Novel Therapeutics:
Bleb–Septin Survival Hubs: Restoring Anoikis to Block Metastatic NRAS Signaling
Joe Ready
- Professor, Department of Biochemistry
- Ronald W. Estabrook, Ph.D. Distinguished University Chair in Biomedical Science
- Southwestern Medical Foundation Scholar in Biomedical Research. UT Southwestern Medical Center, Dallas, Texas, USA.
Gaudenz Danuser
- Roche, Basel Switzerland
- Formerly: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas, USA.
Most metastatic cancer cells must survive while detached from tissue, but normal cells usually die by anoikis, so “anoikis resistance” is a central biological bottleneck in metastasis. The core discovery is that detached melanoma cells form membrane “blebs” that assemble pro-survival signaling hubs at curved bleb edges. Septin scaffolds recruited to these blebs concentrate mutant NRAS and activate the ERK and PI3K survival pathways, effectively substituting for lost anchorage signaling. Blocking blebs or septins has little effect on well-adhered cells but causes NRAS mislocalization, reduced MAPK/PI3K activity, and death in detached cells, creating a selective vulnerability in the metastatic state. UTSW has filed IP covering therapeutic targeting of septins and blebbing, and the translational plan is to convert this mechanism into drug-like small molecules (with forchlorfenuron as a validated septin-inhibition starting point and derivatives as the development path) suitable for IND-grade development.
