PROJECT SUMMARY / ABSTRACT
Small cell lung cancer (SCLC) is a recalcitrant cancer that causes 250,000 deaths
worldwide each year. Patients with SCLC initially respond to cytotoxic therapies but almost
invariably relapse with therapy resistant disease. Moreover, when diagnosed, many patients have
metastases in distant organs including the liver, which represents a major impediment to
successful therapy. The metastatic cascade involves cancer cell interactions with many normal
cell types, which are thought to provide by pro- and anti-metastatic signals. Recent studies have
shown that endothelial cells (ECs) play important and diverse roles in metastasis of different
cancer types. However, our understanding of the molecular and cellular interactions between
SCLC cells and ECs in liver metastasis remains incomplete and no therapies exist to prevent or
stop these interactions, which marks great therapeutic possibilities for target treatment for SCLC
patients in clinic. In this proposed study, I hypothesize that SCLC-EC interactions alter the cell
state of both cell types and these changes are critical for SCLC liver metastasis. To
systemically study the reciprocal interactions between SCLC cells and ECs, I have developed an
innovative method to qualitatively record physical interactions between various cell types (GFP-
based Touching Nexus, G-baToN). Meanwhile, my mentors' labs have generated somatic
CRISPR genome editing mouse models and high-throughput tumor barcode sequencing
platforms which I will employ to deconvolute metastatic burden, metastatic seeding, and clonal
expansion in SCLC liver metastasis. By leveraging all these cutting-edge techniques, this project
aims to characterize the role of SCLC-activated ECs in SCLC liver metastasis through studying
the function of the CXCLs-CXCR2 axis (Aim 1) and other cell-cell interaction related EC genes
(Aim 2). On the other hand, this project will also quantitatively assess the impact of EC-induced
SCLC alternations in liver metastasis (Aim 3). Taken together, this project will uncover new
mechanistic insights in SCLC metastasis, establish new strategies for investigating cancer-
stromal interactions in vitro and in vivo, and identify new therapeutic possibilities to better treat
SCLC patients.