Mechanisms associated with organotropic metastasis

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ABSTRACT Most cancer patients with solid tumors die of metastatic disease and organotropic spread is an understudied aspect of metastasis, for which new insights are urgently required. The prevailing `seed and soil' concept posits that permissive environment in a distant organ (soil) is necessary to support the survival and growth of lurking tumor cells (seeds). Induction of permissive soil in a non-metastatic organ is proposed to re-route metastasis; however, rigorous experimental evidence and mechanistic analyses are lacking. Our preliminary data suggest organotropic metastasis is not solely dependent on the permissive metastatic extracellular matrix (ECM) remodeling and BMDCs in the secondary organs but is also controlled by the vascular endothelial cell junction proteins and their ability to maintain barrier function. Our preliminary studies suggest endothelial barriers guide organotropic spread of metastasis. Our central hypothesis for this proposal is `vascular heterogeneity functionally contributes to organotropic metastasis.' We demonstrate organ-specific vascular diversity may play a role in organotropic metastasis. Here we propose studies to unravel the mechanisms by which tissue fibrosis influences organ-specific changes in the vascular beds, leading to organotropic metastasis associated with breast cancer. The studies from our group established a variety of novel transgenic mouse models and identified the functional roles of type I collagen (Col1), the most abundant protein in the human body, the tumor microenvironment, and fibrotic tissues. The studies from our group generated two novel genetically engineered mouse model (GEMM) systems. In specific, KPPF;Col1smaKO (FSF-KrasG12D/+;Trp53frt/frt;Pdx1-Flp;SMA- Cre;Col1a1loxP/loxP) mouse model allows genetic deletion of Col1 in αSMA+ fibroblasts in the autochthonous PDAC background. Col1 deletion in fibroblasts accelerates tumor progression and immunosuppression, leading to shortened overall survival. In comparison, KPPC (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1- Cre;Col1a1loxP/loxP) mice mouse model allows genetic deletion of Col1 in cancer cells in similar autochthonous PDAC background. Col1 deletion in fibroblasts delays tumor progression and alleviates immunosuppression, leading to prolonged overall survival. Mechanistic studies revealed that fibroblast-derived Col1 is normal Col1 heterotrimers composed of 1 and 2 chains. In contrast, cancer cell-derived Col1 is a unique Col1 homotrimers composed of only 1 chains. In this study, we will further examine the effects of Col1 subtypes (homotrimers versus heterotrimers) on cancer cell invasiveness and metastasis.