Abstract
Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a chromatin modifier, histone deacetylase 11 (HDAC11). Genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, yet substantially increases migration and distant metastasis formation. Collectively, we reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors.
Highlights
Lymph node (LN) metastases correspond with a worse prognosis in most cancers, yet the occurrence of cancer spreading from lymph nodes (LNs) remains controversial
Because a recent report found no evidence that LN metastases were required for the development of distant metastases in breast cancer[11], we first analyzed a cohort of seven breast cancer patients from the University of North Carolina Breast Cancer Rapid Autopsy Program (UNC RAP) for whom primary tumors (T), LN metastasis (L), and distant metastases (D) were collected[21]
If in a patient’s phylogenetic tree we observed that at least one distant metastasis sample was in the same clade with a LN sample and no other primary sample, we concluded it as “LN-met mediated,” which implies that the LN metastases gave rise to one or more distant metastases
Summary
Lymph node (LN) metastases correspond with a worse prognosis in most cancers, yet the occurrence of cancer spreading from LNs remains controversial. We reveal a mechanism explaining how HDAC11 plasticity promotes breast cancer growth as well as dissemination from LNs and suggest caution with the use of HDAC inhibitors. The mechanistic underpinnings explaining how tumor cells exit the LN are still unknown This represents a critical knowledge gap in metastatic biology[20], especially because the mechanisms governing LN metastasis may be unique from those promoting direct hematogenous spread from the primary lesion. While genetic and pharmacologic blockade of HDAC11 decreases LN tumor growth, it substantially increases migration and promotes distant metastasis formation. Our findings demonstrate that establishment of LN metastasis, and egress from LNs to distant sites, is both highly efficient and dynamic These findings reveal a context for evaluation of cancer therapeutics and suggest caution with the use of HDAC inhibitors (HDACis)
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