Regenerative potential of prostate luminal cells revealed by single-cell analysis

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cel RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1 and Psca ) and a large population of differentiated cells (Nkx3.1 , Pbsn ). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells. + + +

Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.This work was supported by the Transcend Program and Janssen Pharmaceuticals, the Howard Hughes Medical Institute, and, in part, by the NIH/NCI Cancer Center Support Grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society, Rita Allen, Josie Robertson Scholar, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI-CA187317. T.J. is supported by NCI-PO1CA42063. A.R. is supported by the Klarman Cell Observatory. J.E.C is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207). P.P.M. is supported by NCI-CA196405. L.M. is supported by The Alan and Sandra Gerry Foundation. We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748, Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSKCC; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute; and the MIT Bio-Micro Center. A.R., T.J.and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar

Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies /

While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers

Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation