An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte–tumor cell crosstalk, local immunosuppression and tumor progression

Abstract

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as “the invasive zone”. We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs’ overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Inferring cell trajectories of spatial transcriptomics via optimal transport analysis

“…We collected ST data from a primary tumor section of intrahepatic cholangiocarcinoma (ICC) (Wu et al, 2023), covering the regions of both intratumor and boundary (Figure 5A, Figure S4A-S4C). Previous study(Wu et al, 2023) detected strong immunosuppression and metabolic reprogramming in the invasive zone of tumor boundary, suggesting the spatially diversity of tumor progress.…”

“…We collected ST data from a primary tumor section of intrahepatic cholangiocarcinoma (ICC) (Wu et al, 2023), covering the regions of both intratumor and boundary (Figure 5A, Figure S4A-S4C). Previous study(Wu et al, 2023) detected strong immunosuppression and metabolic reprogramming in the invasive zone of tumor boundary, suggesting the spatially diversity of tumor progress. Eight subclones were identified in the primary ICC tumor (P0-P7) (Figure 5B), with P0 showed pronounced expression of stemness markers and cell cycling genes (Figure 5C and 5D, Figure S4D).…”

“…In the associated genes of lineage 1, COL1A1 is a major component of the tumor extracellular matrix related with tumor development and immune profile(Chen et al, 2022b). SAA1 and SAA2 lead to recruitment and polarization of macrophages, promoting local immunosuppression (Wu et al, 2023). Annotating associated genes of lineage 1, we observed significant enrichment of ECM organization and regulation of platelet and neutrophils (Figure 5I), which involve in tumor migration, metastasis, and immunosuppression(Winkler et al, 2020; Wu et al, 2023).…”

Artificial tumor matrices and bioengineered tools for tumoroid generation

“…This approach now enter the era of reconstruction of TME with vasculature and immune cell components [18]. The highthroughput sequencing and spatial omics technology play important roles nowadays and has been heavily applied to illustrate tumorigenesis and explore the heterogeneity of cancers [19]. Due to the high heterogeneity of tumors, the therapeutic effects vary significantly from patient to patient.…”

Challenges of clinical translation from single‐cell sequencing to measures in clinical biochemistry of haematology: Definition of immune cell identities

“…Systemic and local immune cells play decisive roles in the maintenance of microenvironmental hemostasis and the development of cancer, inflammation and ageing. Depending on the context, immune cells form a defence zone against or promote invasion and metastasis of cancer cells in the tumour microenvironment, processes that are highly dependent upon the nature of the disease, spatialization of immune cell subsets/subclusters and interventions 1 . The microenvironment immune cells are associated with cancer metastases, response to therapies and prognosis of patients.…”