Calcium signaling mediated by STIM1 and Orai1 activates Src to promote invadopodium assembly while simultaneously promoting MT1-MMP recycling to the plasma membrane to promote ECM degradation.
We present an integrated study to understand the key role of senescent
fibroblasts in driving melanoma progression. Based on the hybrid cellular
automata paradigm we developed an in silico model of normal
skin. The model focuses on key cellular and microenvironmental variables that
regulate interactions among keratinocytes, melanocytes and fibroblasts, key
components of the skin. The model recapitulates normal skin structure, and is
robust enough to withstand physical as well as biochemical perturbations.
Furthermore, the model predicted the important role of the skin microenvironment
in melanoma initiation and progression. Our in vitro
experiments showed that dermal fibroblasts, which are an important source of
growth factors in the skin, adopt a secretory phenotype that facilitates cancer
cell growth and invasion when they become senescent. Our co-culture experiments
showed that the senescent fibroblasts promoted the growth of non-tumorigenic
melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated
by these experimental results, we incorporated senescent fibroblasts into our
model and showed that senescent fibroblasts transform the skin microenvironment
and subsequently change the skin architecture by enhancing the growth and
invasion of normal melanocytes. The interaction between senescent fibroblasts
and the early stage melanoma cells leads to melanoma initiation and progression.
Of microenvironmental factors that senescent fibroblasts produce, proteases are
shown to be one of key contributing factors that promoted melanoma development
from our simulations. Although not a direct validation, we also observed
increased proteolytic activity in stromal fields adjacent to melanoma lesions in
human histology. This leads us to the conclusion that senescent fibroblasts may
create a pro-oncogenic skin microenvironment that cooperates with mutant
melanocytes to drive melanoma initiation and progression and should therefore be
considered as a potential future therapeutic target. Interestingly, our
simulations to test the effects of a stroma-targeting therapy that negates the
influence of proteolytic activity showed that the treatment could be effective
in delaying melanoma initiation and progression.
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