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Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. However, how the necrotic core promotes tumor cell dissemination and metastasis remains unclear. Foundational models for cancer metastasis research include mouse, zebrafish, and chick embryo, but identifying tumor cells in transit is painstaking. Here we used a rat model of breast cancer metastasis to increase detection of dissemination events. Owing to the large size and higher blood volume of rats, we collected 10 times more circulating tumor cells (CTCs) than from mice. In the rat model, tumor dissemination was temporally correlated with the emergence of necrosis in the tumor interior. These findings were corroborated by longitudinal study of CTC abundance and tissue necrosis markers in blood plasma from patients with metastatic breast cancer. Further, we observed that dilated blood vessels were located next to necrotic regions of the tumor and that their increase was concurrent with the initiation of intratumoral necrosis and increase in CTC abundance. Bulk RNA sequencing of mouse-to-rat xenograft tumor necrotic core compared to the non-necrotic rim revealed distinct tumor-specific and host-specific transcripts in the necrotic interior. We identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the peri-necrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, peri-necrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promoted vascular permeability and supported vascular remodeling in the peri-necrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core. Tumor dissemination events are localized spatially to dilated peri-necrotic vessels in the tumor interior, and tumor dissemination is dependent functionally on the expression of a factor, Angptl7, produced by peri-necrotic tumor cells. Our findings in breast cancer models, in conjunction with recent clinical observations, provide strong evidence for tumor dissemination from the tumor interior. Citation Format: Ami Yamamoto, Yin Huang, Brad A. Krajina, Margaux McBirney, Andrea E. Doak, Carolyn L. Wang, Michael C. Haffner, Kevin J. Cheung. Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B049. |
