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.

Comment in Nat Rev Urol. 2021 Dec;18(12):706. Cancer Cell. 2021 Nov 8;39(11):1450-1452.

Author information: (1)Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (2)Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. (3)Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. (4)Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (5)Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (6)Retroviral Immunology, The Francis Crick Institute, London NW1 1AT, UK. (7)Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London NW1 1AT, UK. (8)Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London SW3 6JJ, UK. (9)Department of Pathology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (10)Department of Urology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (11)Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (12)Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Division of Infection and Immunity, University College London, London WC1E 6BT, UK. (13)Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK. (14)Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (15)Translational Immune Oncology Lab, Centre for Molecular Pathology, The Royal Marsden Hospital, Sutton SM2 5PT, UK. (16)Department of Pathology, Cruces University Hospital, Biocruces-Bizkaia Institute, 48903 Barakaldo, Bizkaia, Spain. (17)Department of Cellular Pathology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK. (18)Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (19)Division of Research, Peter MacCallum Cancer Centre, Melbourne VIC 300, Australia; Department of Pathology, GZA-ZNA Hospitals, Wilrijk, Antwerp, Belgium. (20)Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London WC1E 6DD, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK. (21)Division of Infection and Immunity, University College London, London WC1E 6BT, UK; University College London Cancer Institute, London WC1E 6DD, UK. (22)Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK; University College London Cancer Institute, London WC1E 6DD, UK. (23)Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk. (24)Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. Electronic address: samra.turajlic@crick.ac.uk.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.

Comment in Cancer Cell. 2021 Nov 8;39(11):1452-1454. Nat Rev Clin Oncol. 2022 Feb;19(2):73-74.

Comment on Cancer Cell. 2021 Nov 8;39(11):1519-1530.e4.

Comment on Cancer Cell. 2021 Nov 8;39(11):1464-1478.e8.

Comment on N Engl J Med. 2021 Sep 23;385(13):1196-1206.

Gut colonization by colibactin-producing bacteria is associated with colorectal cancer. A mutational signature of this genotoxin in human cancer indicates causality but only partially accounts for cell transformation. Instead, the failure of adequately resolving DNA damage causes genomic aberrations and chromosomal instability, constituting the main starting point for colibactin-driven cancer.

Comment on Sci Transl Med. 2021 Sep 8;13(610):eabc7804.

Comment on Nature. 2021 Sep;597(7878):732-737.

Author information: (1)Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2)Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3)Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5)Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6)Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7)Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8)Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, USA. (9)Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, USA. (10)Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11)Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Infectious Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: viviana.simon@mssm.edu. (13)Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: samir.parekh@mssm.edu.

Erratum in Cancer Cell. 2021 Dec 13;39(12):1654.