Refining colorectal cancer classification and clinical stratification through a single-cell atlas

Genome biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: May 10, 2022

Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms stroma cell contributions pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples analyze multiple independent external cohorts for a total 487,829 single cells enabling high-resolution depiction the cellular diversity heterogeneity within microenvironmental cells.Tumor recapitulate individual subgroups yet exhibit significant intratumoral heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs stable (MSS) demonstrate similar pathway activations at epithelial level. However, CD8+ cytotoxic T phenotype infiltration in MSI-H explain why these tumors respond immune checkpoint inhibitors. Cellular transcriptomic profiles exist continuum contrast discrete proposed by studies utilizing bulk transcriptomics. note dichotomy across exists patients with high cancer-associated fibroblasts (CAFs) C1Q+TAM content poor outcomes, providing higher level personalization precision than would distinct subtypes. Additionally, we discover CAF known be associated immunotherapy resistance.Distinct CAFs C1Q+ TAMs are sufficient predictive ability simpler signature based on phenotypes could stratify patient prognosis greater precision. Therapeutically targeting specific C1Q + promote responses patients.

Language: Английский

---

Identification, discrimination and heterogeneity of fibroblasts

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: June 14, 2022

Abstract Fibroblasts, the principal cell type of connective tissue, secrete extracellular matrix components during tissue development, homeostasis, repair and disease. Despite this crucial role, identification distinction fibroblasts from other types are challenging laden with caveats. Rapid progress in single-cell transcriptomics now yields detailed molecular portraits our bodies, which complement enrich classical histological immunological descriptions, improve class definitions guide further studies on functional heterogeneity subtypes states, origins fates physiological pathological processes. In review, we summarize discuss recent advances understanding fibroblast how they discriminate types.

Language: Английский

---

Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 396 - 412.e5

Published: Jan. 18, 2024

Despite advances in treatment, lung cancer survival rates remain low. A better understanding of the cellular heterogeneity and interplay cancer-associated fibroblasts (CAFs) within tumor microenvironment will support development personalized therapies. We report a spatially resolved single-cell imaging mass cytometry (IMC) analysis CAFs non-small cell cohort 1,070 patients. identify four prognostic patient groups based on 11 CAF phenotypes with distinct spatial distributions show that are independent factors for survival. The presence tumor-like is strongly correlated poor prognosis. In contrast, inflammatory interferon-response associated inflamed microenvironments higher High density matrix low immune infiltration negatively summary, our data phenotypic features outcome NSCLC.

Language: Английский

---

ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(3), P. 799 - 824

Published: June 23, 2022

Adenosine is an evolutionary ancient metabolic regulator linking energy state to physiologic processes, including immunomodulation and cell proliferation. Tumors create adenosine-rich immunosuppressive microenvironment through the increased release of ATP from dying stressed cells its ectoenzymatic conversion into adenosine. Therefore, adenosine pathway becomes important therapeutic target improve effectiveness immune therapies. Prior research has focused largely on two major ectonucleotidases, ectonucleoside triphosphate diphosphohydrolase 1/cluster differentiation (CD)39 ecto-5′-nucleotidase/CD73, which catalyze breakdown extracellular adenosine, subsequent activation different subtypes receptors with mixed findings antitumor protumor effects. New findings, needed for more effective approaches, require consideration redundant pathways controlling intratumoral levels, alternative NAD-inactivating CD38-ectonucleotide pyrophosphatase phosphodiesterase (ENPP)1-CD73 axis, counteracting ATP-regenerating pathway, cellular uptake phosphorylation by kinase. This review provides a holistic view intracellular metabolism as integrated complex network summarizes recent data underlying mechanisms precursors ADP control cancer immunosurveillance, tumor angiogenesis, lymphangiogenesis, cancer-associated thrombosis, blood flow, perfusion. Special attention given differences commonalities in purinome cancers, heterogeneity microenvironment, subcellular compartmentalization system, novel roles purine-converting enzymes targets therapy.

Significance Statement

The discovery role checkpoint led development strategies targeting signaling multiple clinical trials preclinical models. Here we identify gaps knowledge that need be filled gain agents key components and, this basis, provide network.

Language: Английский

---

Heterogeneity of triple negative breast cancer: Current advances in subtyping and treatment implications

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: Sept. 1, 2022

As the field of translational 'omics has progressed, refined classifiers at both genomic and proteomic levels have emerged to decipher heterogeneity breast cancer in a clinically-applicable way. The integration knowledge DNA, RNA protein is further expanding biologic understanding opportunities for customized treatment, particularly pressing need clinically triple negative tumors. For this group aggressive cancers, work from multiple groups now validated least four major biologically distinct omics-based subtypes. While date most clinical trial designs considered cancers as single group, with an arsenal targeted therapies applicable biological pathways, survival benefits may be best realized by designing analyzing trials context molecular RNA-based are developed, proposed based on new technologies potential more directly identify clinically-relevant biomarkers therapeutic targets. Phospho-proteomic data targetable signalling pathways unique subtype-specific manner. Single cell profiling tumor microenvironment represents promising way allow better characterization which could integrated spatially resolved build ecosystem-based patient classification. Multi-omic allows silico analysis genetic pharmacologic screens map vulnerabilities context. This review describes current about subtyping cancer, recent advances genomics proteomics diagnostics addressing diversity disease, key made through approaches, developments treatments including therapeutics being tested trials.

Language: Английский

---