Biology subjects

Weitsman, G.

Publications and source records attributed to Weitsman, G..

3 recordsLinked to original sources

bioRxiv2026

TOPII-targeting and MUS81 deficiency sensitise HER2-low tumour models to T-DXd

In this study, we identify Topoisomerase II (TopII ) targeting and MUS81 deficiency as sensitisers to trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate with a potent topoisomerase I poison payload that is of clinical importance in the treatment of HER2 expressing solid tumours in a range of cancer types. Using preclinical tumour spheroid models of breast and colorectal cancer, we show that TopII targeting with doxorubicin sensitises HER2-low tumour cells to T-DXd, elevating cell cytotoxicity, DNA damage, and checkpoint pathway activation. T-DXd treatment, both as a single agent and in combination with doxorubicin, increases TopII expression, highlighting this nuclear endonuclease as a potential candidate biomarker for T-DXd response in both the HER2-high and HER2-low setting. Using isogenic CRISPR models, we show that genetic loss of the MUS81 structure-specific endonuclease, a key processor of branched DNA structures and under-replicated DNA, sensitises HER2-low colorectal cancer cells to T-DXd. Given that reduced expression of MUS81 is closely related to metastasis and poor prognosis in colorectal carcinoma, our findings highlight the potential utility of these treatment combinations in a subset of colorectal cancer patients that present with HER2-positve/MUS81-low disease.

cancer biology↗

bioRxiv2024

Loss of TLR9 expression in breast cancer tumour cells and its role in the cell cycle.

Toll-like receptor 9 (TLR9), primarily expressed in human dendritic and B cells, recognizes double-stranded DNA motifs from pathogens, initiating an inflammatory response. Recent studies have revealed TLR9s involvement beyond its conventional role in immune response, notably during the tumorigenesis of various cancers such as head and neck, cervical, and ovarian cancers. Here we show by immunohistochemistry analysis demonstrated significantly lower TLR9 levels in breast cancer tumors compared to normal breast tissue epithelium. Similarly, TLR9 downregulation was also observed in several transformed breast cancer cell lines versus untransformed breast epithelial cell lines. Furthermore, overexpression of TLR9 led to reduced proliferation potential of breast cancer cell associated with activation of senescence as was evident by upregulation of proinflammatory cytokine IL-6, chemokines IL-8 and CXCL1; and growth factor GM-CSF. These findings support TLR9s regulatory role in mitigating breast cancer and highlight its critical connection between the inflammatory response and tumor immunity.

cell biology↗

bioRxiv2021

RUNIMC: An R-based package for imaging mass cytometry data analysis and pipeline validation

We propose a novel pipeline for the analysis of imaging mass cytometry data, comparing an unbiased approach, representing the actual gold standard, with a novel biased method. We made use of both synthetic/ controlled datasets as well as two datasets obtained from FFPE sections of follicular lymphoma, and head and neck patients, stained with a 14 and 29-markers panels respectively. The novel pipeline, denominated RUNIMC, has been completely developed in R and contained in a single package. The novelty resides in the ease with which multi-class random forest classifier can be used to classify image features, making the pathologists and expert classification pivotal, and the use of a random forest regression approach that permits a better detection of cell boundaries, and alleviates the necessity of relying on a perfect nuclear staining.

cancer biology↗