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Oncotarget: Transcription and proliferation of human tumor cells


Here is a link to a video interview with Dr. Stuart A. Aaronson about this research on the Oncotarget YouTube Channel

Oncotarget published "Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations" which reported that the evolutionarily conserved Hippo inhibitory pathway plays critical roles in tissue homeostasis and organ size control, while mutations affecting certain core components contribute to tumorigenesis.

Here the researchers demonstrate that proliferation of Hippo pathway mutant human tumor cells exhibiting high constitutive TEAD transcriptional activity was markedly inhibited by dominant negative TEAD4, which did not inhibit the growth of Hippo wild-type cells with low levels of regulatable TEAD-mediated transcription.

The tankyrase inhibitor, XAV939, identified in a screen for inhibitors of TEAD transcriptional activity, phenocopied these effects independently of its other known functions by stabilizing angiomotin and sequestering YAP in the cytosol.

They also identified one intrinsically XAV939 resistant Hippo mutant tumor line exhibiting lower and less durable angiomotin stabilization.

Thus, this Oncotarget study concludes that angiomotin stabilization provides a new mechanism for targeting tumors with mutations in Hippo pathway core components as well as a biomarker for sensitivity to such therapy.

This Oncotarget study concludes that angiomotin stabilization provides a new mechanism for targeting tumors with mutations in Hippo pathway core components as well as a biomarker for sensitivity to such therapy.

Dr. Stuart A. Aaronson from The Icahn School of Medicine at Mount Sinai said, "The Hippo pathway is an evolutionarily conserved signaling pathway that plays a fundamental role in growth control, stem cell function, tissue regeneration, and tumor suppression."

In addition to YAP amplification or over expression observed in various epithelial malignancies as well as YAP or TAZ translocations or point mutation, loss of function mutations of core components of the Hippo inhibitory pathway such as LATS, or NF2 are found at high frequencies in mesotheliomas.

Deep sequencing studies have revealed that almost 20% of human tumors harbor mutations in GPCRs, suggesting that mutations in other GPCRs and G proteins may also deregulate the Hippo pathway.

The emerging role of Hippo pathway deregulation in cancer has increasingly focused attention on this signaling pathway as an anticancer target.

In the present study, the authors genetically validated constitutive high TEAD-mediated transcription levels in human tumor cells with loss of function mutations in well-established Hippo pathway core components, LATS and NF2, as therapeutic targets and identified a mechanism by which small molecule tankyrase inhibitors specifically antagonize such Hippo pathway deregulated tumor cells.

Figure 7: Angiomotin stabilization determines the ability of XAV939 to inhibit TEAD-mediated transcription and proliferation of Hippo pathway mutant tumor cells. A. Western blot analysis of H2052 cell lysates following treatment with 10μM of XAV939 or CTR for 24 hours. B. TEAD reporter activity in H2052 and H2373 cells treated with 10μM of XAV939 or CTR for the indicated time points. Fresh medium with XAV939 was replaced every 2 days. C., D. Relative CTGF mRNA expression level C. and western blot analysis of TNKS, AMOTL2 and PTEN D. in H2052 and H2373 treated as in B. AMOTL2 and Tubulin protein levels in D. were measured with the Odyssey Infrared Imaging System and relative expression normalized to H2052 t = 0 as shown. E., F. Relative AMOTL2 mRNA expression and protein level in H2373 cells stably expressing doxycycline-inducible shRNA, treated with 1μg/ml of doxycycline (DOX) for 72 hours and with 10μM of XAV939 or CTR in the 24 hours prior to lysing the cells. G.-I. TEAD reporter activity G. and relative mRNA expression levels of TEAD target genes H., I. in H2373 cells treated as in E. J. Representative images of colony formation by H2373 cells treated initially as in E and then cultured under the same conditions for a total of 14 days by replacing the media containing XAV939 or DOX, as indicated, every 48 hours. Error bars indicate SD of experiments performed in triplicate. *P≤0.05, **P≤0.01, ***P≤0.001. Student t-Test.

The Aaronson Research Team concluded in their Oncotarget Priority Research Paper that within the PARP superfamily, specific inhibitors of PARP1/2 are now in the clinic.

Efforts aimed at developing TNKS inhibitors to target Wnt activated tumors have recently led to new compounds with better drug-like properties compared to XAV939 with evidence of some efficacy in Wnt tumor models.

Nonetheless, stability issues, dose-limiting toxicity and weight loss attributed to Wnt inhibitory effects in the gastrointestinal tract pose challenges to their application as therapeutic agents.

Thus, TNKS inhibitors with improved drug-like properties and/or less toxicity will likely be needed.

However, the refractory nature of tumors such as mesothelioma to current treatments and the identification of angiomotin, whose stabilization by TNKS inhibitors specifically antagonizes the proliferation of such tumor cells, argues that approaches aimed at angiomotin stabilization could eventually lead to new targeted therapies for the increasing array of Hippo pathway deregulated tumors for which there are as yet no effective therapies.

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DOI - https://doi.org/10.18632/oncotarget.9117

Full text - https://www.oncotarget.com/article/9117/text/

Correspondence to - Stuart A. Aaronson - Stuart.Aaronson@mssm.edu

Keywords - tankyrase inhibitors, TEAD, YAP, angiomotin, tumor cell proliferation

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