Interactions within the tumor microenvironment imprint metastatic traits in cancer cells (TUM6P.1001)

Abstract

Abstract Metastasis accounts for majority of deaths across cancer types. Tumor microenvironment plays an impotant role in enhancing metastatic propensity of cancer cells. To explore the mechanisms, we herein established a model by in vivo passaging the Lewis lung carcinoma (3LL) cells with 1-2 week of culture in between passages. When injected subcutaneously, 3LL cells have minimal metastasis, while in vivo passaged (p-)3LL cells showed robust metastasis. Sorted p-3LL cells from tumors of the whole body RFP transgenic mice were equally metastatic suggesting that cancer cell intrinsic changes are responsible for the metastatic imprinting. To identify the stromal cell population/s that crosstalk and imprint the metastatic traits in cancer cells, in vivo passages were performed in Rag2-/- mice and WT mice depleted of NK cells that resulted in similar metastatic imprinting excluding the role of adaptive immune and NK cells in this process. Depletion studies in WT mice and/or co-culture of 3LL cells with sorted myeloid cells indicated a critical role for CD11b+Gr1dim myeloid cells in metastatic imprinting. Comparison of gene expression profiles between 3LL and p-3LL cells by microarray showed enhanced expression of claudin-9 in p-3LL cells which was validated at protein levels in mouse and human lung cancers. These results indicate that interaction of CD11b+Gr1dim myeloid cells with cancer cell within tumor microenvironment imprints claudin-9 dependent metastatic traits in cancer cells.