Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis
Abstract
1. Introduction
2. Results
2.1. Immunohistochemical Expression of MST1 in TETs
2.2. Immunohistochemical Expression of SAV1 in TETs
2.3. Immunohistochemical Expression of LATS1 in TETs
2.4. Immunohistochemical Expression of MOB1A in TETs
2.5. Immunohistochemical Expression of YAP1 in TETs
2.6. Immunohistochemical Expression of Active YAP (AYAP) in TETs
2.7. Immunohistochemical Expression of TAZ in TETs
2.8. Immunohistochemical Expression of TEAD4 in TETs
2.9. Associations Between the Investigated Molecules of the Hippo Cascade
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Immunohistochemistry
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
TET(s) | Thymic Epithelial Tumor(s) |
WHO | World Health Organization |
TC | Thymic Carcinoma |
MST1/2 | Mammalian STE20-like kinases |
LATS1/2 | Large tumor suppressor kinases). |
TAZ | Transcriptional co-activator with PDZ-binding motif |
YAP | Yes-associated protein |
MOB1(A) | Mps one binder 1(A) |
SAV1 | Salvador homolog 1 |
TEAD4 | TEA domain transcription factor 4 |
RTK | Receptor tyrosine kinase |
AYAP | Active YAP1 |
NSCLC | Non-small-cell lung cancer |
OXPHOS | Mitochondrial oxidative phosphorylation |
FFPE | Formalin-Fixed, Paraffin-Embedded |
RT-qPCR | Reverse Transcription quantitative Polymerase Chain Reaction |
NGS | Next-Generation Sequencing |
WWTR1 | WW domain-containing transcription regulator 1 |
MNT | Micronodular thymoma with lymphoid stroma |
PMU | Paracelsus Medical University |
Appendix A
Appendix A.1. MST1
Parameter | MST1 Cytoplasmic Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = −0.08 | p = 0.465 |
Tumor size | R = 0.18 | p = 0.152 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 15 (0–100) | p = 0.370 |
Female | 10 (1–95) | |
WHO subtypes | ||
Thymomas | 10 (0–95) | p = 0.014 |
Thymic carcinomas (TC) | 70 (1–100) | |
Masaoka–Koga stage | ||
I–II | 10 (0–95) | p = 0.002 |
III–IV | 45 (0–100) |
Appendix A.2. SAV1
Parameter | SAV1 Expression | ||
---|---|---|---|
Numerical Variables | <100% Median (Min–Max) | 100% Median (Min–Max) | p-Value * |
Age (years) | 74 (45–88) | 67 (21–85) | p = 0.264 |
Tumor size (cm) | 4.5 (2.4–9) | 6, (0.9–14) | p = 0.237 |
Categorical/nominal variables | |||
<100% (n) | 100% (n) | p-value ** | |
Gender | |||
Male | 4 | 35 | p = 0.138 |
Female | 9 | 29 | |
WHO subtypes | |||
Rest WHO types | 12 | 37 | p = 0.025 |
B3/TC | 1 | 27 | |
Masaoka–Koga stage | |||
I–II | 11 | 36 | p = 0.027 |
III–IV | 0 | 18 |
Appendix A.3. LATS1
Parameter | LATS1 Cytoplasmic Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = −0.08 | p = 0.788 |
Tumor size | R = −0.07 | p = 0.566 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 90 (10–100) | p = 0.528 |
Female | 90 (20–100) | |
WHO subtypes | ||
Rest WHO types | 80 (10–100) | p < 0.001 |
B3/TC | 100 (15–100) | |
Masaoka–Koga stage | ||
I–II | 80 (20–100) | p = 0.007 |
III–IV | 100 (40–100) |
Appendix A.4. MOB1A
Parameter | MOB1A Cytoplasmic Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = −0.01 | p = 0.879 |
Tumor size | R = −0.10 | p = 0.389 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 100 (10–100) | p = 0.438 |
Female | 100 (55–100) | |
WHO subtypes | ||
Rest WHO types | 100 (55–100) | p = 0.063 |
B3/TC | 100 (10–100) | |
Masaoka–Koga stage | ||
I–II | 100 (55–100) | p = 0.033 |
III–IV | 100 (10–100) |
Appendix A.5. YAP1
Parameter | YAP1 Nuclear Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.04 | p = 0.669 |
Tumor size | R = −0.02 | p = 0.870 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 30 (0–95) | p = 0.506 |
Female | 40 (0–90) | |
WHO subtypes | ||
Thymomas | 50 (0–95) | p = 0.001 |
TC | 5 (0–50) | |
Masaoka–Koga stage | ||
I–II | 60 (0–95) | p = 0.023 |
III–IV | 12.5 (0–95) |
Parameter | YAP1 Cytoplasmic Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.12 | p = 0.273 |
Tumor size | R = −0.18 | p = 0.144 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 20 (0–100) | p = 0.470 |
Female | 10 (0–100) | |
WHO subtypes | ||
Rest WHO types | 50 (0–95) | p = 0.740 |
B3/TC | 5 (0–50) | |
Masaoka–Koga stage | ||
I | 5 (0–80) | p = 0.032 |
II-IV | 30 (0–100) |
Appendix A.6. AYAP
Parameter | AYAP Nuclear Expression | AYAP Cytoplasmic Expression | ||
---|---|---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.01 | p = 0.905 | R = 0.12 | p = 0.281 |
Tumor size | R = 0.04 | p = 0.740 | R = −0.18 | p = 0.131 |
Categorical/Nominal Variables | ||||
Median (min–max) | p-value | Median (min–max) | p-value | |
Gender | ||||
Male | 50 (0–100) | p = 0.299 * | 40 (0–100) | p = 0.384 * |
Female | 35 (0–90) | 17.5 (0–100) | ||
WHO Subtypes | ||||
A/AB | 70 (20–100) | p = 0.001 ** | 60 (0–100) | p = 0.011 ** |
B1, B2, B3 | 30 (0–95) | 10 (0–100) | ||
TC | 5 (0–60) | 12.5 (0–80) | ||
Masaoka–Koga Stage | ||||
I–II | 60 (2–95) | p = 0.007 * | 45 (0–100) | p = 0.947 ** |
III–IV | 17.5 (0–100) | 45 (0–95) |
Appendix A.7. TAZ
Parameter | TAZ Nuclear Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.197 | p = 0.086 |
Tumor size | R = −0.001 | p > 0.999 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 10 (0–90) | p = 0.872 |
Female | 10 (0–70) | |
WHO subtypes | ||
Thymomas A/AB | 20 (0–80) | p = 0.004 |
B1, B2, B3 | 1.5 (0–60) | |
TC | 12.5 (0–90) | |
Masaoka–Koga stage | ||
I–II | 15 (0–70) | p = 0.182 |
III–IV | 0 (0–80) |
Parameter | TAZ Cytoplasmic Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.101 | p = 0.384 |
Tumor size | R = 0.198 | p = 0.123 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 5 (0–90) | p = 0.298 |
Female | 0 (0–80) | |
WHO subtypes | ||
Rest WHO types | 7.5 (0–90) | p = 0.004 |
B3/TC | 3.5 (0–80) | |
Masaoka–Koga stage | ||
I–II | 5 (0–80) | p = 0.281 |
III–IV | 0 (0–90) |
Appendix A.8. TEAD4
Parameter | TEAD4 Nuclear Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.12 | p = 0.292 |
Tumor size | R = −0.15 | p = 0.222 |
Categorical/nominal variables | ||
Median (min–max) | p-value | |
Gender | ||
Male | 20 (0–90) | p = 0.545 * |
Female | 12.5 (0–100) | |
WHO subtypes | ||
A/AB | 25 (0–90) | p = 0.005 ** |
B1, B2, B3 | 0 (0–90) | |
TC | 27.5 (0–100) | |
Masaoka–Koga stage | ||
I–II | 10 (0–90) | p = 0.957 * |
III–IV | 7.5 (0–90) |
Parameter | TEAD4 Cytoplasmic Expression | |
---|---|---|
Numerical Variables | Spearman’s Correlation Coefficient | p-Value |
Age | R = 0.25 | p = 0.027 |
Tumor size | R = −0.11 | p = 0.348 |
Categorical/nominal variables | ||
Median (min–max) | p-value * | |
Gender | ||
Male | 80 (0–100) | p = 0.198 |
Female | 60 (0–100) | |
WHO subtypes | ||
Thymomas | 60 (0–100) | p = 0.002 |
TC | 100 (0–100) | |
Masaoka–Koga stage | ||
I–II | 60 (0–100) | p < 0.001 |
III–IV | 95 (20–100) |
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Molecule | Immunolocalization | Tumor Size | WHO Histological Types | Masaoka-Koga Stage | Survival Analysis |
---|---|---|---|---|---|
MST1 | Cytoplasmic (96.1%) | No significant correlation (Spearman’s correlation coefficient, p = 0.152) | Higher expression in B3/TC (Mann–Whitney U test, p = 0.032) | Higher expression in III/IV (Mann–Whitney U test, p = 0.002) | No significant correlation (log-rank, >10% versus ≥10%, p = 0.99) |
SAV1 | Cytoplasmic (100%) | No significant correlation (Spearman’s correlation coefficient, p = 0.237) | More uniformly high expression in B3/TC (Fisher’s exact test, p = 0.025) | Higher expression in III/IV (Fisher’s exact test, I/II versus III/IV, p = 0.027) | No significant correlation (log-rank, <100% versus 100%, p = 0.479) |
LATS1 | Cytoplasmic (100%) | No significant correlation (Mann–Whitney U test, p = 0.566) | Higher expression in B3/TC (Mann–Whitney U test, p < 0.001) | Higher expression in III/IV (Mann–Whitney U test, p = 0.007) | No significant correlation (log-rank, p = 0.838) |
MOB1A | Cytoplasmic (100%) | No significant correlation (Mann–Whitney U test, p = 0.389) | Higher in B3/TC (Mann–Whitney U test, marginal, p = 0.063) | Higher in III/IV (Mann–Whitney U test, I/II versus III/IV, p = 0.033) | No significant correlation (log-rank, >100% versus 100%, p = 0.592) |
YAP1 | Nuclear (90.9%), Cytoplasmic (63.4%) | No significant correlation (Mann–Whitney U test, nuclear: p = 0.870; cytoplasmic: p = 0.144) | Lower nuclear expression in B3/TC (Mann–Whitney U test, p = 0.010) | Lower nuclear in III/IV (Mann–Whitney U test, I/II versus III/IV, p = 0.023); higher cytoplasmic in III/IV (Mann-Whitney U test, I versus II/III/IV, p = 0.032) | No significant correlation (nuclear: log-rank, <40% versus ≥40%, p = 0.323; cytoplasmic: <15% versus ≥15%, p = 0.468) |
AYAP | Nuclear (93.5%), Cytoplasmic (75.3%) | Nuclear and cytoplasmic: no significant correlation (Mann–Whitney U test, p = 0.131) | Lower nuclear expression in TC (Mann–Whitney U test, p < 0.001); highest cytoplasmic expression in A/AB (Kruskal–Wallis ANOVA, p = 0.011) | Lower nuclear in III/IV (Mann–Whitney U test, I/II versus III/IV, p = 0.007) | No significant correlation (nuclear: log-rank, <40% versus ≥40%, p = 0.296; cytoplasmic: <30% versus ≥30%, p = 0.614) |
TAZ | Nuclear (68.8%), Cytoplasmic (51.9%) | No significant correlation (Mann–Whitney U test, nuclear: p > 0.999; cytoplasmic: p = 0.123) | Nuclear higher in A/AB (Kruskal–Wallis ANOVA, p = 0.004); cytoplasmic lower in B3/TC (Mann–Whitney U test, p = 0.004) | No significant correlation (nuclear: Mann–Whitney U test, I/II versus III/IV, p = 0.182; cytoplasmic: Mann–Whitney U test, I/II versus III/IV, p = 0.281) | No significant correlation ( nuclear: log-rank, <10% versus ≥10%, p = 0.951; cytoplasmic: log-rank, <2% versus ≥2%, p = 0.218) |
TEAD4 | Nuclear (63.6%), Cytoplasmic (94.8%) | No significant correlation (Mann–Whitney U test, nuclear: p = 0.348; cytoplasmic: p = 0.222) | Higher cytoplasmic in TCs (Mann–Whitney U test, p = 0.002); higher nuclear in A/AB and TCs (Kruskal–Wallis ANOVA, p = 0.005) | Higher cytoplasmic in III/IV (Mann–Whitney U test, I/II versus III/IV, p < 0.001) | Nuclear: no siginifcant correlation (log-rank, <15% versus ≥15%, p = 0.850) Worse OS if cytoplasmic ≥70% (log-rank, p = 0.003) |
n- MST1 | c-MST1 | c-SAV1 | c-LATS1 | c-MOB1A | n-TAZ | c-TAZ | n-YAP1 | c-YAP1 | n-AYAP | c-AYAP | n-TEAD4 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
c-MST1 | R = −0.19 p = 0.095 | |||||||||||
c-SAV1 | R = 0.048 p = 0.68 | R = 0.19 p = 0.096 | ||||||||||
c-LATS1 | R = −0.14 p = 0.206 | R = 0.45 p < 0.001 | R = 0.33 p = 0.003 | |||||||||
c-MOB1A | R = 0.09 p = 0.441 | R = 0.24 p = 0.032 | R = 0.05 p = 0.624 | R = 0.34 p = 0.002 | ||||||||
n-TAZ | R = 0.12 p = 0.275 | R = −0.08 p = 0.459 | R = −0.10 p = 0.366 | R = 0.25 p = 0.025 | R = 0.02 p = 0.814 | |||||||
c-TAZ | R = 0.13 p = 0.246 | R = 0.24 p = 0.038 | R = 0.01 p = 0.919 | R = 0.22 p = 0.056 | R = 0.23 p = 0.042 | R = 0.19 p = 0.097 | ||||||
n-YAP1 | R = −0.02 p = 0.816 | R = −0.21 p = 0.070 | R = −0.21 p = 0.064 | R = −0.05 p = 0.631 | R = 0.04 p = 0.729 | R = 0.30 p = 0.007 | R = 0.32 p = 0.004 | |||||
c-YAP1 | R = −0.13 p = 0.244 | R = 0.11 p = 0.340 | R = −0.02 p = 0.857 | R = 0.35 p = 0.001 | R = 0.23 p = 0.044 | R = 0.13 p = 0.239 | R = 0.27 p = 0.016 | R = 0.36 p = 0.001 | ||||
n-AYAP | R = 0.16 p = 0.16 | R = −0.20 p = 0.07 | R = −0.20 p = 0.080 | R = −0.02 p = 0.826 | R = 0.05 p = 0.653 | R = 0.37 p = 0.001 | R = 0.44 p < 0.001 | R = 0.80 p < 0.001 | R = 0.30 p = 0.009 | |||
C-AYAP | R = 0.08 p = 0.497 | R = −0.01 p = 0.872 | R = −0.03 p = 0.788 | R = 0.29 p = 0.010 | R = 0.29 p = 0.009 | R = 0.28 p = 0.013 | R = 0.23 p = 0.047 | R = 0.45 p < 0.001 | R = 0.68 p < 0.001 | R = 0.58 p < 0.001 | ||
n-TEAD4 | R = −0.01 p = 0.867 | R = 0.13 p = 0.265 | R = −0.01 p = 0.892 | R = 0.36 p = 0.001 | R = 0.01 p = 0.940 | R = 0.34 p = 0.002 | R = 0.06 p = 0.600 | R = 0.07 p = 0.526 | R = 0.24 p = 0.038 | R = 0.07 p = 0.519 | R = 0.13 p = 0.245 | |
c-TEAD4 | R = 0.08 p = 0.468 | R = 0.31 p = 0.005 | R = 0.13 p = 0.265 | R = 0.62 p < 0.001 | R = 0.29 p = 0.012 | R = 0.25 p = 0.029 | R = 0.11 p = 0.318 | R = −0.04 p = 0.706 | R = 0.27 p = 0.017 | R = −0.07 p = 0.523 | R = 0.24 p = 0.031 | R = 0.31 p = 0.007 |
Parameter | Median | Min–Max |
---|---|---|
Age (years) | 69 | 21–88 |
Tumor size (cm) | 6.5 | 0.9–14 |
Number | % | |
Gender | ||
Male | 39 | 50.6 |
Female | 38 | 49.4 |
WHO subtypes | ||
Type A | 3 | 3.9 |
Type AB | 26 | 33.7 |
Type B1 | 7 | 9 |
Type B2 | 11 | 14.3 |
Type B3 | 14 | 18.2 |
Micronodular with lymphoid stroma (MNT) | 2 | 2.6 |
Thymic carcinoma (TC) | 14 | 18.2 |
Masaoka–Koga stage | ||
I | 22 | 33.8 |
II | 25 | 38.5 |
III | 9 | 13.8 |
IVa | 5 | 7.7 |
IVb | 4 | 6.1 |
Presence of myasthenia Gravis | 11 | 14.1 |
Event | ||
Cencored-Alive | 51/60, follow-up 0.3–109, 4 months | 85 |
Dead | 9/60, within 0.1–48.6 months | 15 |
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Elm, L.; Gerlitz, N.; Hochholzer, A.; Papadopoulos, T.; Levidou, G. Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis. Int. J. Mol. Sci. 2025, 26, 5938. https://doi.org/10.3390/ijms26135938
Elm L, Gerlitz N, Hochholzer A, Papadopoulos T, Levidou G. Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis. International Journal of Molecular Sciences. 2025; 26(13):5938. https://doi.org/10.3390/ijms26135938
Chicago/Turabian StyleElm, Lisa, Nadja Gerlitz, Anke Hochholzer, Thomas Papadopoulos, and Georgia Levidou. 2025. "Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis" International Journal of Molecular Sciences 26, no. 13: 5938. https://doi.org/10.3390/ijms26135938
APA StyleElm, L., Gerlitz, N., Hochholzer, A., Papadopoulos, T., & Levidou, G. (2025). Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis. International Journal of Molecular Sciences, 26(13), 5938. https://doi.org/10.3390/ijms26135938