Mutated HRAS Activates YAP1–AXL Signaling to Drive Metastasis of Head and Neck Cancer

Sankar Jagadeeshan, Manu Prasad, Mai Badarni, Talal Ben-Lulu, Vijayasteltar Belsamma Liju, Sooraj Mathukkada, Claire Saunders, Avital Beeri Shnerb, Jonathan Zorea, Ksenia M. Yegodayev, Monica Wainer, Liza Vtorov, Irit Allon, Ofir Cohen, Gro Gausdal, Dinorah Friedmann-Morvinski, Sok Ching Cheong, Alan L. Ho, Ari J. Rosenberg, Linda KesslerFrancis Burrows, Dexin Kong, Jennifer R. Grandis, J. Silvio Gutkind, Moshe Elkabets*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 syngeneic 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 promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling 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 vascular 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 tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.

Original languageEnglish
Pages (from-to)1031-1047
Number of pages17
JournalCancer Research
Issue number7
StatePublished - 1 Apr 2023


FundersFunder number
Kura Oncology
NSFC Israel–China3409/20
Pangea Therapeutics
National Institutes of Health
National Cancer InstituteP30 CA008748
National Cancer Institute
United States-Israel Binational Science Foundation2021055
United States-Israel Binational Science Foundation
Israel Science Foundation302/21
Israel Science Foundation
Tel Aviv University
Ben-Gurion University of the Negev
Council for Higher Education


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