Defining the role of macropinocytosis in solid tumor growth and therapeutic resistance

摘要 癌细胞需要源源不断的营养物质来支持其癌基因驱动的生长。然而，血液 供应这些营养物质的容器通常是曲折和漏水的。促结缔组织增生症也可导致 间质压力使肿瘤血管塌陷，进一步影响营养物质的输送。癌细胞 通过从微环境中清除大分子来克服这些供应方的限制。一 肿瘤的清除策略是巨噬细胞吞噬作用，这是一种细胞外物质非 特别是被吞噬，然后在溶酶体中降解以产生营养。RAS的致癌突变， PI3K通路的激活，以及EGFR和WNT信号驱动胰腺，前列腺， 肺癌、结肠癌、膀胱癌和乳腺癌细胞株。当给这些癌细胞提供大胞饮燃料时，这些癌细胞 能够在营养有限的条件下繁殖。然而，目前还不清楚是否有数量和 肿瘤微环境中存在的物质质量足以使巨噬细胞增多症 对肿瘤合成代谢有重大贡献。所有已发表的研究都依赖于EIPA进行体内试验 巨噬细胞吞噬抑制。EIPA是一种具有多效性抗肿瘤作用的Na+/H+交换抑制剂 不依赖于巨噬细胞吞噬抑制的效果。目前缺乏的是一种有选择地扰乱 体内巨噬细胞吞噬。因此，不可能准确地界定 巨噬细胞吞噬对肿瘤生长的作用或靶向该途径的潜在治疗价值。考虑到 通过自噬的营养循环在肿瘤进展和治疗耐药中发挥着重要作用，它是 很可能，通过巨噬细胞吞噬来清除营养物质也将扮演同样重要的角色。目标1 该提案将评估选择性巨噬细胞吞噬抑制限制肿瘤生长的程度。目标2将 评估巨噬细胞增多在治疗耐药中的作用。目标3将剖析促进 肿瘤细胞内的大胞体形成。完成这些研究将填补我们在知识和知识方面的主要空白 可能导致治疗癌症的新的单剂和/或联合疗法。因为一些最难的 治疗癌症是巨噬细胞癌(例如胰腺癌、KRAS+结直肠癌、三阴性乳腺癌和去势- 对于耐药前列腺癌)，这些研究有可能对患者的生存产生重大影响。

ABSTRACT Cancer cells require a steady stream of nutrients to support their oncogene-driven growth. However, the blood vessels that supply these nutrients are often tortuous and leaky. Desmoplasia can also lead to elevated interstitial pressure that collapses tumor blood vessels, further compromising nutrient delivery. Cancer cells overcome these supply-side limitations by scavenging macromolecules from the microenvironment. One scavenging strategy employed by tumors is macropinocytosis, a process by which extracellular material is non- specifically engulfed and then degraded in the lysosome to produce nutrients. Oncogenic mutations in RAS, activation of the PI3K pathway, and EGFR and WNT signaling drive macropinocytosis in pancreatic, prostate, lung, colon, bladder, and breast cancer cell lines. When provided with macropinocytic fuel, these cancer cells are able to proliferate in nutrient-limiting conditions. However, is not currently clear whether the quantity and quality of material present in the tumor microenvironment is sufficient for macropinocytosis to make a significant contribution to tumor anabolism. All published studies have depended upon EIPA for in vivo macropinocytosis inhibition. EIPA is an inhibitor of Na+/H+ exchangers that has pleiotropic anti-neoplastic effects independent of macropinocytosis inhibition. What is currently lacking is a strategy to selectively disrupt macropinocytosis in vivo. As a result, it has not been possible to accurately define the contribution of macropinocytosis to tumor growth or the potential therapeutic value of targeting this pathway. Given that nutrient recycling via autophagy plays a major role in both tumor progression and therapeutic resistance, it is likely that nutrient scavenging through macropinocytosis will play a similarly important role. Aim 1 of this proposal will assess the extent to which selective macropinocytosis inhibition limits tumor growth. Aim 2 will evaluate the role of macropinocytosis in therapeutic resistance. Aim 3 will dissect the signals that promote macropinosome formation in tumor cells. Completing these studies will fill major gaps in our knowledge and could lead to new single-agent and/or combination therapies for cancer. Because some of the most difficult to treat cancers are macropinocytic (e.g. pancreas, KRAS+ colorectal, triple-negative breast, and castration- resistant prostate cancers), these studies have the potential to make a significant impact on patient survival.