⚙
AI-generated deep summary
by qwen3.7-flash, 2026-09-11
· read from full text
ⓘ
This study investigated how epithelial-mesenchymal transition (EMT) states influence cell cycle-dependent invadopodia formation and extracellular matrix degradation in human breast cancer cells. Researchers utilized TGFβ1 treatment and Slug overexpression to model different EMT stages, revealing that early hybrid cells degrade matrix primarily in the G2 phase while late hybrid and fully mesenchymal cells do so in G1. The analysis identified FILIP1L as a novel invadopodia component whose expression correlates with these invasive phases; notably, its absence increased matrix degradation but decreased overall migration and 3D spheroid invasion. High FILIP1L expression was also associated with poor prognosis in breast cancer patients, indicating its role in regulating tumor progression through cell cycle- and EMT-dependent mechanisms. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Invadopodia are actin- and protease-rich membrane structures that enable cancer cells to degrade extracellular matrix (ECM). Invadopodia activity is cell cycle-dependent, but how their regulation across the cell cycle is influenced by epithelial-to-mesenchymal transition (EMT) remains unclear. We show that as the EMT progresses, cell engagement in invadopodia-mediated ECM degradation shits from G2 phase in Early E/M cells to G1 phase in Late E/M or M cells. Using bulk mRNA sequencing of Early- versus Late- E/M cells sorted by cell cycle phase, we identified FILIP1L as an EMT- and cell cycle-regulated candidate whose expression peaks in the invasive phase of each cell state: G2 in Early E/M cells and G1 in Late E/M cells. We next demonstrated that FILIP1L is a novel invadopodia component, whose loss increases ECM degradation while impairing migration and 3D invasion. In mouse models, FILIP1L KD tumors develop fewer metastatic colonies, suggesting that FILIP1L supports productive invasion by coordinating between invadopodia and migratory cell states. FILIP1L expression increases with EMT progression and correlates with poor outcomes in breast cancer patients. Together, these findings identify a previously unrecognized link between EMT, cell cycle and invadopodia and establish FILIP1L as the key regulator of this process.
Full text
2,461 characters
· extracted from
oa-html
· click to expand
Summary
Invadopodia are actin- and protease-rich membrane structures present on metastatic cancer cells. We have previously shown that invadopodia-mediated ECM degradation is cell cycle-dependent. In mesenchymal human breast cancer cells, invadopodia degrade predominantly in G1 phase of the cell cycle. More recently, we have discovered that the hybrid epithelial/mesenchymal (E/M) metastatic cells also have the ability to assemble invadopodia. Here, we investigated how different EMT states affect the cell cycle regulation of invadopodia and invasion of breast cancer cells. Starting with the Early E/M cell line 4T1, we used TGFβ1 treatment to transition cells to a Late E/M state, or the induced Slug overexpression to achieve a fully mesenchymal (M) state, characterized by the complete loss of E-cadherin. We demonstrated that in Early E/M cells, invadopodia-mediated ECM degradation and invasion occur predominantly during the G2 phase, while Late E/M preferentially degrade ECM and invade during the G1, similarly to M cells. Moreover, when E cells are treated with TGFβ1, they transition to Early E/M state and degrade in G2 phase. To identify invadopodia components responsible for EMT- and cell cycle-dependent ECM degradation, we performed bulk mRNA sequencing of Early-versus Late-E/M cells in G1-or G2-phase of the cell cycle. The top candidate of our RNASeq analysis, FILIP1L, was expressed at significantly higher levels during G2 phase in Early E/M cells and during G1 phase in Late E/M cells, matching the invasive phase of each cell population. Expression of FILIP1L is upregulated in cells transitioning from E/M to M state. We next demonstrate FILIP1L is a novel invadopodia component, which colocalizes with Tks5 and cortactin. In the absence of FILIP1L expression, ECM degradation is significantly increased. Meanwhile, cell migration is significantly decreased, resulting in an overall decrease in the 3D spheroid invasion. Finally, we demonstrate that the high expression of FILIP1L is associated with poor prognosis in breast cancer patients. In summary, FILIP1L is a novel invadopodia component which regulates breast cancer invasion and tumor progression in a cell cycle– and EMT–dependent manner by controlling invadopodia and motility of cancer cells.
Full Text Availability
The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.
Text is read by the "Ask this paper" AI Q&A widget below.
Extraction quality varies by source — PMC NXML preserves structure
cleanly, OA-HTML may include some navigation residue, and OA-PDF can
have broken hyphenation. The publisher copy
(via DOI)
is the canonical version.