Adrenomedullin 2 drives intratumoral cancer cell invasion, intravasation and metastasis
- 1Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1 Canada
- 2Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218 USA
- 3Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E1 Canada
Abstract
Cancer cell intravasation requires both directed invasion toward the vasculature and access to functional blood vessels that act as intravasation sites. Using intravital video microscopy, we identified the peptide hormone adrenomedullin 2 (ADM2) as a critical regulator of this process. ADM2 was selectively upregulated in a highly invasive subpopulation of cancer cells that localize near blood vessels and actively drive intravasation. Knockdown of ADM2 significantly impaired intratumoral cancer cell invasion and intravasation in a chicken embryo metastasis model and in vitro. ADM2-deficient tumors exhibited reduced vascularization, limiting the availability of competent intravasation sites. Moreover, loss of ADM2 suppressed the formation of invasive metastatic lesions, indicating a requirement for ADM2 at multiple stages of the metastatic cascade. Consistently, targeting ADM2 in a mouse metastasis model inhibited the development of large intratumoral blood vessels and reduced metastasis. Collectively, these findings establish ADM2 as a previously unrecognized regulator of tumor–vascular interactions and highlight its potential as a therapeutic target to simultaneously disrupt invasion, vascular support, and metastatic dissemination.
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BibTeX
@article{stoletov2026adrenomedullin,
title = {{Adrenomedullin 2 drives intratumoral cancer cell invasion, intravasation and metastasis}},
author = {Konstantin Stoletov and Seyedeh Sara Karimian and Douglas Brown and Alice Amitrano and Bishwa Ranjan Si and Varinder Madhav Verma and Somnath Gupta and Amirali B. Bukhari and Suellen Lamb and Konstantinos Konstantopoulos and Gane Ka-Shu Wong and John D. Lewis},
journal = {Oncogene},
year = {2026},
month = oct,
doi = {10.1038/s41388-026-04012-3},
url = {https://doi.org/10.1038/s41388-026-04012-3},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Adrenomedullin 2 drives intratumoral cancer cell invasion, intravasation and metastasis
AU - Konstantin Stoletov
AU - Seyedeh Sara Karimian
AU - Douglas Brown
AU - Alice Amitrano
AU - Bishwa Ranjan Si
AU - Varinder Madhav Verma
AU - Somnath Gupta
AU - Amirali B. Bukhari
AU - Suellen Lamb
AU - Konstantinos Konstantopoulos
AU - Gane Ka-Shu Wong
AU - John D. Lewis
PY - 2026
DA - 2026/10/10
JO - Oncogene
DO - 10.1038/s41388-026-04012-3
UR - https://doi.org/10.1038/s41388-026-04012-3
AB - Cancer cell intravasation requires both directed invasion toward the vasculature and access to functional blood vessels that act as intravasation sites. Using intravital video microscopy, we identified the peptide hormone adrenomedullin 2 (ADM2) as a critical regulator of this process. ADM2 was selectively upregulated in a highly invasive subpopulation of cancer cells that localize near blood vessels and actively drive intravasation. Knockdown of ADM2 significantly impaired intratumoral cancer cell invasion and intravasation in a chicken embryo metastasis model and in vitro. ADM2-deficient tumors exhibited reduced vascularization, limiting the availability of competent intravasation sites. Moreover, loss of ADM2 suppressed the formation of invasive metastatic lesions, indicating a requirement for ADM2 at multiple stages of the metastatic cascade. Consistently, targeting ADM2 in a mouse metastasis model inhibited the development of large intratumoral blood vessels and reduced metastasis. Collectively, these findings establish ADM2 as a previously unrecognized regulator of tumor–vascular interactions and highlight its potential as a therapeutic target to simultaneously disrupt invasion, vascular support, and metastatic dissemination.
SN - 0950-9232
SN - 1476-5594
ER -