Publications
Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote cancer immune evasion. Ando T (corresponding author), Okamoto K, Sato K, Goto Y, Izumi H, Kataoka N, Ueda Y, Iglesias-Bartolome R, Yoshimoto T, Shintani T, Yanamoto S, Miyauchi M, Gutkind JS, Kajiya M. preprint, 2025.
Cancer cells not only enhance their proliferative capacity but also evade attacks from surrounding immune cells—a process known as immune evasion.
Immune checkpoint inhibitors (ICIs) have emerged as effective therapies that counteract this mechanism and restore immune surveillance.
In oral squamous cell carcinoma (OSCC), YAP/TAZ is known to be aberrantly activated, contributing to tumor proliferation and drug resistance. However, its role in immune evasion has remained unclear.
In our recent study, we found that patients with genetic alterations associated with Hippo pathway inactivation tend to respond more favorably to immune checkpoint inhibitors. One underlying mechanism involves YAP/TAZ activation, which leads to dedifferentiation and increased genomic instability, resulting in a higher tumor mutational burden (TMB). This promotes the recruitment of cytotoxic T cells into the tumor microenvironment.
However, we also discovered that YAP/TAZ activation promotes immune evasion by upregulating PD-L2 expression through the formation of super enhancers in collaboration with BRD4. PD-L2 then binds to PD-1 on cytotoxic T cells, rendering them inactive.
This paradox—recruiting T cells while simultaneously suppressing them—may explain why tumors with Hippo pathway inactivation show increased sensitivity to ICIs.
Moving forward, we aim to further investigate the impact of YAP/TAZ activation on the tumor immune microenvironment, and to explore novel therapeutic strategies targeting PD-L2 or YAP/TAZ for future drug development.
Link for the artcile
YAP/TAZ interacts with RBM39 to confer resistance against indisulam. Ando T (corresponding author), Okamoto K, Ueda Y, Kataoka N, Shintani T, Yanamoto S, Miyauchi M, Kajiya M. Oncogenesis, 13(1):25, 2024
In oral squamous cell carcinoma (OSCC), YAP/TAZ is frequently activated and translocated into the nucleus. However, the full spectrum of nuclear interaction partners of YAP/TAZ has remained largely unexplored.
In this study, we identified RBM39, an RNA-binding protein, as a novel nuclear interactor of YAP.
RBM39 enhances transcriptional activity of various transcription factors and plays a key role in maintaining normal mRNA splicing.
Indisulam, an aryl sulfonamide compound, promotes the degradation of RBM39 by recruiting it to a ubiquitin ligase complex, leading to aberrant splicing and ultimately cell death. Despite promising preclinical results, its clinical efficacy has been limited, and the mechanisms of resistance have remained unclear. Interestingly, indisulam has also been reported to induce neoantigen generation via abnormal splicing, thereby enhancing the efficacy of immune checkpoint inhibitors. This raises hopes for future combination therapies—yet such applications remain limited unless resistance mechanisms are better understood.
Our study revealed that YAP binds directly to RBM39, resulting in:
enhanced transcription of YAP/TAZ target genes, and
suppression of RBM39 degradation by indisulam.
Moreover, YAP/TAZ activation promoted the expression of integrins and collagens, activating the FAK pathway, and helped maintain proper splicing of genes involved in cell cycle regulation and DNA metabolism. Together, these effects contributed to indisulam resistance.
Given that YAP/TAZ activation is common in many solid tumors, our findings may help explain why indisulam has shown limited efficacy in clinical trials. These results highlight the need to develop novel therapeutic strategies that disrupt the YAP–RBM39 interaction, in order to overcome resistance and enhance the therapeutic potential of indisulam-based regimens.
DOI: 10.1038/s41389-024-00527-0
AXL activates YAP through the EGFR–LATS1/2 axis and confers resistance to EGFR-targeted drugs in head and neck squamous cell carcinoma, Okamoto K, Ando T (corresponding author), Izumi H, Kobayashi SS, Shintani T, Gutkind JS, Yanamoto S, Miyauchi M, Kajiya M. Oncogene, 42:2869-2877, 2023.
EGFR Activates YAP, but Why Is the Efficacy of EGFR Inhibitors Limited?
Although the receptor tyrosine kinase EGFR is known to activate YAP, the clinical efficacy of EGFR inhibitors in oral squamous cell carcinoma (OSCC) has been limited. We hypothesized that other receptor tyrosine kinases (RTKs) may be involved, particularly in cases where YAP reactivation occurs despite EGFR blockade.
Through database analysis, we identified AXL as a novel RTK associated with EGFR inhibitor resistance. We discovered that AXL forms heterodimers with EGFR, and activates YAP via the EGFR–LATS1/2 axis. This mechanism contributes to the reactivation of YAP and continued tumor proliferation, even in the presence of EGFR-targeted therapies.
Our findings demonstrate that co-inhibition of AXL and EGFR is essential to overcome this resistance. These results highlight the importance of developing combination therapies or new therapeutic strategies targeting the Hippo–YAP/TAZ axis in resistant OSCC.
This study was selected as a Readers’ Choice: The Best of Oncogene 2023 (January 9, 2024).
DOI: 10.1038/s41388-023-02810-7
EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1. Ando T, Arang N, Wang Z, Costea DE, Feng X, Goto Y, Izumi H, Gilardi M, Ando K, Gutkind JS. Communications Biology, 4:1237, 2021.
The receptor tyrosine kinase EGFR is activated upon binding to its ligand EGF, triggering downstream signaling cascades that promote cell proliferation. In oral squamous cell carcinoma (OSCC), EGFR is frequently amplified and overexpressed, while in lung adenocarcinoma, activating mutations are observed in approximately 50% of cases.
Despite its central role in cancer biology, the link between EGFR and YAP/TAZ activation had remained unclear. In this study, we demonstrated for the first time that EGFR phosphorylates three tyrosine residues on MOB1, a core component of the Hippo pathway. This phosphorylation leads to inactivation of LATS1/2, resulting in the nuclear translocation and activation of YAP/TAZ, ultimately promoting tumor cell proliferation.
What makes this discovery particularly impactful is the unexpected cross-talk between two historically distinct signaling systems: the well-established EGFR pathway and the more recently discovered Hippo pathway. Our findings reveal that EGFR directly regulates Hippo signaling, shedding new light on the molecular mechanisms underlying cancer progression and opening novel avenues for therapeutic targeting.
DOI: 10.1038/s42003-021-02744-4
