Tumor stiffness creates a ferroptotic Achilles heel through YAP SKP2 signaling
- 1Duke University
Abstract
Matrix stiffness is a hallmark of aggressive solid tumors and strongly associated with therapeutic resistance and poor prognosis. This mechanical barrier represents a major unmet challenge in oncology, as current strategies rarely address how matrix mechanics themselves drive treatment resistance. Here, we identified ferroptosis, an iron-dependent form of cell death, as a potential long-sought vulnerability that can be exploited to eliminate mechanically resistant tumors. Using genetic and chemical approaches, we investigated how matrix stiffness sensitizes cancer cells to ferroptosis and whether this vulnerability can be therapeutically targeted. We found that cancer cells cultured on stiff matrices were more sensitive to ferroptosis than those on soft matrices, as evidenced by reduced cell viability and elevated lipid peroxidation. Furthermore, we found that matrix stiffness induced YAP activation, which upregulated its target gene SKP2, a key mediator required for the heightened ferroptosis sensitivity observed under stiff conditions. Finally, using an injectable hydrogel system, we demonstrated that stiffened tumors were resistant to chemotherapy but remained highly susceptible to ferroptosis induction, resulting in markedly reduced tumor volume and weight. Our findings established ferroptosis as a stiffness-dependent vulnerability mediated by a YAP-SKP2 signaling axis, revealing a mechanotransductive pathway that may be leveraged to target treatment-refractory tumors.
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BibTeX
@misc{villares2026tumor,
title = {{Tumor stiffness creates a ferroptotic Achilles heel through YAP SKP2 signaling}},
author = {E. Villares and N. Taber and S.-C. Wu and C. Amelung and J. Wu and C.-C. Lin and J.-T. A. Chi and S. Gerecht},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755825},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755825v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Tumor stiffness creates a ferroptotic Achilles heel through YAP SKP2 signaling
AU - E. Villares
AU - N. Taber
AU - S.-C. Wu
AU - C. Amelung
AU - J. Wu
AU - C.-C. Lin
AU - J.-T. A. Chi
AU - S. Gerecht
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755825
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755825v1
AB - Matrix stiffness is a hallmark of aggressive solid tumors and strongly associated with therapeutic resistance and poor prognosis. This mechanical barrier represents a major unmet challenge in oncology, as current strategies rarely address how matrix mechanics themselves drive treatment resistance. Here, we identified ferroptosis, an iron-dependent form of cell death, as a potential long-sought vulnerability that can be exploited to eliminate mechanically resistant tumors. Using genetic and chemical approaches, we investigated how matrix stiffness sensitizes cancer cells to ferroptosis and whether this vulnerability can be therapeutically targeted. We found that cancer cells cultured on stiff matrices were more sensitive to ferroptosis than those on soft matrices, as evidenced by reduced cell viability and elevated lipid peroxidation. Furthermore, we found that matrix stiffness induced YAP activation, which upregulated its target gene SKP2, a key mediator required for the heightened ferroptosis sensitivity observed under stiff conditions. Finally, using an injectable hydrogel system, we demonstrated that stiffened tumors were resistant to chemotherapy but remained highly susceptible to ferroptosis induction, resulting in markedly reduced tumor volume and weight. Our findings established ferroptosis as a stiffness-dependent vulnerability mediated by a YAP-SKP2 signaling axis, revealing a mechanotransductive pathway that may be leveraged to target treatment-refractory tumors.
ER -