The Hanahan lab’s research program is centered upon the use of genetically engineered mouse models (GEMMs) of multistep de novo tumor development, growth, and malignant progression, where we chart pathways of tumorigenesis, seeking to understand the deterministic rate-limiting steps – and their mechanistic underpinnings – that define pathways to cancer. Historically the lab’s research has touched upon most of the hallmarks of cancer, the acquired capabilities thought to be instrumental for the disease. The strategic plan is twofold: 1) to elucidate functional and phenotypic manifestations, molecular and cellular mechanisms, and regulation of acquired hallmark capabilities, and 2) to translate knowledge of mechanisms toward clinical applications, in part via preclinical therapeutic trials that have promise to guide consideration of clinical trials. Currently the lab studies a number of organ-specific cancer models, each with distinctive attributes and potential to impact knowledge and cancer therapy.

The capability for invasion and metastasis acquired during tumor progression stands as the basis for much of the morbidity and mortality associated with cancer. It is also a remarkably diverse and complex parameter. We are studying various facets of this cancer phenotype, in multiple model systems. For example, we discovered a regulatory pathway, which activates invasiveness and is triggered by mechanical forces resultant to differences in hydrostatic pressure between solid tumors and their surrounding tissue, resulting in fluid flow out of the tumor. The pressure-driven fluid flow induces secretion of glutamate, which, in cancer cells expressing the neuronal signaling receptor NMDAR, activates it, stimulating an invasive growth program (Li and Hanahan, 2013). We continue to investigate this invasive growth program in pancreatic and triple negative breast cancer, where it may define a heretofore unappreciated subtype that has coopted glutamate signaling to help drive the malignant phenotype.

One fascinating research direction involves elucidating adaptive resistance mechanisms – acquired and intrinsic – to hallmark targeting therapies. The game plan is to identify such mechanisms, and then circumvent them pharmacologically, directly or indirectly. In regard to the latter, we are testing the hypothesis that multi-targeting distinct hallmarks may pose a significant challenge to the evolution of drug resistance, requiring simultaneous adaptations to multiple therapy-impaired hallmarks, thereby improving the duration of treatment response. One can envision, in a future where incipient resistance can be detected early, a war plan involving multi-pronged sequential attacks. The Hanahan lab is flight-testing mechanism-targeted drugs aimed at adaptive resistance as well as hallmark co-targeting strategies, in models of pancreas cancer, melanoma, glioblastoma, and cervical cancer.