Papillary thyroid cancer (PTC), often abbreviated as papillary carcinoma, is the most prevalent malignant endocrine tumor, with its incidence steadily on the rise. The cellular heterogeneity within the tumor microenvironment plays a pivotal role in determining the prognosis of PTC. Spatial transcriptomics emerges as a potent tool for dissecting cellular heterogeneity. On March 2, 2024, Professors Lian Zhexiong, Guan Haixia, and Zhang Qingling from Guangdong Provincial People’s Hospital, in collaboration with Prof. Xu Bo’s team from Guangzhou First People’s Hospital, unveiled their research titled “Spatial transcriptomics Reveals Prognosis-Associated Cellular Heterogeneity in the Papillary Thyroid Carcinoma Microenvironment” in Clinical and Translational Medicine (JCR Q1, 2022 IF = 10.69). This study pioneered an analytical approach melding spatial transcriptomics gene expression patterns with pathological diagnosis to illuminate the tumor heterogeneity of papillary thyroid carcinoma. It further pinpointed atypical follicular cells transitioning from normal follicular epithelial cells to tumor cells. Additionally, the research unearthed distinct types of tumor foci within tumor tissues, their genetic makeup intricately linked to the prognosis of PTC.

In the study, the authors conducted spatial transcriptome sequencing on PTC tissue samples and devised a method that integrates clinical pathological information and RNA analysis to scrutinize PTC’s heterogeneity and identify features that may be prognostically significant. Validation was achieved through single-cell sequencing, multiplex immunofluorescence staining, and verification cohort testing. Findings revealed that, across gene, developmental trajectory, and spatial analysis, atypical follicular cells were observed in a transitional state from normal follicular epithelial cells to tumor cells. Attention to these atypical follicular cells could potentially guide subsequent clinical surgical decisions. Furthermore, multiple small tumor cell aggregation foci were observed within tumors, displaying heterogeneity within tumor foci yet sharing commonalities among patients. Among these, tumor foci exhibiting high expression of 7 characteristic genes such as SFTPA2 were associated with poorer prognosis in PTC. Moreover, the TGF-β receptor signaling in these tumor foci was found to be low, hinting at the possibility of TGF-β from immune cells originating from tertiary lymphoid structures (TLS) regulating the prognosis-affecting process. Experimental validation indeed demonstrated the influence of TGF-β (transforming growth factor-β) signaling on PTC cell proliferation. Overall, through the devised spatial transcriptome-clinical pathological information integration analysis method, the study identified and preliminarily validated heterogeneity issues in PTC, furnishing methodologies and validation concepts for further exploration in PTC research.

Dr. Yan Kai, Dr. Huang Rongrong from Prof. Lian’s team at Guangdong Provincial People’s Hospital, and Dr. Liu Qingzhi from South China University of Technology jointly stand as the first authors of this article. Prof. Xu Bo from Guangzhou First People’s Hospital, Prof. Guan Haixia from the Department of Endocrinology at Guangdong Provincial People’s Hospital, and Prof. Zhang Qingling from the Department of Pathology at Guangdong Provincial People’s Hospital serve as the co-corresponding authors of this article.

Dr. Huang Rongrong

Updated: April 16, 2024