Spatial profiling of cancer-associated fibroblasts of sporadic early onset colon cancer microenvironment

Satoru Furuhashi; Matias A Bustos; Shodai Mizuno; Suyeon Ryu; Yalda Naeini; Anton J Bilchik; Dave S B Hoon

doi:10.1038/s41698-023-00474-w

Spatial profiling of cancer-associated fibroblasts of sporadic early onset colon cancer microenvironment

NPJ Precis Oncol. 2023 Nov 14;7(1):118. doi: 10.1038/s41698-023-00474-w.

Authors

Satoru Furuhashi¹, Matias A Bustos¹, Shodai Mizuno¹, Suyeon Ryu², Yalda Naeini³, Anton J Bilchik⁴, Dave S B Hoon^{5

6}

Affiliations

¹ Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA, 90404, USA.
² Department of Genome Sequencing Center, SJCI, Providence SJHC, Santa Monica, CA, 90404, USA.
³ Department of Surgical Pathology, Providence SJHC, Santa Monica, CA, 90404, USA.
⁴ Department of Gastrointestinal and Hepatobiliary Surgery, Providence SJHC, Santa Monica, CA, 90404, USA.
⁵ Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA, 90404, USA. [email protected].
⁶ Department of Genome Sequencing Center, SJCI, Providence SJHC, Santa Monica, CA, 90404, USA. [email protected].

Abstract

The incidence of sporadic early-onset colon cancer (EOCC) has increased worldwide. The molecular mechanisms in the tumor and the tumor microenvironment (TME) in EOCC are not fully understood. The aim of this study is to unravel unique spatial transcriptomic and proteomic profiles in tumor epithelial cells and cancer-associated fibroblasts (CAFs). Here, we divide the sporadic colon cancer tissue samples with transcriptomic data into patients diagnosed with EOCC (<50 yrs) and late-onset colon cancer (LOCC, ≥50 yrs) and then, analyze the data using CIBERSORTx deconvolution software. EOCC tumors are more enriched in CAFs with fibroblast associated protein positive expression (FAP(+)) than LOCC tumors. EOCC patients with higher FAP mRNA levels in CAFs have shorter OS (Log-rank test, p < 0.029). Spatial transcriptomic analysis of 112 areas of interest, using NanoString GeoMx digital spatial profiling, demonstrate that FAP(+) CAFs at the EOCC tumor invasive margin show a significant upregulation of WNT signaling and higher mRNA/protein levels of fibroblast growth factor 20 (FGF20). Tumor epithelial cells at tumor invasive margin of EOCC tumors neighboring FAP(+) CAFs show significantly higher mRNA/protein levels of fibroblast growth factor receptor (FGFR2) and PI3K/Akt signaling activation. NichNET analysis show a potential interaction between FGF20 and FGFFR2. The role of FGF20 in activating FGFR2/pFGFR2 and AKT/pAKT was validated in-vitro. In conclusion, we identify a unique FAP(+) CAF population that showed WNT signaling upregulation and increased FGF20 levels; while neighbor tumor cells show the upregulation/activation of FGFR2-PI3K/Akt signaling at the tumor invasive margin of EOCC tumors.