University of Cambridge > > Cambridge Oncology Seminar Series > Metastasis latency: new molecular insights

Metastasis latency: new molecular insights

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Host: Sakari Vanharanta

Roger R. Gomis

Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain and ICREA , Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

Although breast cancer (BCa) can relapse to bones, lungs and liver as well as brain, metastasis frequently becomes prevalent in one organ long before it does in others, and brain metastasis tends to be a late event. The ability to metastasize to a secondary site can be stochastic, owing to new interactions between the tumor cell and the target microenvironment, or can be encoded by the arriving tumor cell. The slow progression of certain subtypes of BC under these different selective conditions gives rise to metastatic speciation, as suggested by the different kinetics of BC relapse to different sites in the same patient, and by the coexistence of malignant cells with different organ tropisms in patient-derived samples. We aimed to set the stage for the detailed study of the mechanisms of metastasis and their potential value as therapeutic targets.

For many BCa patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometmastatic lesions remain dormant and undetectable yet initiate colonization, are major questions in cancer research. We identify and functionally analyse a molecular mechanism involved in bone metastatic latency of estrogen receptor–positive (ER)+ BCa. We developed an in vivo loss-of-function, genome-wide shRNA screening to identify genes relevant for long-latent relapse in BCa. This screen revealed an important regulator of metastatic dormancy. Notably, low expression associates with early metastasis in ER+ BCa patients and reduced levels impaired cellular differentiation of metastatic cells. These effects are mediated through modulation of chromatin status at promoters to regulate the expression of luminal differentiation genes, which prevent the progression of ER+ BCa towards metastasis. Our results identify the regulation of luminal cell differentiation via modulation of chromatin remodelling to be a key mechanism for controlling metastatic dormancy in BCa.

Recently, we have also examined the mechanisms that allow prostate and BCa cells to metabolically sustain rapid growth in the primary and distant sites. Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Cancer genes (oncogenes and tumor suppressors) maintain the metabolic homeostasis when functional, and alterations in these genes promote an imbalance in the metabolic homeostasis and induce the metabolic switch. The metabolic switch in cancer encompasses a plethora of discrete enzymatic activities that must be coordinately altered to ensure the generation of biomass, reductive power and the remodeling of the microenvironment. In BCa, we reveal that FoxA factors provide a central metabolic growth function by specifically regulating LIPG expression, thereby allowing the acquisition of indispensable extracellular lipids for tumor proliferation, whereas in prostate cancer, PGC1 α acts a master regulator of metabolism that opposes the dissemination of the disease.

This talk is part of the Cambridge Oncology Seminar Series series.

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