胰腺癌因强大的纤维化和缺氧表现出特征性的肿瘤微环境（TME），特别是对传统化疗有很强的耐药性。然而，在胰腺癌的TME相关治疗耐药性的分子机制尚不完全清楚。在这里，我们开发了一个体外TME模拟系统，包括胰腺癌细胞、成纤维细胞和免疫细胞，以及应激条件，包括缺氧和吉西他滨。在应激条件下存活率高的细胞表现出了生物分子的直接细胞间转移的增加迹象。所得到的衍生细胞（CD44高/SLC16A1高）类似于增强的无定形生长或侵袭性的癌干细胞样细胞（CSCs），并获得代谢重组。此外，CD24是肿瘤球形体形成或侵袭性转化的决定因素。相比其他群体，表达CD44low/SLC16A1low的胰腺癌患者有更好的预后。研究结果表明，直接细胞间转移的细胞成分的交互作用促进了化疗诱导的肿瘤演化，而定位CD44和MCT1（由SLC16A1编码）可能是预防吉西他滨接触后胰腺癌复发的有用策略。© 2022. 作者（们）发表。

Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44high/SLC16A1high) were similar to cancer stem cell-like-cells (CSCs) with enhanced anchorage-independent growth or invasiveness and acquired metabolic reprogramming. Furthermore, CD24 was a determinant for transition between the tumorsphere formation or invasive properties. Pancreatic cancer patients with CD44low/SLC16A1low expression exhibited better prognoses compared to other groups. Our results suggest that crosstalk via direct cell-to-cell transfer of cellular components foster chemotherapy-induced tumor evolution and that targeting of CD44 and MCT1(encoded by SLC16A1) may be useful strategy to prevent recurrence of gemcitabine-exposed pancreatic cancers.© 2022. The Author(s).