The CD44v6-LRP6(S1490)/LRP6-signalosome is internalized through endosomal sorting resulting in nuclear accumulation of a β-catenin/TCF4-CD44v6 complex, which then transcriptionally activates stemness-associated MDR1 and a CD44v6-containing isoform, which sustains drug-resistance in CRC-CICs. The gene discussed is LRP6; the disease is colorectal carcinoma.