Abstract 3859: Remodeling the extracellular matrix environment enables the dissemination of primary tumor cells through a chemokine gradient to establish brain metastasis in non-small cell lung cancer adenocarcinoma
Authors: Wang Albert R. , Khullar Saniya , Brown Jared , Baschnagel Andrew , Buehler Darya , Kendziorski Christina , Iyer Gopal 
Published: June 2022

Abstract
Dissemination of tumor cells from the primary site of the lung to distant sites in non-small cell lung cancer (NSCLC) is poorly understood. With distinct mutation signatures in patients, altering pathways is critical to preventing tumor cell dissemination to distant sites. Towards this, we characterized 21 "trios" patient-matched brain metastases (BT), primary tumors (LT), and normal samples (LN), revealing a pattern of extracellular matrix remodeling which suppressed immune cell infiltration. Our objectives were to (i) determine if clinically sampled primary lung tumors encode gene expression patterns distinct from normal tissue, suggestive of increased tumor invasiveness including brain metastasis (ii) determine the biologic underpinning of immune-suppressive information carryover from primary lung tumor to brain metastasis and (iii) determine if synchronous and metachronous (time to disease) clinically sample brain metastases tumors converge on a common signaling mechanism. Transformation of the normal lung cells to primary tumor cells suggested a breakdown in ECM axes primarily governed by upregulation of collagen (COL1A1, COL1A2, COL3A1, COL10A1), fibronectin (FN1), and matrix metalloproteinases (MMP7, MMP9, MMP11, MMP12, MMP13, MMP14) genes. Collectively, the primary tumor cells used MMPs to break down the main components of lung ECM and reorganized collagen and fibronectin in the tumor microenvironment to facilitate migration and invasion. With a disorganized ECM present in LT, a chemokine gradient from LT to BT was discernable with sustained FN1 expression that allowed dissemination into the brain microenvironment. Migration and subsequent cell adhesion in the brain microenvironment revealed upregulation of neural cell adhesion molecule (NCAM1) and phosphoprotein 1 (SPP1). These changes in ECM profiles between LT and BT signify primary tumor cells' adaptation in the brain microenvironment. Further computational deconvolution revealed reduced HLA class II gene expression (HLA-DMA, HLA-DOB, HLA-DPA1, HLADPB1, HLA-DQA2, HLA-DQB2, HLA-DRA) correlated with a lower immune enrichment score of CD4+ T cells in synchronous tumors while metachronous tumors had distinct HLA expression profile. Overall, using the matched sequencing information, we will present the underlying signaling gradients that dictate dissemination of primary lung tumor cells to the brain environment in the background of altered ECM environment using cellular models harboring EGFR, KRAS, and ALK driver mutations cocultured with other cell types such as liver and breast.
Citation Format: Albert R. Wang, Saniya Khullar, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer. Remodeling the extracellular matrix environment enables the dissemination of primary tumor cells through a chemokine gradient to establish brain metastasis in non-small cell lung cancer adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3859.