Metastatic Reactivation and Progression Result From Fak-Mediated Disruption of Innate Immune Signaling

<p>Metastatic relapse may arise from disseminated tumor cells (DTCs) that undergo a period of dormancy before reactivating and progressing to life-threatening disease. How cancer cells evade ensuing immune surveillance upon reactivation is poorly understood, but critical for the development of novel therapies to prevent metastatic relapse. Here, we identify focal adhesion kinase (Fak) as a critical regulator of metastatic reactivation and progression and describe a novel mechanism by which it facilitates immune evasion. Fak ablates stimulator of interferon genes (Sting)-dependent type I interferon production when DTCs awaken from dormancy, thus preventing immune-mediated elimination. Fak may therefore represent the elusive arbiter of Sting’s role as both an anti- and pro-metastatic signaling pathway. Mechanistically, through its FERM domain, Fak disrupts phosphorylation, dimerization, and nuclear translocation of interferon regulatory factor 3 (Irf3) downstream of Sting activation. Single-cell RNA sequencing analysis from both patients and human xenograft models, spanning dormancy to metastasis, further substantiates this role of Fak. Genetic deletion or targeted degradation with proteolysis targeting chimera (PROTAC) of Fak, but not inhibition of its kinase activity, restores interferon production and enhances the sensitivity of incipient and established metastases to Sting agonists and immune checkpoint blockade. These findings highlight a novel, kinase-independent function of Fak in modulating immunity and present promising therapeutic strategies for preventing metastatic relapse.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Ling, Hsiang-Hsi
• <p>0000-0002-1678-4845</p>

Contributors dc:contributor

• Filippo G. Giancotti, M.D., Ph.D.
• Benjamin Izar, M.D., Ph.D.
• Yejing Ge, Ph.D.

• Metastatic dormancy
• Metastasis
• STING
• Focal Adhesion Kinase
• Tumor immune surveillance
• Cancer Biology
• Cell Biology
• Neoplasms
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1466

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2523