Abstract 80: Utilizing a decellularized PDX tumor matrix model to investigate LKB1 regulation of ECM remodeling in TNBC

Abstract

Abstract Triple negative breast cancer (TNBC) is an aggressive disease with poor prognoses, partly due to the lack of clinically approved targeted therapeutics. The mechanisms underlying the process of drug resistance in TNBC remain elusive, prompting the need for the identification of kinase targets. Our lab previously found that liver kinase B1 (LKB1) overexpression inhibits the migratory phenotype and pathways involved in EMT of TNBC. However, the specific mechanisms in which LKB1 suppresses TNBC metastasis have not been fully elucidated. We believe that overexpression of LKB1 inhibits the migratory axis by inhibiting ECM remodeling that promotes invasion in TNBC. Here we utilize our novel decellularized patient-derived xenograft (PDX) TNBC model, TU-BcX-2K1 (“2K1”) tumor scaffold, to test this hypothesis. We seeded MDA-MB-231-LKB1 overexpressed and MDA-MB-231-vector cells onto decellularized 2K1 PDX tumor scaffold or decellularized adipose tissue (“AT”) and implanted our model into SCID/beige mice. Results demonstrated that tumor matrix enhanced cancer cell growth in both MDA-MB-231-vector and -LKB1 cell lines. LKB1 on adipose scaffold did not have tumor formation. These data suggest a novel microenvironment dependent function of LKB1. We compared the number of metastases in the lungs and livers excised from mice in each group. There were significantly more lung metastases in the 2K1+MDA-MB-231-vector group than in the AT+MDA-MB-231-vector group (p-value = 0.0144). There were slightly more lung metastases in the AT-MDA-MB-231-LKB1 group than in the 2K1+MDA-MB-231-LKB1 group, albeit not significantly. There were more liver metastases in the 2K1+MDA-MB-231-vector group than in the AT+MDA-MB-231-vector group, albeit not significantly. There were also more liver metastases in the 2K1+MDA-MB-231-LKB1 group than in the AT+MDA-MB-231-LKB1 group; however, there was no significance. LKB1 appeared to inhibit stromal remodeling in tumor, evident from decreased collagen composition and stromal cell infiltration. In vitro validation of this demonstrated that LKB1 secretome was able to inhibit adipogenesis of stem cells. To further test LKB1's role in stromal remodeling, we performed an in vivo experiment co-injecting MDA-MB-231-LKB1 and MDA-MB-231-vector cells with ASCs into SCID/beige mice. MDA-MB-231-LKB1 tumors grew significantly slower than MDA-MB-231-vector tumors (p-value = 0.0097). There was no significant difference in tumor growth in the MDA-MB-231-LKB1+ASCs and MDA-MB-231-vector+ASCs groups. We compared differences in the number of lung and liver metastases in each group. We investigated stromal remodeling in tumors in each group. Our data show how the ECM alters cancer cell response, inducing LKB1 overexpressed cells to become more aggressive. The data presented here will help elucidate the cell-matrix interactions that are vital in migration and invasion in TNBC. Citation Format: Maryl Wright, Margarite Matossian, Madlin Alzoubi, Conner King, Steven Elliott, Melyssa Bratton, Elizabeth Martin, Bridgette Collins-Burow, Matthew Burow. Utilizing a decellularized PDX tumor matrix model to investigate LKB1 regulation of ECM remodeling in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 80.