Abstract
Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.
Highlights
Tumor is a complex and heterogeneous ecosystem, composed of various cell types and its surrounding tumor microenvironment (TME)
After strict quality control (QC) and filtration, we collected 25,318, 15,347, 6,019, 14,991, and 21,447 single cells originating from normal tissues; 57,486, 32,509, 17,732, 40,940, and 25,772 tumor-derived cells in colorectal cancer (CRC), lung cancer (LC), ovarian cancer (OV), pancreatic ductal cancer (PDAC), and skin cancer (SCC), respectively; and 24,160 tumor-derived cells in breast cancer (BC)
The results revealed that angiogenesis, glycolysis, and epithelial– mesenchymal transition (EMT) were the biological process most correlated with CD44 expression, while the TNFα signaling via NFκB, angiogenesis, IL6_JAK_STAT3 pathway, and EMT were correlated with TNFRSF12A in cancer cells across CRC, LC, and SCC (Figure 5A and Supplementary Table 7)
Summary
Tumor is a complex and heterogeneous ecosystem, composed of various cell types and its surrounding tumor microenvironment (TME). Experimental and clinical studies suggest that T cells, as well as cancer-associated fibroblasts (CAFs) and (TAMs), play significant roles in cancer development and progression under hypoxia TME. IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells, and CAFs promote cancer progression (Lappano et al, 2020). Galectin-3 expressed and secreted from TAMs induced by hypoxia promotes breast tumor growth (Wang et al, 2020). As T cells infiltrated cholesterol-enriched tumor tissues, it would express high levels of immune checkpoints and become exhausted through increasing endoplasmic reticulum stress (Ma et al, 2019). Explaining the molecular crosstalk between various cells and changes of cellular compositions to environmental pressure is significant for understanding how cancer develops. The molecular interaction between tumors and hypoxia TME remains largely unknown
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