Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles, which are aggregated under this term because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Massively parallel sequencing and other omics technologies have demonstrated the level of heterogeneity in TNBCs and shed light into the pathogenesis of this therapeutically challenging entity in breast cancer. In this review, we discuss the histologic and molecular classifications of TNBC, the genomic alterations these different tumor types harbor, and the potential impact of these alterations on the pathogenesis of these tumors. We also explore the role of the tumor microenvironment in the biology of TNBCs and its potential impact on therapeutic response. Dissecting the biology and understanding the therapeutic dependencies of each TNBC subtype will be essential to delivering on the promise of precision medicine for patients with triple-negative disease.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

Apnoeas constitute an acute existential threat to neonates and adults. In large part, this threat is detected by the carotid bodies, which are the primary peripheral chemoreceptors, and is combatted by arousal and acute cardiorespiratory responses, including increased sympathetic output. Similar responses occur with repeated apnoeas but they continue beyond the last apnoea and can persist for hours [i.e. ventilatory and sympathetic long-term facilitation (LTF)]. These long-term effects may be adaptive during acute episodic apnoea, although they may prolong hypertension causing chronic cardiovascular impairment. We report a novel mechanism of acute carotid body (CB) plasticity (sensory LTF) induced by repeated apnoea-like stimuli [i.e. acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc)]. This plasticity did not require chronic intermittent hypoxia preconditioning, was dependent on P2X receptors and protein kinase C, and involved heat-sensitive transient receptor potential vanilloid type 1 (TRPV1) receptors. Reactive oxygen species (O ·¯) were involved in initiating plasticity only; no evidence was found for H O involvement. Angiotensin II and 5-HT receptor antagonists, losartan and ketanserin, severely reduced CB responses to individual hypoxic-hypercapnic challenges and prevented the induction of sensory LTF but, if applied after AIH-Hc, failed to reduce plasticity-associated activity. Conversely, TRPV1 receptor antagonism had no effect on responses to individual hypoxic-hypercapnic challenges but reduced plasticity-associated activity by ∼50%. Further, TRPV1 receptor antagonism in vivo reduced sympathetic LTF caused by AIH-Hc, although only if the CBs were functional. These data demonstrate a new mechanism of CB plasticity and suggest P2X-TRPV1-dependent sensory LTF as a novel target for pharmacological intervention in some forms of neurogenic hypertension associated with recurrent apnoeas.

Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer (PCa) initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary PCa. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in PCa relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice-variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small molecule SR-BI antagonist Block Lipid Transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and non-steroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.

Mainly known for its role in peripheral glucose homeostasis, insulin has also significant impact within the brain, functioning as a key neuromodulator in behavioral, cellular, biochemical and molecular studies. The brain is now regarded as an insulin-sensitive organ with widespread, yet selective, expression of the insulin receptor in the olfactory bulb, hypothalamus, hippocampus, cerebellum, amygdala and cerebral cortex. Insulin receptor signaling in the brain is important for neuronal development, glucoregulation, feeding behavior, body weight, and cognitive processes such as with attention, executive functioning, learning and memory. Emerging evidence has demonstrated insulin receptor signaling to be impaired in several neurological disorders. Moreover, insulin receptor signaling is recognized as important for dendritic outgrowth, neuronal survival, circuit development, synaptic plasticity and postsynaptic neurotransmitter receptor trafficking. We review the multiple roles of insulin in the brain, as well as its endogenous trafficking to the brain or its exogenous intervention. Although insulin can be directly targeted to the brain via intracerebroventricular (ICV) or intraparenchymal delivery, these invasive techniques are with significant risk, necessitating repeated surgical intervention and providing potential for systemic hypoglycemia. Another method, intranasal delivery, is a non-invasive, safe, and alternative approach which rapidly targets delivery of molecules to the brain while minimizing systemic exposure. Over the last decades, the delivery of intranasal insulin in animal models and human patients has evolved and expanded, permitting new hope for associated neurodegenerative and neurovascular disorders.