Summary We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.

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Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management. These advances, along with an improved understanding of the adaptive responses to conventional cancer therapies, anti-androgen therapy, and immunotherapy, are catalyzing development of more effective therapeutic strategies for advanced disease. In particular, knowledge of the heterotypic interactions between and coevolution of cancer and host cells in the tumor microenvironment has illuminated novel therapeutic combinations with a strong potential for more durable therapeutic responses and eventual cures for advanced disease. Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.

The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer. Significance We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell non-autonomous function of Hippo-YAP pathway in regulation of Cxcl5, a ligand for Cxcr2 expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CxCl5-Cxcr2 signaling circuit elicits robust anti-tumor responses and prolongs survival.

Cellular senescence has been recently shown to play an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or loss of tumour suppressor genes is thought to critically dependent on the induction of the p19Arf-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumor-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic stress driven senescence neither elicits activation of the p19Arf-p53 pathway nor DNA damage, but instead depends on ATF4, p27, and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf/p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/PTEN deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof of principle evidence that Skp2 pharmacological inhibition may represent a general approach for cancer prevention and therapy.