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Targeting invadopodia in head and neck cancer metastasis

Institution: University of California, San Diego
Investigator(s): Jing Yang, Ph.D.
Award Cycle: 2019 (Cycle 28) Grant #: 28IP-0023 Award: $498,393
Subject Area: Cancer
Award Type: High Impact Pilot Award

Initial Award Abstract

Tobacco use is a main rick factor for head and neck squamous cell carcinoma (HNSCC).

While localized HNSCCs have 70-90% cure rates, the median survival for metastatic HNSCCs is only 5-9 months.  Therefore, there are urgent unmet needs to provide better prognostic markers for metastatic disease stratification and to develop effective therapies to prevent HNSCC metastasis.

Degradation of extracellular matrix (ECM) is essential for cancer cell invasion and metastasis.  Proteolytic activity is associated with increased metastasis and poor clinical outcome in HNSCC.  However, numerous MMP inhibitors have failed in clinical trials of HNSCC cancer partially due to the anti-tumorigenic roles of MMPs in immune cells.   Recent research shows that instead of using secreted MMPs, HNSCC tumor cells concentrate various matrix proteases, including MMPs, at specialized membrane protrusions termed invadopodia to carry out focal ECM degradation.  The ability to concentrate proteases at focal points for ECM degradation differentiates invadopodia from other actin-based protrusions.  This unique character presents a regulatory program to target invadopodia for anti-metastatic HNSCC therapy without affecting actin dynamics in normal cells and causing overall toxicity.  However, the molecular mechanism to recruit and activate proteases at invadopodia in metastatic HNSCC tumor cells remains largely unexplored. 

In this pilot project, we aim to use an innovative new technology to identify novel proteins that promote matrix degradation and HNSCC tumor metastasis.  The ultimate goal of this pilot project is to understand how invadopodia are assembled and regulated to degrade matrix and drive HNSCC tumor metastasis. 

Our proposed research has direct therapeutic implication.  First, our research could identify novel proteins that promote HNSCC tumor invasion and metastasis.  These candidate could serve as prognosis markers for HNSCC metastasis and patient long-term survival.   Given the essential role of invadopodia in HNSCC tumor metastasis, our research will also identify effective molecular targets for anti-metastasis therapy in HNSCC.