Monday, May 12, 2025
5/12/2025
Novel functions of PlexinB2 in circulating tumor cell clusters - Abstract The outcomes of cancer metastasis result from the dynamic battles and interactive reprogramming between malignant cancer cells and the host defense system, especially immune cells. As one of the most challenging and unmet tasks in the cancer clinic, effective metastasis control or prevention demands better understanding and targeting strategies to reprogram the tumor-host ecosystems. The interplay is not only determined by evolving heterogeneity and regeneration of tumor cells but also the fitness of immune system. While tumor- infiltrated immune cells have been relatively well studied, the interactions between white blood cells (WBCs) and circulating tumor cells (CTCs) are only at the beginning to be elucidated. In this proposal, our goal is to identify molecular regulators of CTC-host interactions in one of the most aggressive subtypes of breast cancer, triple- negative breast cancer (TNBC) which lacks expression of estrogen receptor (ER), progesterone receptor (PR), and HER2 for targeted therapies, thereby blocking its metastasis to visceral organs such as the lungs. Combining computational ranking of proteomic candidates, tumor specific expression, and clinical association of breast cancer outcomes, we have identified one of the top enriched surface proteins in TNBC, PlexinB2 (PB2), which drives the formation of homotypic tumor clusters and heterotypic CTC-monocyte clusters through interactions with the Semaphorin ligands. CTC clusters with properties of stem cell plasticity and immune evasion are considered the seeds of distant metastases which account for 90% of solid tumor-related mortality. We hypothesize that targeting the PB2 pathway interferes with CTC-immune interactions and inhibits metastasis of TNBC. Three specific aims are proposed to test the hypothesis: (1) determine clinical relevance of the PB2 network in human TNBC, (2) dissect the molecular mechanisms underlying PB2-driven CTC cluster formation, and (3) targeting PB2 in CTC clusters and metastasis in preclinical modelsin vivo. As proof-of-concept, anti-PB2 neutralizing antibodies provide a new therapeutic opportunity to block CTC clusters and metastasis in TNBC.
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