Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated ß2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of ß2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer.

The complex web of canonical and non-canonical Hedgehog signaling.

Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non-canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia - microtubule-based signaling hubs - an extensive list of crucial functions mediated by non-canonical Hh signaling has emerged. Moreover, amounting evidence indicates that canonical and non-canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non-canonical signaling and discuss new evidence indicating inter-relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics.

A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.

Primary cilia function as critical signaling hubs whose absence leads to severe disorders collectively known as ciliopathies; our knowledge of ciliogenesis remains limited. We show that Smo induces ciliogenesis through two distinct yet essential noncanonical Hh pathways in several cell types, including neurons. Surprisingly, ligand activation of Smo induces autophagy via an LKB1-AMPK axis to remove the satellite pool of OFD1. This is required, but not sufficient, for ciliogenesis. Additionally, Smo activates the Gαi-LGN-NuMA-dynein axis, causing accumulation of a portion of OFD1 at centrioles in early ciliogenesis. Both pathways are critical for redistribution of BBS4 from satellites to centrioles, which is also mediated by OFD1 centriolar translocation. Notably, different Smo agonists, which activate Smo distinctly, activate one or the other of these pathways; only in combination they recapitulate the activity of Hh ligand. These studies provide new insight into physiological stimuli (Hh) that activate autophagy and promote ciliogenesis and introduce a novel role for the Gαi-LGN-NuMA-dynein complex in this process.

Microtubules and actin crosstalk in cell migration and division.

Crosstalk between the actin cytoskeleton and microtubules promotes symmetry break to polarize cells for division, shape changes, and migration. These cellular events are crucial for forming tissues, and drive the metastasis of cancer cells. Rho GTPases mediate the formation of different types of F-actin that confer changes in cortical tension and contraction, and can be regulated by microtubules. For example, central spindle microtubules of the mitotic spindle stimulate RhoA activity to form long, unbranched F-actin that is crosslinked by nonmuscle myosin to form the contractile ring in the equatorial plane of the cell. There is greater cortical tension in this area of the cell in comparison to the poles, where the formation of short, branched F-actin is favored. In migrating cells, growing microtubules that reach into the leading edge promote Rac activation and the formation of short, branched F-actin for lamellipodia formation. A common theme that is emerging in many fields is that feedback can also occur from the cortex to alter microtubule stability. In this manner, cells can dynamically respond to intrinsic or extrinsic cues to ensure that their division plane is always coupled with the segregation of DNA and cell fate determinants, or that they migrate properly to form a tissue.