WEHI Wednesday Seminar hosted by Professors Andrew Roberts & David Huang
 

Dr Thomas Lew
PhD Student – Roberts & Huang Lab, Blood Cells and Blood Cancer division, WEHI
(this is a PhD Completion seminar)
 

The MFN2:MARCH5:UBE2J2 complex forms a stress-sensitive cell death rheostat and synthetic lethal vulnerability in cancer

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Subpopulations of stress-tolerant cancer cells frequently endure therapeutic pressure and significant organellar damage, driving treatment failure. We developed a novel CRISPR “death” screen to discover synthetic lethal vulnerabilities to stress-induced apoptosis. These uncover a previously unrecognized tripartite ubiquitin axis (MARCH5:UBE2J2:MFN2) which tonically suppresses apoptosis across multiple solid and hematologic tumor models, mechanistically unifying disparate previous findings. Remarkably, the MARCH5:MFN2 interaction is highly stress-sensitive, acting as a rheostat that orchestrates commitment to apoptosis in response to converging death signals. When this interaction is disrupted genetically or in response to compromised organellar function, the apoptotic threshold is markedly lowered, forcing dependency on pro-survival BCL-2 proteins, eroding stress tolerance, and importantly reversing treatment-refractoriness in vivo. We establish that the relevant ubiquitin-substrates are likely diverse and reveal critical molecular interactions within the axis as promising novel targets capable of selectively collapsing cancer cell resilience and significantly enhancing current therapies.

All welcome!