect gene expression, we hypothesized that cancer-type specific aneuploidies, which emerge at early stages of tumor evolution, confer adaptive advantages to the physiological requirements of the tissue of origin. To test this hypothesis, we compared chromosomal aneuploidies reported in the TCGA database to chromosome arm-wide gene expression levels of normal tissues from the GTEx database. We find that cancer-type specific chromosomal aneuploidies mirror differential gene expression levels specific to the respective normal tissues which cannot be explained by copy number alterations of resident cancer driver genes. We propose that cancer-type specific aneuploidies "hard-wire" chromosome arm-wide gene expression levels present in normal tissues, favoring clonal expansion and tumorigenesis. One sentence summaryThe clonal evolution of cancer is initiated by tissue-specific transcriptional requirements

cancer biology↗