Regulation of PDAC metabolism and immunity by collagen and its cleavage products

摘要 胰腺导管腺癌(PDAC)是一种高度促结缔组织增生性和治疗耐药的癌症。的作用 PDAC中的促结缔组织间质仍然难以捉摸，研究同时支持促肿瘤或肿瘤- 限制功能。间质靶向治疗的失败表明，对 需要复杂的癌症-间质相互作用。I型胶原(Col I)是PDAC中主要的ECM蛋白，它可以 在身体上抑制肿瘤，限制营养供应。然而，PDAC细胞适应并利用周围的间质 以获得更高级的恶性特征。此外，促结缔组织增生的富含胶原的间质可能会抑制 免疫监视和激活促进肿瘤的机械敏感信号。很可能是促进肿瘤的 CAF和ECM的肿瘤抑制作用是平行的，它们的平衡决定了净效果。 关于PDAC的增长。我们试图通过将第一列作为关键调解人来更好地理解这些相反的功能 STORMA-PDAC串扰。临床研究显示卵巢癌切除后无进展生存期(PFS)的改善 以广泛的ECM沉积和低纤维溶解活性为特征的“惰性间质”患者，而高度 纤维溶解间质与较短的PFS时间有关。基于这一发现，我们假设 比钙调蛋白和间质的绝对数量、胶原纤维溶解和受体的差异效应更重要 区分完整和裂解的I型胶原决定了肿瘤的生长和免疫。我们的初步数据支持 这一假说表明，完整和裂解的胶原蛋白通过 特异性受体DDR1；以及免疫细胞高表达抑制性Col I受体LAIR1和 Col I在PDAC扩散到肝脏的免疫细胞渗透和激活中的作用 转移和全身性抗肿瘤免疫的抑制因子。我们的长期目标是开发出 通过裂解靶向胶原受体，改变免疫抑制和促进肿瘤的平衡 胶原蛋白对肿瘤的饥饿、生长抑制和增强的抗肿瘤免疫作用，而不是CAF耗竭或 调制，到目前为止已经造成了不利的影响。我们的基础和临床跨学科团队- 翻译研究人员将利用临床标本、肿瘤切片培养、单细胞RNA测序、空间 转录学、小鼠模型和PDAC-ECM共培养阐明胶原受体信号转导的作用 通过两个紧密结合的特定目标：1.检验胶原蛋白碎片和纤维拮抗的假设 通过PDAC固有的胶原受体DDR1控制PDAC的代谢，其抑制可以关闭 肿瘤代谢和诱导细胞死亡。2.检验刺激和抑制胶原蛋白受体的假设 控制抗PDAC免疫，可与免疫检查点抑制剂联合使用，提高抗肿瘤能力 豁免权。这些研究目标的成功完成将为我们提供新的工具来转换 间质介导的肿瘤生长和免疫抑制，以抑制生长和抗肿瘤免疫。

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic and therapy-resistant cancer. The role of the desmoplastic stroma in PDAC remains elusive with studies supporting both tumor-promoting or tumor- restricting functions. The failure of stroma targeting therapies suggests that a deeper understanding of the complex cancer-stroma interaction is needed. Type I collagen (Col I), the major ECM protein in PDAC, can physically restrain tumors and limit nutrient availability. Yet, PDAC cells adapt and exploit the surrounding stroma to acquire more advanced malignant traits. Moreover, the desmoplastic collagen-rich stroma may suppress immunosurveillance and activate tumor-promoting mechanosensitive signaling. It is likely that tumor-promoting and tumor-suppressive effects of CAF and ECM occur in parallel and that their balance determines the net effect on PDAC growth. We seek to better understand these opposing functions by focusing on Col I as a key mediator of stroma-PDAC crosstalk. Clinical studies show improved progression-free survival (PFS) after resection in patients with “inert stroma” characterized by extensive ECM deposition and low fibrolytic activity, whereas highly fibrolytic stroma is associated with much shorter PFS times. Based on this finding we hypothesize that rather than the sheer quantity of CAF and stroma, collagen fibrolysis and differential effects of receptors that discriminate between intact and cleaved Col I dictate tumor growth and immunity. Our preliminary data support this hypothesis, indicating differential regulation of cancer cell metabolism by intact and cleaved collagen through a specific receptor, DDR1; as well as high expression of the inhibitory Col I receptor LAIR1 on immune cells and a role for Col I in immune cell infiltration and activation in PDAC spread to the liver, the most common site of metastasis and a suppressor of systemic anti-tumor immunity. Our long-term goal is to develop therapies that target collagen receptors and shift the balance from immunosuppression and tumor promotion by cleaved collagen to tumor starvation, growth inhibition and enhanced anti-tumor immunity, rather than CAF depletion or modulation, which so far had resulted in untoward effects. Our interdisciplinary team of basic and clinical- translational investigators will utilize clinical specimens, tumor slice cultures, single cell RNA-sequencing, spatial transcriptomics, mouse models and PDAC-ECM co-cultures to elucidate the role of collagen receptor signaling via two closely integrated specific aims: 1. Test the hypothesis that collagen fragments and fibers antagonistically control PDAC metabolism through the PDAC-intrinsic collagen receptor DDR1, whose inhibition can switch off tumor metabolism and induce cell death. 2. Test the hypothesis that stimulatory and inhibitory collagen receptors control anti-PDAC immunity and can be combined with immune checkpoint inhibitors to increase anti-tumor immunity. The successful completion of these research goals will provide us with novel tools for converting stroma-mediated tumor growth and immunosuppression to growth inhibition and anti-tumor immunity.