Biology subjects

Gammon, L.

Publications and source records attributed to Gammon, L..

4 recordsLinked to original sources

bioRxiv2025

SAMP-Score: A morphology-based machine learning classification method for screening pro-senescence compounds in p16 positive cancer cells

BackgroundSenescence identification is rendered challenging due to a lack of universally available biomarkers. This represents a bottleneck in efforts to develop pro-senescence therapeutics - agents designed to induce the arrest of cellular proliferation associated with a senescence response in cancer cells for therapeutic gain. This is particularly true in contexts such as basal-like breast cancer (BLBC), which often express high levels of widely reported senescence hallmarks, which has led to the designation of these subtypes as senescence marker positive (Sen-Mark+). Unfortunately, these are often cancers with the most limited treatment options, where novel pro-senescence compounds would be of potential clinical utility. ResultsTo address these challenges, we have developed SAMP-Score, a machine learning classification tool for identifying senescence induction in Sen-Mark+ cancers. This technique builds upon our previous observation that senescent cells develop distinct senescence-associated morphological profiles (SAMPs), which can be assessed readily in traditionally challenging contexts for senescence identification, including high-throughput screens. ConclusionsThrough application of SAMP-Score, we have identified QM5928, a novel pro-senescence compound, that is able to induce senescence in a variety of Sen-Mark+ cancers and has potential utility as a tool molecule to explore the mechanisms and pathways through which senescence induction occurs in these cells.

cancer biology↗

bioRxiv2023

A CD24+CD271+ melanoma cancer stem cell generates a diffuse hierarchy of attributes that promote metastasis and therapeutic resistance

An important role for phenotype switching has been demonstrated in metastasis and therapeutic resistance of both melanoma and epithelial tumours. Phenotype switching in epithelial tumours is driven by a minority cancer stem cell sub-population with lineage plasticity, but such a sub-population has not been identified in melanoma. We investigated whether cell surface markers used to identify cancer stem cells in epithelial tumours could identify a cancer stem cell sub-population with lineage plasticity in melanoma. We identified a CD24+CD271+ minority sub-population in melanoma that possesses the stem cell characteristics of lineage plasticity and self-renewal. This population displayed hybrid characteristics, combining the attributes of discrete CD24+ and CD271+ cellular sub-populations but with heightened sphere formation, lineage plasticity, migratory ability and drug resistance over its single-marker counterparts. CD24+ and CD24+CD271+ stem cell sub-populations were observed in 10% of human melanomas, mainly at the invasive front. The lack of CD24+ and CD24+CD271+ stem cells in the majority of human melanoma specimens led us to conclude that they may be dispensable for melanoma progression. Nevertheless, the enhanced sphere formation, lineage plasticity, migratory ability and drug resistance of the CD24+CD271+ sub-population may signal a contextual requirement for these stem cells when melanomas face challenging environments both clinically and in experimental systems.

cancer biology↗

bioRxiv2020

Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis

Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as markers of EMT CSCs with enhanced plasticity. This afforded the opportunity to investigate whether retention of EpCAM and CD24 alongside upregulation of the EMT marker Vimentin can identify disseminating EMT CSCs in human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 84 human oral cancer specimens, we see a significant enrichment of single EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.

cancer biology↗

bioRxiv2018

Ribosomal stress-induced senescence as a novel pro-senescence strategy for p16 positive basal-like breast cancer

Re-engaging the senescent programme represents an attractive yet underexplored strategy for cancer therapy, particularly for those tumour subtypes where targeted agents are limited or unavailable. Here, we identify a specific subset of ribosomal proteins as novel pro-senescence therapeutic targets for a highly aggressive subtype of breast cancer, p16 positive basal-like breast cancer. Mechanistically, ribosomal stress-induced senescence generates a stable cell cycle arrest, is dependent on endogenous p16 triggering a resensitisation to the p16/RB tumour suppressor axis, followed by establishment of a senescence-associated secretory phenotype, and is independent of DNA damage. Conversely, ribosomal protein knockdown in a p16 negative breast cancer model results in caspase-mediated apoptosis. Importantly, individual ribosomal protein loss is well tolerated by a panel of normal human cells. We demonstrate a reciprocal feedback loop between loss of RPS3A and RPS7 at both the transcriptional and post-transcriptional level during ribosomal stress-induced senescence. Further, our ribosomal hits are co-ordinately dysregulated in breast cancer, with elevated expression associated with a poor prognosis. Clinical relevance is demonstrated in tissue microarrays, and a RPS3AHIGHRPS7HIGH signature is associated with an earlier disease onset and synergises with p16 to further worsen patient outcome. We conclude that dysregulation of ribosomal proteins constitutes a cancer cell-specific mechanism of senescence evasion and that engaging ribosomal stress-induced senescence may be relevant for future pro-senescence therapies.

cancer biology↗