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Dissection of the impact of tissue context on anti-cancer drug activity through the use of high dimensional combinatorial microenvironment analysis


Breast cancer alone accounts for 29 % of all new cancer diagnoses and is the second leading cause of cancer related death. Improvement in early detection and the understanding of oncogenic drivers connected to malignant transformation and cancer progression has lead to an overall decrease in breast cancer related mortality1. However, therapeutic durability remains a problem for both chemotherapies and pathway-targeted drugs. Furthermore, the poor translation from pre-clinical screening results to clinical outcomes impedes therapeutic development.

Genomic heterogeneity and other cell intrinsic mechanisms are commonly examined as a major source of therapeutic failure. Using a reductionist approach, I examined the hypothesis that the tissue microenvironment is a potent modulator of drug activity and therapeutic response. I first tested the hypothesis that matrix rigidity of microenvironments can modulate the efficacy of the targeted-therapeutic small molecule, lapatinib, in HER2-amplified breast cancer cell lines. The anti-proliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesive substrates. The modulus-dependent lapatinib responses were eliminated with treatment of mechanosensing inhibitors, Y27632 and blebbistatin. Knockdown of the hippo pathway mechanotransducer, YAP, eliminated the modulus-dependent lapatinib responses, and pharmacological inhibition of YAP phenocopied the effect of YAP knockdown. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, these showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus, I addressed the role of stiffness in resistance to, and efficacy of, a HER2 pathway-targeted therapeutic via the mechanotransduction arm of the hippo pathway.

In order to dissect and investigate the microenvironmental impact on drug responses, we developed the MicroEnvironmental microarray, (MEArray) platform. The method allows for simultaneous control of the molecular composition and the elastic modulus. Utilizing the MEArray, I further tested the hypothesis that in addition to matrix rigidity, molecular composition can modulate lapatinib responses. I systematically quantified the microenvironmental impact on cellular morphological changes and the lapatinib responses. The results were consistent with our previous report that matrix rigidity conferred lapatinib resistance. I also identified that cells adhered to fibronectin showed higher lapatinib resistance independent of stiffness. The validations showed that fibronectin conferred nuclear YAP translocation, which may explain partly the mechanism of the lapatinib resistance. Further studies for elucidation of fibronectin-induced lapatinib resistance are needed. However, simultaneous modulation of stiffness and molecular composition revealed a continuum of drug responses resulting from cell-microenvironment interactions.

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