Significance: These human data are consistent with reproductive control of liver size and function in women and concur with recent observations in rodents, suggesting a conserved liver biology. The question of whether this described liver biology has implications for maternal health during pregnancy or sex-specific risk for liver disease remains to be determined. However, our evidence suggestive of weaning-induced liver involution in women may lead to improved understanding of the high rates of liver metastasis observed in young postpartum breast cancer patients.

T cells are often compromised within cancers, allowing disease progression. We previously found that intratumoral elevations in extracellular K+, related to ongoing cell death, constrained CD8+ T-cell Akt–mTOR signaling and effector function. To alleviate K+-mediated T-cell dysfunction, we pursued genetic means to lower intracellular K+. CD8+ T cells robustly and dynamically express the Na+/K+ ATPase, among other K+ transporters. CRISPR-Cas9–mediated disruption of the Atp1a1 locus lowered intracellular K+ and elevated the resting membrane potential (i.e., Vm, Ψ). Despite compromised Ca2+ influx, Atp1a1-deficient T cells harbored tonic hyperactivity in multiple signal transduction cascades, along with a phenotype of exhaustion in mouse and human CD8+ T cells. Provision of exogenous K+ restored intracellular levels in Atp1a1-deficient T cells and prevented damaging levels of reactive oxygen species (ROS), and both antioxidant treatment and exogenous K+ prevented Atp1a1-deficient T-cell exhaustion in vitro. T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will require balancing the beneficial aspects of intracellular K+ with the ROS-dependent nature of T-cell effector function. See related Spotlight by Banuelos and Borges da Silva, p. 6

In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.

Lactation insufficiency is variously defined and includes the inability to produce milk, not producing enough milk to exclusively meet infant growth requirements, and pathological interruption of lactation (e.g., mastitis). Of women with intent-to-breastfeed, lactation insufficiency has been estimated to affect 38%–44% of newly postpartum women, likely contributing to the nearly 60% of infants that are not breastfed according to the World Health Organization’s guidelines. To date, research and clinical practice aimed at improving feeding outcomes have focused on hospital lactation support and education, with laudable results. However, researchers’ reports of recent rodent studies concerning fundamental lactation biology have suggested that the underlying pathologies of lactation insufficiency may be more nuanced than is currently appreciated. In this article, we identify mucosal biology of the breast and lactation-specific liver biology as two under-researched aspects of lactation physiology. Specifically, we argue that further scientific inquiry into reproductive state-dependent regulation of immunity in the human breast will reveal insights into novel immune based requirements for healthy lactation. Additionally, our synthesis of the literature supports the hypothesis that the liver is an essential player in lactation—highlighting the potential that pathologies of the liver may also be associated with lactation insufficiency. More research into these biologic underpinnings of lactation is anticipated to provide new avenues to understand and treat lactation insufficiency.

Pancreatic ductal adenocarcinoma (PDAC) tumors are hypovascular with collapsed and dysfunctional vessels that limit immunosurveillance and contribute to early metastatic events. However, current antiangiogenic therapies have failed in PDAC, highlighting the need to uncover the mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein human antigen R (HuR; ELAVL1) plays an important role in reshaping the tumor microenvironment by regulating the stability and translation of cell communication–encoding transcripts. We demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the tumor microenvironment via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. PDAC EVs contain an HuR-dependent mRNA and protein cargo related to endothelial cell function and angiogenesis. Treating endothelial cells with HuR wild-type (WT) EVs increased the expression of genes involved in barrier function and endothelial cell development and increased their migratory and tube-forming functions. In an immunocompetent mouse model of PDAC, we showed that HuR increased endothelial cell presence and sprouting, while decreasing intercellular adhesion molecule 1 (ICAM-1) expression. Using a genetic EV reporter, we found that ICAM-1 suppression in WT tumors occurred specifically in endothelial cells that had internalized WT EVs, suggesting that this signaling axis modulates endothelial cell behavior in vivo. Furthermore, administration of WT EVs rescued impaired HuR-knockout tumor growth, increased endothelial cell abundance, and decreased endothelial cell ICAM-1 expression. Collectively, our data reveal a novel role for HuR as a key mediator of EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior. Significance: Targeting the abnormal pancreatic cancer vasculature remains a significant barrier to immunosurveillance and drug delivery. This study demonstrated that the tumor-intrinsic protein HuR regulates pancreatic cancer EVs, which, in turn, alters endothelial cell behavior. These findings reveal a novel mechanism by which tumor-intrinsic factors shape the vascular microenvironment and suggest that altering EV content could modulate endothelial cell function.