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Publications of the Week

Oncogenic Activation of PI3K Induces Progenitor Cell Differentiation to Suppress Epidermal Growth

By November 21, 2018No Comments

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This week we profile a recent publication in Nature Cell Biology from the
laboratory of Dr. Slobodan Beronja (pictured) at Fred Hutchinson Cancer Center.

Can you provide a brief overview of your lab’s current research focus?

Cancer is a disease of two independent processes. The first one of these is clonal expansion, where a cell carrying a cancer driving mutation gains growth advantage over its neighbours and expands. The other is invasion, where clonally expanded populations of cells with cancer driving mutations break the constrains of the tissue and spread. Both of these processes are required but not sufficient for the disease. My lab’s general interest is in identifying cellular and molecular principles that contribute to clonal expansion. Specifically, we are focused on how stem cells and their biology contribute to this critical and early step in tumorigenesis. In our studies, we use skin (tissue of origin for the two most common cancers) and mammary epithelia in mice, together with sophisticated methods to disrupt gene function in vivo.

What is the significance of the findings in this publication?

Our recent work discovered stem cell differentiation as the primary block to oncogene-driven clonal expansion in skin epithelium. In doing so our study made several significant contributions. First, it established differentiation along with senescence and apoptosis as oncogene-driven tumor suppressive processes. Second, it provideed a detailed cellular and molecular mechanism for how skin may tolerate and therefore accumulate oncogenic lesions over time without showing any functional or morphological defects. Third, our study was focused on the most commonly mutated oncogene in epithelial cancer, and further highlighted the importance and feasibility of using physiological models of tissue growth where the full complement of cellular behaviors and molecular mechanisms can be investigated.

What are the next steps for this research?

Our study suggests a completely new and unanticipated hypothesis that stem cell differentiation is the dominant tumor suppressive force in skin. In effect, this suggests that stem cell fate choice rather than the trinity of proliferation/apoptosis/senescence is the critical driver of cancer. We are currently testing this hypothesis, under two independent conditions. One, where cell fate choice is regulated through cell autonomous means (i.e. additional mutations in cancer drivers), and the other where cell fate regulation is guided by signals coming from the microenvironment.

This research was funded by:

This research was supported by grants from the NIH (R00-AR061469) and a Thomsen Family Fellowship.

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