Converging deep learning and human-observed tumor-adipocyte interaction as a biomarker in colorectal cancer

Background: Tumor-Adipose-Feature (TAF) as well as SARIFA (Stroma AReactive Invasion Front Areas) are two histologic features/biomarkers linking tumor-associated adipocytes to poor outcomes in colorectal cancer (CRC) patients. Whereas TAF was identified by deep learning (DL) algorithms, SARIFA was established as a human-observed histopathologic biomarker. Methods: To study the overlap between TAF and SARIFA, we performed a systematic pathological review of TAF based on all published image tiles. Additionally, we analyzed the presence/absence of TAF in SARIFA-negative CRC cases to elucidate the biologic and prognostic role of a direct tumor-adipocyte contact. TCGA-CRC gene expression data is investigated to assess the association of FABP4 (fatty-acid binding protein 4) and CD36 (fatty-acid translocase) with both TAF and CRC prognosis. Results: By investigating the TAF/SARIFA overlap, we show that many TAF patches correspond to the recently described SARIFA-phenomenon. Even though there is a pronounced morphological and biological overlap, there are differences in the concepts. The presence of TAF in SARIFA-negative CRCs is not associated with poor outcomes in this cohort, potentially highlighting the importance of a direct tumor-adipocyte interaction. Upregulation of FABP4 and CD36 gene expression seem both linked to a poor prognosis in CRC. Conclusions: By proving the substantial overlap between human-observed SARIFA and DL-based TAF as morphologic biomarkers, we demonstrate that linking DL-based image features to independently developed histopathologic biomarkers is a promising tool in the identification of clinically and biologically meaningful biomarkers. Adipocyte-tumor-cell interactions seem to be crucial in CRC, which should be considered as biomarkers for further investigations.