Biology subjects

Deka, K.

Publications and source records attributed to Deka, K..

2 recordsLinked to original sources

bioRxiv2024

TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer

Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fn14 receptor overexpression in ER-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of NAMPT, which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients.

cancer biology↗

bioRxiv2024

Aberrant non-canonical NF-kappaB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-{kappa}B pathway to nurture their survival while they accumulate pro- proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-{kappa}B activation. Here, we find that sustained NF-{kappa}B/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis- regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-{kappa}B signalling potentiates transcriptional programs beneficial for multiple myeloma progression.

cancer biology↗