Jagadeeshan, Sankar and Prasad, Manu and Badarni, Mai and Ben-Lulu, Talal and Liju, Vijayasteltar Belsamma and Mathukkada, Sooraj and Saunders, Claire and Shnerb, Avital Beeri and Zorea, Jonathan and Yegodayev, Ksenia M. and Wainer, Monica and Vtorov, Liza and Allon, Irit and Cohen, Ofir and Gausdal, Gro and Friedmann-Morvinski, Dinorah and Cheong, Sok Ching and Ho, Alan L. and Rosenberg, Ari J. and Kessler, Linda and Burrows, Francis and Kong, Dexin and Grandis, Jennifer R. and Gutkind, J. Silvio and Elkabets, Moshe (2023) Mutated HRAS activates YAP1-AXL signaling to drive metastasis of head and neck cancer. Cancer Research, 83 (7). pp. 1031-1047. ISSN 0008-5472, DOI https://doi.org/10.1158/0008-5472.CAN-22-2586.
Full text not available from this repository.Abstract
The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut synge-neic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut pro-moted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS sig-naling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vas-cular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifar-nib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.Significance: Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.
| Item Type: | Article |
|---|---|
| Funders: | National Cancer Institute [Grant No: P30 CA008748] |
| Uncontrolled Keywords: | Cell Line, Tumor; Head and Neck Neoplasms; Humans; Proteomics; Proto-Oncogene Proteins p21(ras); Signal Transduction; Transcription Factors |
| Subjects: | R Medicine > RC Internal medicine R Medicine > RD Surgery |
| Divisions: | Faculty of Dentistry > Department of Oral & Maxillofacial Clinical Sciences |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 08 Nov 2024 02:46 |
| Last Modified: | 08 Nov 2024 02:46 |
| URI: | http://eprints.um.edu.my/id/eprint/38340 |
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