Abstract 6431: Endothelial SPARCL1 suppresses colorectal cancer metastases through dormancy induction and EMT inhibition in colonizing tumor cells

Colorectal cancer (CRC) is a leading cause of cancer-related death, with distant metastases as the major cause of death. Tumor progression is highly influenced by the tumor microenvironment (TME). Within the TME, angiogenesis is generally considered to support primary tumor growth and metastasis. However, we recently found that in prognostically favorable TME, the vasculature can also actively counteract primary tumor progression. This is due to the secretion of anti-tumorigenic proteins such as SPARCL1, which is actively released by endothelial cells of the blood vessels, fostering vascular homeostasis and inhibiting tumor cell growth. During metastatic colonization of distant organs, tumor cells frequently enter a latent state in close proximity to blood vessels, which can sometimes last for decades. It is currently unknown which factors regulate this long-term latency of tumor cells. Probable candidates are factors released by the endothelial cells, since both cell types are in close proximity to each other. In the present study, we investigated whether endothelial SPARCL1 can contribute to latency induction of disseminated metastatic tumor cells in the target tissues of CRC metastases. Through an integrative analysis of several CRC animal models and human patient samples, we found that SPARCL1 expression is associated with lower rates of metastasis after surgery. Moreover, SPARCL1 downregulation in three different CRC animal models, including novel metastatic organoid models, resulted in the formation of significantly increased numbers of micro-metastases. This increase was observed in particular under conditions in which tumors initiated from single or small numbers of tumor cells, which closely resembles metastatic colonization in humans. RNAseq of CRC lung metastases tissue and re-isolated tumor organoids thereof revealed deregulation of EMT and dormancy-related signaling pathways. Consistent with this, the addition of recombinant SPARCL1 to mouse tumor organoids, 2D mouse colorectal cancer cell lines, or patient-derived tumor organoids induced quiescence and downregulated key EMT markers in the tumor cells, without affecting cell death in vitro and in vivo. In summary, this study demonstrates that SPARCL1 secreted by endothelial cells of blood vessels in the target organs of CRC metastases induces dormancy in disseminated tumor cells and inhibits EMT, thereby significantly reducing metastasis. These results emphasize the potential of the tumor vasculature to actively contribute to tumor control in a TME-dependent manner and open up new perspectives for therapeutic interventions and patient stratification. Citation Format: Bisan A. Zohud, Qi Fang, Clara Tenkerian, Tim Thoenissen, Jisheng Chen, Johannes Schloderer, Zoltán Winter, Philip Eichhorn, Susanne Merkel, Renato Liguori, Fulvia Ferrazzi, Florian R. Greten, Tobias Bäuerle, Marc P. Stemmler, Thomas Brabletz, Rene Jackstadt, Claudia Günther, Michael Stürzl, Elisabeth Naschberger. Endothelial SPARCL1 suppresses colorectal cancer metastases through dormancy induction and EMT inhibition in colonizing tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6431.