Abstract A041: Deciphering the crosstalk between cancer cells and stroma that drives EMT- coupled fibrosis

Abstract

Abstract In the tumor microenvironment (TME) cancer cells engage dynamically with the stromal component in promoting tumor progression and metastasis formation that are accompanied by intratumor fibrosis. Extensive extracellular matrix (ECM) remodeling and stiffness boost fibrosis which co-occurs with poor immune infiltration. Very little is known about the cross-interactions between tumor cells and stroma. A better understanding of this dynamic relationship may advance the development of new therapies. Transforming growth factor (TGF)-β signaling in both cancer epithelial cells and stroma is crucial for the establishment of intratumor fibrosis that enhances tumor progression. We previously discovered that in cancer cells, TGF-β signaling synergizes with RAS signal to regulate classical EMT transcription factors (Snail, Zeb1) and fibrogenic factors (Il11, Pdgf, Ctgfb, Wisp and others). This synergistic program is required for metastasis formation in pancreatic and lung adenocarcinoma (LUAD) models. However, how this dual program is affecting the stromal population in vivo remains unknown. Additionally, the role of each TGF-β dependent fibrogenic factor in regulating the stroma is still unclear. Using metastasis in vivo assays, we tested the metastatic ability of LUAD cells wild-type in comparison to Knock-Out cells targeting each one of the TGF-β dependent fibrogenic factors. We found that these factors are drivers of metastasis. More interestingly, these fibrogenic factors have a preferential effect depending on the metastatic site, suggesting that survival of the cancer cells in a certain tissue is dependent on the stromal niche within the site, which will act in favor or not of their growth. We also deeply characterize the stroma of micro-metastatic lesions by using high-throughput multiplex immunofluorescence to analyze the whole tissue TME at single cell resolution and found that lack of any of these fibrogenic factors compromise the establishment of a robust ECM at the very beginning of the metastatic colonization, to favor immune infiltration and consequently lead to cancer cell clearance. Together, these findings shed light on the potential role of these specific fibrogenic factors in metastasis, how their absence impacts the TME and how targeting these factors could be beneficial in metastatic disease. Citation Format: Elena Spina, Liangji Li, Junho Lee, Joan Massaguè. Deciphering the crosstalk between cancer cells and stroma that drives EMT- coupled fibrosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A041.