Biology subjects

Haloul, M.

Publications and source records attributed to Haloul, M..

3 recordsLinked to original sources

bioRxiv2026

Ionic Regulation of Mechanosurveillance and Metastasis via the MRTFA/KCNMB1 Axis

Cellular stiffness profoundly impacts cancer metastasis at multiple levels, but mechanisms that regulate cancer cells stiffness remain poorly understood. Here, we identified potassium efflux and KCNMB1, an auxiliary subunit of the large conductance potassium efflux (BK) channels, as regulators of cellular stiffness downstream of myocardin related transcription factor A (MRTFA). In primary pericytes, KCNMB1 knockdown increased cellular stiffness, which is consistent with the role of potassium efflux in promoting relaxation during excitation-contraction coupling. In a striking contrast, however, KCNMB1 knockdown decreased cellular stiffness in cancer cells. Softer cancer cells were resistant to NK cell mediated cytotoxicity and the low KCNMB1 expression was associated with worse survival in breast cancer patients. Importantly, pharmacological activation of BK channels reduced metastatic burden in mice and improved lysis of cancer cells by cytotoxic T-lymphocytes. These results highlight the unique ionic regulation of stiffness in cancer cells and point to BK channel agonism as a new therapeutic approach in cancer.

cancer biology↗

bioRxiv2024

Multiplex Imaging Reveals Novel Subcellular, Microenvironmental, and Racial Patterns of MRTFA/B Activation in Invasive Breast Cancers and Metastases

Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin related transcription factors A and B (MRTFA/B) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we used a combination of multiplexed immunofluorescence and bioinformatics analyses to show that MRTFA/B are concurrently activated in tumor cells, but they show distinct patterns of expression across different histological subtypes and in the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen presenting cells (APCs) and its expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR). These results provide unique insights into how MRTFA and MRTFB can promote metastasis in human cancer, into the racial disparities of their expression patterns, and their function within the complex breast cancer TME. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/573909v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@12037b3org.highwire.dtl.DTLVardef@28e2feorg.highwire.dtl.DTLVardef@4e95e1org.highwire.dtl.DTLVardef@152019b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations.

In non-small cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumor suppressor STK11 encoding the kinase LKB1 result in aggressive tumors prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant (KL) cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analyzed tumor metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards an activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KL mutant tumors. KL cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Our results define a new metabolic vulnerability in KL tumors and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.

cancer biology↗