Biology subjects

Lodillinsky, C.

Publications and source records attributed to Lodillinsky, C..

3 recordsLinked to original sources

bioRxiv2026

Thiosemicarbazone T2 suppresses WNT/β-catenin signaling and limits progression to invasive disease in a mouse intraductal model of triple-negative breast cancer

T2, an N4-aryl-substituted thiosemicarbazone, has previously been shown to exert cytotoxic and anti-invasive effects in triple-negative breast cancer (TNBC) and to increase expression of the metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1). Given the role of NDRG1 in regulating epithelial-mesenchymal transition (EMT) and WNT/{beta}-catenin signaling, we investigated the contribution of this pathway to the anti-invasive activity of T2. The effects of T2 on WNT/{beta}-catenin signaling and associated microRNAs (miR-182-5p and miR-200c) were evaluated in 4T1 cells. In vivo activity was assessed using a fully immunocompetent intraductal 4T1 mouse model that recapitulates the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Tumor progression, invasion, NDRG1 expression, and WNT/{beta}-catenin pathway components were analyzed. T2 reduced WNT/{beta}-catenin signaling and modulated the expression of miR-182-5p and miR-200c in vitro. In the MIND model, T2 decreased the frequency of invasive lesions and reduced {beta}-catenin, ZEB1, and c-Myc expression while increasing NDRG1 levels. {beta}-catenin localization differed between lesion types, showing predominantly membrane-associated staining in DCIS lesions and a diffuse cytoplasmic distribution in invasive foci. These findings identify WNT/{beta}-catenin signaling and NDRG1-associated pathways as potential mediators of the anti-invasive effects of T2 in TNBC. The reduction in invasive progression observed in the MIND model supports further investigation of this compound in preclinical models of TNBC.

cancer biology↗

bioRxiv2025

SPARC is a new driver of early breast tumor progression via TGF-β -dependent mechanism.

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor of invasive ductal carcinoma (IDC). The challenge lies in discriminating between DCIS progressors and DCIS non-progressors, often resulting in over- or under-treatment in many cases. Membrane type 1 (MT1)-matrix metalloproteinase (MMP) has been previously identified as an essential gene involved in DCIS progression. Here, RNA-sequencing analysis of MT1-MMPhigh subpopulation derived from invasive breast tumors in the intraductal xenograft model was compared against a dataset of human high-grade DCIS, and Secreted Protein Acidic and Cysteine Rich (SPARC) has emerged as a master candidate involved in early breast tumor progression. We report that SPARC is up-regulated in DCIS as compared to normal breast epithelial tissues, and further increased in IDC relative to synchronous DCIS foci. We found a positive correlation between SPARC and MT1-MMP expression in DCIS lesions. At the mechanistic level, depletion of SPARC reduced MT1-MMP expression, the degradative capacity of the cells and the activation of the TGF-{beta} signalling canonical pathway. Pharmacological inhibition of the TGF-{beta} signalling pathway decreased SPARC and MT1-MMP at the mRNA and protein level, and concomitantly the cell degradative capacity and 3D cell migration. Strikingly, inhibition of the TGF-{beta} signalling pathway limits the invasive transition of breast tumors in a new triple-negative mouse intraductal syngeneic xenograft model. Moreover, high SPARC expression was positively correlated with both, TGF-{beta} and its receptor, TGFBRI, in a basal type of breast cancer collection supporting our findings. This study identifies SPARC as a new driver of early breast tumor progression via a TGF-{beta}-dependent mechanism, suggesting TGF-{beta} signaling pathway as a potential target for patients with high SPARC expression.

cancer biology↗

bioRxiv2020

Compromised nuclear envelope integrity drives tumor cell invasion

While mutations leading to a fragile envelope of the cell nucleus are well known to cause diseases such as muscular dystrophies or accelerated aging, the pathophysiological consequences of the recently discovered mechanically induced nuclear envelope ruptures in cells harboring no mutation are less known. Here we show that repeated loss of nuclear envelope integrity in nuclei experiencing mechanical constraints promotes senescence in nontransformed cells, and induces an invasive phenotype including increased collagen degradation in human breast cancer cells, both in vitro and in a mouse xenograft model of breast cancer progression. We show that these phenotypic changes are due to the presence of chronic DNA damage and activation of the ATM kinase. In addition, we found that depletion of the cytoplasmic exonuclease TREX1 is sufficient to abolish the DNA damage in mechanically challenged nuclei and to suppress the phenotypes associated with the loss of nuclear envelope integrity. Our results also show that TREX1-dependent DNA damage induced by physical confinement of tumor cells inside the mammary duct drives the progression of in situ breast carcinoma to the invasive stage. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.

cell biology↗