Biology subjects

Turnbull, A. K.

Publications and source records attributed to Turnbull, A. K..

3 recordsLinked to original sources

bioRxiv2026

Deciphering the association of spatial landscapes of DCIS with recurrence as invasive breast cancer

Stromal cell composition has been proposed as a potential biomarker in ductal carcinoma in situ (DCIS) for assessing the risk of subsequent recurrence or progression to invasive breast cancer (IBC). However, the characteristics of the tumor microenvironment within DCIS associated with these outcomes remain poorly understood. Here, we perform spatial transcriptomic analyses of 49 primary DCIS specimens from patients with no recurrence, DCIS recurrence, or recurrence as IBC. Cell mapping reveals spatially organized stromal cell gradients within DCIS, with enrichment of TREM2+ macrophages and myofibroblastic cancer-associated fibroblasts (myCAFs) in tumor-proximal niches. Notably, the abundance of TREM2+ macrophages near tumor nests is associated with subsequent recurrence as IBC. Moreover, ligand-receptor pair analysis identifies GRN--SORT1, SPP1--CD44, and LGALS9--CD44 interactions as spatially plausible signaling interactions between TREM2+ macrophages and epithelial cells. Finally, these findings are validated at the protein level by multiplex immunostaining of serial sections. This study characterizes the spatial landscape of the DCIS tumor microenvironment associated with subsequent recurrence, providing a basis for developing biomarkers of disease progression and identifying potential therapeutic targets.

cancer biology↗

bioRxiv2020

Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

BackgroundInvasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance. MethodsWe used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast. Results45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets. PAPPA was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. PAPPA encodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis of PAPPA and IGF1 associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identified PAPPA as a potential ILC-specific prognostic marker. ConclusionsThis is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.

cancer biology↗

bioRxiv2018

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

BackgroundThe risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate, previous efforts have been limited to in vitro or in vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant endocrine treatment were characterised as a novel clinical model.\n\nMethodsConsecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor, letrozole, therapy were subjected to transcriptomic and proteomic analysis, representing before ([≤]0), early-on (13-120 days) and long-term (>120 days) neoadjuvant letrozole treatment. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as \"dormant\", and the remaining 20 patients as \"acquired resistant\".\n\nResultsChanges in gene expression in dormant tumours begin early and become more pronounced at later timepoints. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared to dormant tissues after extended letrozole treatment.\n\nConclusionsThis is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients supporting a potential role for therapy targeted at these epigenetic alterations in the management of endocrine resistant breast cancer.

cancer biology↗