Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Cancer Res. 2020 Apr 1;80(7):1461-1474. doi: 10.1158/0008-5472.CAN-19-2578. Epub 2020 Feb 6.
The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. SIGNIFICANCE: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.
胰腺导管腺癌 (PDAC) 的预后仍然很差，尽管已经进行了几十年的努力。PDAC 中丰富的细胞外基质 (ECM) 构成了肿瘤块的主要部分，并在促进对治疗的耐药性方面发挥着各种作用。然而，ECM 的非选择性耗竭导致患者预后不良。与该观察结果一致，我们之前表明，源自基质细胞的单个基质蛋白与患者的长期或短期生存相关。相比之下，源自癌细胞的基质蛋白与较差的生存密切相关。在这里，我们研究了在 PDAC 进展过程中显著过表达的三种源自癌细胞的基质蛋白，即 Agrin (AGRN)、SerpinB5 (丝氨酸蛋白酶抑制剂 B5) 和 Cystatin B (CSTB)。通过过表达和敲低实验，我们证明这三种蛋白均促进 PDAC 的转移。此外，这些蛋白在不同的转移步骤起作用。AGRN 在原发性肿瘤中促进上皮-间充质转化，而 SERPINB5 和 CSTB 通过提高侵袭小窝的形成和血管外渗来增强转移级联的晚期步骤。这三种基因在人类患者中均与预后不良相关，并且癌细胞分泌并沉积在 ECM 中的 SERPINB5 水平较高与患者预后不良相关。这项研究提供了强有力的证据，证明源自癌细胞的基质蛋白可作为促进肿瘤发生和转移的原因，并导致患者的生存不良。因此，与主要由基质细胞产生的大块基质相比，针对源自癌细胞的基质蛋白（如 AGRN、SERPINB5 和 CSTB）的精确干预可能代表了更优的潜在治疗靶点。意义：本研究深入了解了源自癌细胞的基质蛋白在 PDAC 中的生物学作用，并支持了这些蛋白具有促肿瘤发生作用且是更好的治疗靶点的观点。
