Our understanding of the function of the transcriptional regulators YAP/TAZ in cancer is advancing. In this Review, we provide an update on recent progress in YAP/TAZ biology, their regulation by Hippo signaling and mechanotransduction, and highlight open questions. YAP/TAZ signaling is an addiction shared by multiple tumor types and their microenvironments, providing many malignant attributes. As such, it represents an important vulnerability that may offer a broad window of therapeutic efficacy, and here we give an overview of the current treatment strategies and pioneering clinical trials.
Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs—elicited by the loss of Rag GTPases—inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
Cells live and interact in three-dimensional (3D) cellular neighborhoods. However, histology and spatial omics methods mostly focus on 2D tissue sections. Here we present a 3D spatial atlas of a routine clinical sample, an aggressive human lung carcinoma, by combining in situ quantification of 960 cancer-related genes across ~340,000 cells with measurements of tissue-mechanical components. 3D cellular neighborhoods subdivided the tumor microenvironment into tumor, stromal, and immune multicellular niches. Interestingly, pseudotime analysis suggested that pro-invasive epithelial-to-mesenchymal transition (EMT), detected in stroma-infiltrating tumor cells, already occurred in one region at the tumor surface. There, myofibroblasts and macrophages specifically co-localized with pre-invasive tumor cells and their multicellular molecular signature identified patients with shorter survival. Moreover, cytotoxic T-cells did not infiltrate this niche but colocalized with inhibitory dendritic and regulatory T cells. Importantly, systematic scoring of cell-cell interactions in 3D neighborhoods highlighted niche-specific signaling networks accompanying tumor invasion and immune escape. Compared to 2D, 3D neighborhoods improved the characterization of immune niches by identifying dendritic niches, capturing the 3D extension of T-cell niches and boosting the quantification of niche-specific cell-cell interactions, including druggable immune checkpoints. We believe that 3D communication analyses can improve the design of clinical studies investigating personalized, combination immuno-oncology therapies.
1032 Background: Despite the clinical impact of breast cancer (BC) brain metastases (BM), their biological complexity still remains poorly understood. We here evaluate the genomic profile of paired primary and metastatic samples to characterize biological changes acquired by BC during metastatization to the brain. Methods: The expression of 758 BC–related genes was evaluated using the BC360 Panel (nCounter platform) in matched primary BC and their associated BM. Intrinsic molecular subtyping was determined using the PAM50 subtype predictor (Parker et al. JCO 2009). Hormone receptor (HR) and HER2 status were evaluated on the BCBM. A False Discovery Rate (FDR) corrected paired two-class SAM was used to identify changes in single genes expression between paired BC and BMs samples. Results: Twenty-one matched primary BC and BMs samples were analyzed. BC subtype evaluated on the BMs was distributed as follows: 24% (N=5) HR-/HER2-, 24% (N=5) HR+/HER2- and 52% (N=11) HER2+. A considerable shift in PAM50 subtype was observed between primary BC and paired BM. While subtype concordance was high for HER2-enriched (HER2-E) tumors (100%), all Luminal A (LumA) primary BCs switched to either HER2-E (75%) or Luminal B (LumB, 25%) on the BM sample, as did 45% of Basal-like BCs (Basal to HER2-E). A clinical switch from HER2- primary BC to HER2+ BM (defined by IHC and ISH) was observed in only one pair (5%). Consistently, HER2-E (p<0.001) and LumB (p=0.001) PAM50 signatures were significantly more expressed, while the LumA (p<0.001) and Normal-like (p=0.001) signatures were significantly less expressed in BMs as compared to paired primary BCs (FDR-corrected Wilcoxon paired signed rank test). No significant change was observed in the expression of the Basal-like signature (p=0.562). Among the 758 evaluated genes, 60 and 318 genes, respectively, were significantly up- and downregulated in BMs as compared to primary BC (FDR<5%). Upregulated genes were enriched, among others, in genes involved in survival and migration (e.g. FGFR4), cell proliferation (e.g. CCNB1, CDK1) and HER2-amplicon (e.g. ERBB2, GRB7). Downregulated genes were enriched in genes involved in immune response (e.g. CD8A, CCL5, PDCD1LG2, TNF), angiogenesis (e.g. PDGFRB) and response to hormonal stimuli (e.g. ESR1, BCL2). Conclusions: Gene-expression profiling of matched primary BCs and BMs shows recurrent gene expression modifications in metastatic samples which might have potential therapeutic implications (e.g. acquisition of HER2-E subtyping and increase in ERBB2 mRNA levels). [Table: see text]
Background: The incidence of breast cancer (BC) brain metastases (BM) is increasing as a result of both improved diagnostic techniques and longer survival due to better treatment approaches. However, the biological complexity of BCBMs is still poorly understood. We here evaluate the genomic profile of BCBMs and assess its prognostic implications. Methods: Clinical data and BM samples (FFPE) from BC patients undergoing neurosurgery (2003-2019) at three institutions were collected. Hormone receptor (HR) and HER2 status were evaluated on the BCBM. RNA extracted from BM samples was used to measure the expression of 758 BC–related genes and 18 housekeeping genes using the Breast Cancer 360 Panel on an nCounter platform (NanoString Technologies). Intrinsic molecular subtyping was determined using the previously reported PAM50 subtype predictor (Parker et al. JCO 2009). Median overall survival from neurosurgery (OS) was calculated using the Kaplan-Meier method. The correlations between expression of each gene/PAM50 signature, BC subtype and OS were studied using univariate and multivariate Cox-models. Results: Sixty-five BCBM samples were analyzed: 32% (N=21) were HR+/HER2-, 38% (N=25) HER2+ and 29% (N=19) HR-/HER2-. With a median follow-up of 33 months, no clinical variable was significantly associated with OS, despite a trend towards a shorter survival for patients with HR-/HER2- BMs, as compared to patients with HR+/HER2- and HER2+ subtypes (median OS 9.4 versus 22.1 and 20.0 months, respectively, log-rank p=NS). The intrinsic subtype distribution, as assessed by gene-expression profiling, was 37% Basal-like, 46% HER2-enriched (HER2-E), 15% Luminal B and 2% Normal-like. Non-luminal subtypes (basal-like and HER2-E) were extensively represented, both overall and in each BC subtype (52% in HR+/HER2- subgroup, 96% in HER2+ subgroup, see Table). The PAM50 basal-like signature was significantly associated with a worse OS (HR 2.7, 95% CI 1.0-7.2, p=0.045), even after correcting for BC subtype (HR 5.2, 95% CI 1.1-23.4, p=0.032). In fact, even within the subgroup of HR+/HER2- BCBMs, the PAM50 basal-like signature was strongly associated with a worse OS (HR 92.6, 95% CI 5.0-1860.1, p=0.003) and patients with basal-like HR+/HER2- BCBMs presented a median OS similar to patients with HR-/HER2- BCBMs (mOS 9.0 vs 9.4 months). We identified 36 genes whose high expression was significantly associated with a worse OS (p< 0.05) and one gene (LINC02381) whose high expression was significantly associated with better OS (p< 0.05); for 33 of these genes (BCL11A, BMP2, BNIP3, CAV1, CDH3, CDK6, CKB, CRYAB, CXCL12, EGFR, EYA4, FOXC1, FZD8, FZD9, GABRP, GAS1, GDF5, GPC4, IL6, KRT17, KRT5, KRT6B, KRT7, LAMB3, LINC02381, MYC, NOTCH1, PRKX, PSAT1, RUNX3, SNAI1, SPRY2, TTYH1), the association was confirmed even after correcting for BC subtype (p< 0.05). Conclusions: Non-luminal intrinsic subtypes are extensively represented in resected BCBMs, even if clinically classified as HR+/HER2-. Our data suggest that basal-like genomic features might be enriched in BCBMs and might be associated with worse survival. Distribution of PAM50 intrisic subtyping on the 65 brain metastases evaluated according to hormone receptor (HR) and HER2 status Citation Format: Gaia Griguolo, Maria Vittoria Dieci, Susan Fineberg, claudia Pinato, Michele Bottosso, Luc Bauchet, Federica Miglietta, Jack Jacob, Giovanni Zarrilli, Valérie Rigau, Maria Cristina Guarascio, Francesca Zanconato, Francesca Schiavi, Matteo Fassan, William Jacot, Stefano Piccolo, Amelie Darlix, Valentina Guarneri. Gene Expression Profiling of Breast Cancer Brain Metastasis shows enrichment for non-luminal subtypes with potential prognostic implications [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-08.
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