Elucidation and targeting of paracrine cascades in PDAC

摘要 胰腺导管腺癌(Pdac)是最致命的恶性肿瘤之一，这主要是由于缺乏它们。 对当前的细胞毒、靶向和免疫疗法的反应。PDAC肿瘤组织含有扩张性、 促结缔组织间质，既抑制血管生成又限制血流和扩散。因此， 通过全身给药的治疗药物输送受阻，降低药物疗效和 增加了全身毒性。事实上，PDAC基质的多种成分支持其生存和生长， 例如，通过调节局部免疫抑制的微环境，促进肿瘤存活。 相反，我们先前表明，至少某些肿瘤间质成分抑制了PDAC的生长，并 进展，例如Hedgehog途径反应的肌成纤维细胞。早期对PDAC进行调制的尝试 基质，以促进药物输送失败的临床翻译。最终进行临床后试验 证明了在抑制单个通路时间质的重新调制可以导致不可预测的 在多种附加单元格类型中的后果。基于这些数据，我们假设个体旁分泌 通路通常链接在一起形成“旁分泌级联”，通过多条通路传播，并 单元类型。我们认为，重建这些旁分泌瀑布提供了更好的机会 了解治疗干预的后果，并推断作用于 PDAC TME内广泛的细胞类型，以实施间质再调节。 为了测试这一点，我们将利用由成员们构建的一系列创新系统生物学工具 我们的跨学科团队。其中包括一套利用监管计算领域的算法 网络分析，以及研究单细胞数据集中结果的技术创新技术。 此外，我们将从我们的多学科临床成员收集的样本中获取独特的数据集 纽约长老会医院胰腺中心的服务。其中包括获取人类PDAC 肿瘤间质液和生成匹配的肿瘤、正常胰腺、脾和血液样本 PDAC患者。我们还将例行公事地使用新鲜的PDAC组织样本来使肿瘤“外植体”成为一种新的实验 用于PDAC短期、中等吞吐量研究的活体模型系统。这一新型号的系统使 对复杂的多细胞表型的解剖是通过研究完整的肿瘤或 纯化细胞类型的共培养 使用这些方法，我们将重建PDAC中的旁分泌级联网络，并验证 试验性地挑选候选人。我们还将测试通过研究发现的特定候选路径 连接肌成纤维细胞和髓系抑制细胞和细胞毒性淋巴细胞的HH通路。 我们期望拟议的研究将提供对PDAC中旁分泌串扰的广泛了解 并为PSRC财团提供了多种有价值的资源和技术。

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due largely to their lack of response to current cytotoxic, targeted, and immune therapies. PDAC tumor tissues harbor an expansive, desmoplastic stroma that both suppresses angiogenesis and limits perfusion and diffusion. Consequently, delivery of therapeutic agents through systemic administration is impeded, lowering drug efficacy and increasing general toxicity. Indeed, multiple components of the PDAC stroma support its survival and growth, for example by conditioning a locally immunosuppressed microenvironment that facilitates tumor survival. Conversely, we previously showed that at least some elements of the tumor stromal restrain PDAC growth and progression, for example Hedgehog pathway-responsive myofibroblasts. Early attempts to modulate the PDAC stroma in order to facilitate drug delivery failed upon clinical translation. Post-clinical trials ultimately demonstrated that stromal remodulation upon inhibition of individual pathways can lead to unpredictable consequences in multiple additional cell types. Based on these data, we hypothesize that individual paracrine pathways typically link together to form “paracrine cascades” that propagate through multiple pathways and cell types. We advance that reconstructing these paracrine cascades offers both the opportunity to better understand the consequences of therapeutic intervention and also to infer candidate targets that act on a broad range of cell types within the PDAC TME to enact stromal remodulation. In order to test this, we will make use of a series of innovative systems biology tools built by members of our transdisciplinary team. These include a suite of algorithms leveraging the computational field of regulatory network analysis, as well as technically innovative techniques for studying outcomes in single cell datasets. Moreover, we will acquire unique dataset from samples collected by members of our multidisciplinary clinical service at the Pancreas Center of New York Presbyterian Hospital. These include acquiring human PDAC tumor interstitial fluid and generating matched sets of tumor, normal pancreas, spleen, and blood samples from PDAC patients. We will also routinely utilize fresh PDAC tissue samples to make tumor “explants” a novel ex vivo model system for the short-term, medium throughput study of PDAC. This new model system enables the dissection of complex multi-cellular phenotypes in ways that are not possible through study of intact tumors or co-cultures of purified cell types Using these approaches, we will reconstruct the network of paracrine cascades in PDAC and validate selected candidates experimentally. We will also test a specific candidate pathway uncovered through study of the Hh pathway that connects myofibroblasts to myeloid derived suppressor cells and cytotoxic lymphocytes. We expect that the proposed studies will provide an expansive understanding of paracrine crosstalk in PDAC and also provide multiple valuable resources and techniques to the PSRC consortium.