Cell membrane protrusions called “blebs” could contribute to anoikis resistance in melanoma, suggesting a source to target in potential treatments of this and other cancer types. Healthy cells that detach from larger tissues typically undergo a form of this programmed cell death. But malignant cells that detach have been shown to survive and spread, forming blebs indefinitely.
In melanoma cells, blebbing attracts septin proteins, which form molecular scaffolds for active mutant NRAS and effectors. These signaling hubs activate ERK and PI3K, both well-established promoters of pro-survival pathways in cancer cells. Interestingly, inhibition of blebs or septin assembly ultimately causes cell death.
New research published in Nature by Gaudenz Danuser, Ph.D., Chair of the Lyda Hill Department of Bioinformatics and Professor of Cell Biology at UT Southwestern, suggests that septin inhibition could be part of a new therapeutic intervention strategy for melanoma as well as other cancers. Dr. Danuser co-led the study with Andrew D. Weems, Ph.D., an Instructor of Bioinformatics and researcher in the Danuser Lab.
“Our old adage in biology is that form follows function. But here, we’re flipping that concept on its head,” Dr. Danuser says. “By changing the form, we’re showing that you can change chemical processes inside the cell that control their functions.”
Discovery of a New Target
The study initially focused on Ras-transformed melanoma. Ras family mutants are found in 30%-35% of cancers, and 30% of melanomas harbor a mutation in the NRAS gene. Locked in a constitutively active state, mutant NRAS signaling results in cellular hyperproliferation and the avoidance of cell death.
Despite their clinical importance, these oncoproteins have been notoriously difficult to target – there are no selective therapies currently available for NRAS mutants.
The researchers discovered that NRAS depends on a specific subcellular architecture to operate as an efficient oncoprotein. This yields the proposal that Ras-driven pathways can be attacked by modulation of cell morphological programs that determine NRAS’ penetrance as an oncogene. While BRAF-driven melanoma cells do not rely on blebs or septins under basal conditions, they observed that these cells became strongly bleb- and septin-dependent when treated with MAPK-inhibitor therapy.
“These findings show that ‘so-called’ oncogenic mutations alone are not sufficient to drive cancer functions, but that they may depend on specific cellular configurations to do so,” Dr. Danuser says. “On the other hand, promoting these cellular configurations alone can enable cancer-generating functions in perfectly healthy cells with no mutations, which offers a fundamentally new perspective of cancer development.”
Progress Toward Clinical Trials
Unpublished preclinical work at UT Southwestern has shown that a low toxicity agricultural chemical already approved by the Environmental Protection Agency effectively targets septin-signaling hubs in mouse models of cancer.
When the researchers treated melanoma cells with a compound that inhibits septins, called forchlorfenuron (FCF), the septins could no longer scaffold Ras proteins, resulting in an inability of the cells to sustain the chemical reactions that were keeping them alive.
“FCF has been used as an agricultural chemical in the U.S. for nearly 20 years,” Dr. Weems says. “This septin-inhibiting compound and its chemical derivatives could be promising candidates for new anti-cancer therapies.”
Based on these findings, Dr. Danuser and Dr. Weems are now looking for industrial partners interested in optimizing this therapeutic avenue or collaborating to create a de novo design and test novel inhibitors.
This study was funded by grants from the National Institutes of Health (R35 GM136428) and The Welch Foundation (I-1840-20200401).
The Board of Regents of The University of Texas System has filed for a patent on the therapeutic targeting of septins and blebbing, which was based in part on data from this study. Drs. Danuser and Weems, along with Erik S. Welf, Ph.D., and Meghan K. Driscoll, Ph.D., are named as inventors.
Gaudenz Danuser, Ph.D., is Chair of the Lyda Hill Department of Bioinformatics, Director of the Cecil H. and Ida Green Center for Systems Biology, Professor of Cell Biology, and a member of the Cellular Networks in Cancer Research Program at Simmons. His research interests include causal inference in molecular pathways, machine learning of cell dynamics, and regulation of cell morphogenesis in metastasis.
Andrew Weems, Ph.D., is a Jane Coffin Childs Fellow and Research Instructor with the Lyda Hill Department of Bioinformatics at UT Southwestern in the Danuser Lab. His research interests include the regulation of the septin cytoskeleton as well as cell morphological control of signaling and its influence on cancer disease progression, cancer drug resistance, and cell fate determination.