Mechanisms of Tumor Cell Plasticity

Research focus

In spite of significant improvement in cancer therapy, most cancer patients will not experience lasting benefit. Understanding why therapies fail and developing novel biomarkers and treatment paradigms to address these resistance mechanisms remains a central goal for cancer research. The group discovered that the receptor tyrosine kinase AXL is a key driver of acquired resistance to multiple cancer agents. By determining the molecular mechanism of AXL regulation of the tumor microenvironment, in concert with combination clinical trials with AXL targeting agents, a new paradigm to improve cancer treatment has emerged.

Subprojects and important results

1. AXL is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer 
Single-cell RNA-sequencing revealed that AXL is highly expressed in tumor cells that have EMT. AXL deficiency extended survival, reduced primary and metastatic burden, and enhanced sensitivity to gemcitabine in murine models of pancreatic ductal adenocarcinoma (PDA). PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, the group demonstrated that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA.

2. AXL in renal carcinoma 
High AXL-expression level in tumor cells was associated with lower response rates and a trend to shorter progression-free survival following anti-PD-1 treatment in clear-cell renal cell carcinoma (ccRCC). AXL expression was strongly associated with tumor-PD-L1 expression, especially in tumors with VHL inactivation. Moreover, patients with tumors displaying concomitant PD-L1 expression and high AXL expression had the worst overall survival. In orthotopic ccRCC murine models, AXL targeting with small molecule kinase inhibitor or function-blocking antibody inhibited tumor progression. These findings propose AXL as a candidate therapeutic target in advanced ccRCC.

Current challenges

Deeper understanding of the role of the tumor microenvironment (TME) during cancer initiation and progression is critical both to further cancer biology and as a source of improved molecular diagnostics and therapeutics.

Future plans

The group will focus on determining how AXL receptor signaling regulates acquired resistance to cancer therapy. The unique signal transduction of GAS6–AXL complexes will be studied using systems-level signal transduction analysis and high dimensional singlecell mapping of phenotypic-spatial features of the tumor microenvironment in preclinical models and cancer patient biopsy samples.