Purpose: We describe the fibrotic rim formed in the desmoplastic growth pattern (DHGP) of colorectal cancer liver metastasis (CLM) using in situ sequencing (ISS). The origin of the desmoplastic rim is still a matter of debate, and the detailed cellular organization has not yet been fully elucidated. Understanding the biology of the DHGP in CLM can explore targeted treatment to improve survival. Experimental design: We used ISS, targeting 150 genes, to characterize the desmoplastic rim by unsupervised clustering of gene co-expression patterns. The cohort comprised 10 chemo-naïve liver metastasis resection samples with a DHGP. Results: Unsupervised clustering of spatially mapped genes revealed molecular and cellular diversity within the desmoplastic rim. We confirmed the presence of the ductular reaction and cancer-associated fibroblasts. Importantly, we discovered angiogenesis and outer and inner zonation in the rim, characterized by NGFR and POSTN expression. Conclusions: ISS enabled the analysis of the cellular organization of the fibrous rim surrounding CLM with a DHGP and suggests a transition from the outer part of the rim, with nonspecific liver injury response, into the inner part, with gene expression indicating collagen synthesis and extracellular matrix remodeling influenced by the interaction with cancer cells, creating a cancer cell supportive environment. Moreover, we found angiogenic processes in the rim. Our results provide a potential explanation of the origin of the rim in DHGP and lead to exploring novel targeted treatments for patients with CLM to improve survival.

中文翻译：

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通过原位测序对结直肠肝转移瘤的促纤维增生生长模式进行空间转录组图谱揭示促纤维增生边缘的生物学相关分区


目的：我们使用原位测序（ISS）描述结直肠癌肝转移（CLM）的促纤维增生生长模式（DHGP）中形成的纤维化边缘。促纤维增生边缘的起源仍然是一个有争议的问题，详细的细胞组织尚未完全阐明。了解 DHGP 在 CLM 中的生物学特性可以探索靶向治疗以提高生存率。实验设计：我们使用 ISS，针对 150 个基因，通过基因共表达模式的无监督聚类来表征促纤维增生边缘。该队列由 10 个未接受化疗的 DHGP 肝转移切除样本组成。结果：空间映射基因的无监督聚类揭示了促纤维增生边缘内的分子和细胞多样性。我们证实了导管反应和癌症相关成纤维细胞的存在。重要的是，我们发现了边缘的血管生成以及外部和内部分区，其特征是 NGFR 和 POSTN 表达。结论：ISS 能够使用 DHGP 分析 CLM 周围纤维边缘的细胞组织，并表明从边缘的外部（具有非特异性肝损伤反应）到内部的过渡，其基因表达表明胶原合成和细胞外基质重塑受到与癌细胞相互作用的影响，创造了癌细胞支持环境。此外，我们在边缘发现了血管生成过程。我们的结果为 DHGP 边缘的起源提供了潜在的解释，并导致探索 CLM 患者的新型靶向治疗以提高生存率。