TAOK3 marks an invasion‑competent epithelial subset in cervical cancer, and its inhibition restrains tumor growth, sensitizes to paclitaxel, and remodels the immune microenvironment
Year: 2026
Type: preprint
Abstract: TAOK3 is a lesser-studied MAPK family serine/threonine kinase our group has shown to be targeted by HPV integration, suggesting a potential role in driving invasive cervical cancer (ICC). Here, we profiled TAOK3 expression in patient tumors, metastases, and cervical cancer models and localized TAOK3 within a tumor epithelial subpopulation by integrating two single-cell RNA-seq datasets. Functional consequences of TAOK3 loss were assessed with siRNA and CRISPRi in cell lines and 3D spheroids. In vivo effects were evaluated in intracervical xenografts with species-specific RNA-seq to resolve tumor versus microenvironmental responses. TAOK3 mRNA/protein were elevated in primary and metastatic ICC and primarily localized to a keratin-positive epithelial subset (T3epi) enriched for cadherin/S100 binding, vesicle/endocytic pathways, and leading-edge programs. TAOK3 silencing reprogrammed transcriptomes and proteomes toward reduced WNT/cell-cycle and motility signaling, altered endocytosis and cytoskeleton organization, and reshaped phospho-networks linked to chromatin remodeling and ERBB2–ERBB3/cytoskeletal kinase activity. Functionally, TAOK3 inhibition prolonged G2/M, suppressed invasion, and enhanced sensitivity to low dose paclitaxel. Prolonged inactivation induced methuosis-like cell death with extracellular ATP release. In xenografts, TAOK3 knockdown reduced tumor burden, downregulated KRT14 —a leader cell marker—within the human tumor compartment, and enriched microenvironmental pathways for immune activation, with a specific decrease in CD206 + M2 macrophages. TAOK3 delineates a putative leader cell state (T3epi) in ICC and coordinates cell-cycle control, cytoskeleton–membrane dynamics, and tumor–immune crosstalk. Genetic or pharmacologic TAOK3 inhibition constrains tumor growth, potentiates paclitaxel, and remodels the microenvironment toward anti-tumor immunity, supporting TAOK3 as a potential therapeutic target and biomarker in ICC.
Source: Research Square
Authors: Marissa Iden, Rachel Schmidt, Rameesa Darul Amne Syed Mohammed, Theresa A. Dlugi, Roshan Kumar, Shirng-Wern Tsaih, Bakhtiyor Nosirov, Ishaque P. Kadamberi, Sonam Mittal, Shruti L. Narayan, William H. Bradley, Beth Erickson, Rebecca C. Czaja, Juan C. Felix, Victor Jin, Akinyemi I. Ojesina, Sunila Pradeep, Brian C. Smith, Janet S. Rader
Institution: Medical College of Wisconsin
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212584339