Biology subjects

Sflomos, G.

Publications and source records attributed to Sflomos, G..

3 recordsLinked to original sources

bioRxiv2025

LOX inhibition disrupts a collagen-integrin-MYC axis as a translatable targeting strategy in invasive lobular carcinoma

Invasive lobular carcinoma (ILC) accounts for 15% of breast cancers yet lacks specific therapy because ILCs are underrepresented in clinical trials and preclinical models are lacking. We established intraductal xenograft models to test whether the clinical pan-lysyl-oxidase PXS-5505, now in phase trials for myelofibrosis can exploit the collagen-rich matrix dependency created by CDH1 loss. PXS-5505 remodels fibrillar collagen, and halts tumor expansion and metastatic seeding across ER+ and triple negative models without systemic toxicity. Genome-wide CRISPR screens reveal ITGAV and ITGB5 as synthetic lethal partners of CDH1 and LOX inhibition downregulates their expression together with MYC, NF-{kappa}B, and AP-1 transcriptional programmes. Collagen fibre density/alignment, and MYC/AP-1 gene signatures serve as pharmacodynamic readouts of drug activity. These data uncover a tractable ECM-integrin-MYC axis in ILC and nominate PXS-5505, alone or with endocrine therapy, for window of opportunity trials in this understudied breast cancer subtype. One Sentence SummaryTargeting matrix remodelling in ILC inhibits ILC progression and alters multiple molecular endpoints, providing a translatable therapeutic strategy for this understudied subtype that requires better treatments.

cancer biology↗

bioRxiv2021

Epithelial-mesenchymal plasticity determines estrogen receptor positive (ER+) breast cancer dormancy and reacquisition of an epithelial state drives awakening

Estrogen receptor -positive (ER+) breast cancers (BCs) represent more than 70% of all breast cancers and pose a particular clinical challenge because they recur up to decades after initial diagnosis and treatment. The mechanisms governing tumor cell dormancy and latent disease remain elusive due to a lack of adequate models. Here, we compare tumor progression of ER+ and triple-negative (TN) BC subtypes with a clinically relevant mouse intraductal xenografting approach (MIND). Both ER+ and TN BC cells disseminate already during the in situstage. However, TN disseminated tumor cells (DTCs) proliferate at the same rate as cells at the primary site and give rise to macro-metastases. ER+ DTCs have low proliferative indices, form only micro-metastases and lose epithelial characteristics. Expression of CDH1 is decreased whereas the mesenchymal marker VIM and the transcription factors, ZEB1/ZEB2, which control epithelial-mesenchymal plasticity (EMP) are increased. EMP is not detected earlier during ER+ BC development and not required for invasion or metastasis. In vivo, forced transition to the epithelial state through ectopic E-cadherin expression overcomes dormancy with increased growth of lung metastases. We conclude that EMP is essential for the generation of a dormant cell state and the development of latent disease. Targeting exit from EMP is of therapeutic potential.

cancer biology↗

bioRxiv2018

Intraductal patient derived xenografts of estrogen receptor positive breast cancer recapitulate the histopathological spectrum and metastatic potential of human lesions

Estrogen receptor positive (ER+) or \"luminal\" breast cancers were notoriously difficult to establish as patient-derived xenografts (PDXs). We and others recently demonstrated that the microenvironment is critical for ER+ tumor cells; by grafting them into milk ducts >90% take rates are achieved and many features of the human disease are recapitulated. This intra-ductal (ID) approach holds promise for personalized medicine, yet human and murine stroma are organized differently and this and other species specificities may limit the value of this model. Here, we analyzed 21 ER+ ID-PDXs histopathologically. We find that ID-PDXs vary in extent and define four histopathological patterns: flat, lobular, in situ, and invasive, which occur in pure and combined forms. The ID-PDXs replicate earlier stages of tumor development than their clinical counterparts. Micrometastases are already detected when lesions appear in situ. Tumor extent, histopathological patterns, and metastatic load correlate with biological properties of their tumors of origin. Our findings add evidence to the validity of the intraductal model for in vivo studies of ER+ breast cancer and raise the intriguing possibility that tumor cell dissemination may occur earlier than currently thought.\n\nConflict of interest statementThe authors declare no conflict of interest.

cancer biology↗