Biology subjects

Liby, T. A.

Publications and source records attributed to Liby, T. A..

3 recordsLinked to original sources

bioRxiv2025

Oncostatin M orchestrates collective epithelial migration via HIF1A activation

Extracellular signals strongly influence cell behavior, yet the mechanisms by which specific ligands mediate changes in phenotype remain unclear. The cytokine Oncostatin M (OSM) regulates homeostasis, wound healing, inflammation, and cancer progression. We previously found that OSM induces collective cell migration (CCM), a process where cells move as cohesive units while retaining cell-cell contacts, in MCF10A mammary epithelial cells. Here, we investigated how OSM drives CCM by comparing its effects with those elicited by epidermal growth factor (EGF) and interferon gamma (IFNG), defining ligand-specific phenotypes and molecular networks. Integrative transcriptomic and proteomic analyses identified hypoxia-inducible factor-1 (HIF1A) and signal transducer and activator of transcription 3 (STAT3) as central regulators of OSM responses. Functional validation revealed that HIF1A drives transcriptional programs associated with hypoxia, metabolic reprogramming, and immune pathways. Complement signaling emerged as a downstream effector of HIF1A, and its inhibition disrupted OSM-induced clustering and CCM. These findings establish a mechanistic link between OSM signaling, HIF1A activation, and CCM, demonstrating how cytokine-driven transcriptional reprogramming coordinates epithelial migration. Analysis of public breast cancer data suggests this pathway is active in human tumors and may contribute to tissue remodeling, repair, and metastasis.

cell biology↗

bioRxiv2025

Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." We document neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and are enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation protein by neoplastic cells confers a proliferative advantage that facilitates early tumor growth and therefore conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in additional breast cancer cohorts to determine its potential for patient stratification. Future research should evaluate correlates with distal metastases, progression-free survival, overall survival, and therapeutic response/resistance. Statement of SignificanceNeoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

cancer biology↗

bioRxiv2024

TNBC response to paclitaxel phenocopies interferon response which reveals cell cycle-associated resistance mechanisms

Paclitaxel is a standard of care neoadjuvant therapy for patients with triple negative breast cancer (TNBC); however, it shows limited benefit for locally advanced or metastatic disease. Here we used a coordinated experimental-computational approach to explore the influence of paclitaxel on the cellular and molecular responses of TNBC cells. We found that escalating doses of paclitaxel resulted in multinucleation, promotion of senescence, and initiation of DNA damage induced apoptosis. Single-cell RNA sequencing (scRNA-seq) of TNBC cells after paclitaxel treatment revealed upregulation of innate immune programs canonically associated with interferon response and downregulation of cell cycle progression programs. Systematic exploration of transcriptional responses to paclitaxel and cancer-associated microenvironmental factors revealed common gene programs induced by paclitaxel, IFNB, and IFNG. Transcription factor (TF) enrichment analysis identified 13 TFs that were both enriched based on activity of downstream targets and also significantly upregulated after paclitaxel treatment. Functional assessment with siRNA knockdown confirmed that the TFs FOSL1, NFE2L2 and ELF3 mediate cellular proliferation and also regulate nuclear structure. We further explored the influence of these TFs on paclitaxel-induced cell cycle behavior via live cell imaging, which revealed altered progression rates through G1, S/G2 and M phases. We found that ELF3 knockdown synergized with paclitaxel treatment to lock cells in a G1 state and prevent cell cycle progression. Analysis of publicly available breast cancer patient data showed that high ELF3 expression was associated with poor prognosis and enrichment programs associated with cell cycle progression. Together these analyses disentangle the diverse aspects of paclitaxel response and identify ELF3 upregulation as a putative biomarker of paclitaxel resistance in TNBC.

cancer biology↗