SPHK1 and neoplasm: Central genes of the invGRN, including INHBA, LAMC2, LAMB3, ITGB4, ITGA5, and SPHK1, were significantly associated with tumor budding, most strongly INHBA. Oppositely, CXCL8, KLF6, and PHLDA1, which were not enhanced in the LE, were not tumor budding-associated genes (Fig. 8E).