Cancer cell proliferation is driven by a complex series of signaling cascades, and several types of cancer therapies are designed to inhibit these pro-proliferative signals. In prostate cancer, androgen deprivation therapy can inhibit the androgen receptor (AR) growth signaling pathway. While androgen deprivation drugs are effective, tumors can quickly become resistant to them, leading to castration-resistant prostate cancer. One factor that contributes to this resistance is transdifferentiation of the cancer into a different tumor subtype known as neuroendocrine prostate cancer, which does not express androgen receptor and therefore does not respond to androgen deprivation therapy. Currently, doctors do not have a cure for neuroendocrine prostate cancer, and patient outcomes are poor. “It is a highly aggressive form of the disease that will progress rapidly. There is a chemotherapy available, but tumors become resistant to treatment in a matter of months,” explains Dr. Colm Morrissey, a researcher at the University of Washington specializing in prostate cancer.
AR-positive prostate cancers frequently express a protein called YAP that also promotes cell proliferation. However, expression of YAP is lost when AR-positive tumors become neuroendocrine tumors even though the neuroendocrine tumors continue to proliferate quickly. This paradox puzzled Morrissey, leading him to wonder about the other possible functions of YAP. YAP is part of the Hippo signaling pathway, which is known to influence tumor identity. In short, when Hippo signaling is ‘off,’ YAP enters the nucleus and interacts with TEAD transcription factors to promote proliferation. When Hippo signaling is ‘on,’ YAP is targeted for protein degradation by the LATS proteins. To understand how Hippo and YAP signaling changed in subtypes of prostate cancer, Morrissey collaborated with Dr. Michael Haffner at Fred Hutch to evaluate the abundance of Hippo signaling components in AR-positive and neuroendocrine prostate cancer. “We wanted to understand how [Hippo signaling] changed and how the tumor acquired a new tumor identity,” says Morrissey.
To start, they analyzed RNA sequencing data from previously published cohorts of castration-resistant prostate cancer patients. They found that YAP expression was much higher in AR-positive samples, confirming that this signaling axis is suppressed in the neuroendocrine subtype. Next, they looked at the levels of other Hippo signaling genes and saw that TEAD1 expression increased in neuroendocrine tumors. When they looked at metastatic AR-positive and neuroendocrine tumors, they saw the same patterns of YAP and TEAD1 expression, suggesting that TEAD1 could be a major driver of subtype switching in prostate cancer.
TEAD1 has two different isoforms. The most common isoform requires TEAD1 to interact with YAP to initiate transcriptional activity. Another isoform called TEAD1∆6 has transcriptional activity independent of YAP. Because TEAD1 was enriched in neuroendocrine tumors while YAP levels went down, the team hypothesized that TEAD1∆6 was the major isoform driving neuroendocrine identity. To test this, they looked at TEAD1 isoform expression in mouse models of prostate cancer. They found that neuroendocrine tumors exclusively expressed TEAD1∆6, and that this isoform was not detected in AR-positive tumors. They next looked at TEAD1 expression in metastatic tumors from patients and again saw that neuroendocrine tumors expressed TEAD1∆6, while AR-positive tumors did not express this isoform. These results suggest that TEAD1∆6 is the predominant isoform driving TEAD-associated transcription in neuroendocrine tumors.
To identify how TEAD1∆6 influences the proliferation and survival of neuroendocrine prostate cancer, the group knocked down TEAD1 in a neuroendocrine prostate cancer cell line and performed RNA sequencing analysis. They found that TEAD1 knockdown cells had higher expression of epithelial-associated genes compared to control cells. Epithelial genes are typically present in AR-positive prostate cancer, so these results suggest that TEAD1 regulates the switch from AR-positive to neuroendocrine prostate cancer by altering gene expression.
In the future, Morrissey is hopeful that the results presented here can inform patient therapies. “There are TEAD inhibitors available, and there are research groups who believe that targeting TEAD proteins may be an approach worth pursuing in cancer treatment. This work highlights the role of TEAD1 specifically in the maintenance of the neuroendocrine tumor type in prostate cancer,” he says.
This work was supported by funding from the Pacific Northwest Prostate Cancer SPORE, the National Institutes of Health, the Prostate Cancer Foundation, and Bob and Ann Vessella through the Institute for Prostate Cancer Research.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Daniel Lin, Eva Corey, Peter Nelson, Li Xin, Michael Haffner, and Colm Morrissey contributed to this work.
Brown LG, Coleman IM, Chu TLH, Sayar E, Patel RA, Hanratty B, Adil M, Li D, Li Y, Nguyen HM, Sessions CJ, Sweeney EL, Alumkal JJ, Gil da Costa RM, Wang Y, Lin DW, True LD, Dumpit R, Corey E, Lee JK, Nelson PS, Xin L, Haffner MC, Morrissey C. 2026. Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer. Neoplasia. 2026 Aug:78:101321.
doi: 10.1016/j.neo.2026.101321
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.