Tumor Cell Autonomous and Non-Autonomous Mechanisms of Lipocalin-2 Function in Metastasis

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Metastasis is the leading cause of mortality among patients diagnosed with solid tumors. In this regard, identifying common mechanisms within primary, premetastatic and metastatic niches that contribute to progression of solid tumors represents a significant need. The Lipocalin-2 gene (LCN2, neutrophil gelatinase- associated lipocalin or NGAL) encodes a cytosolic and secreted protein (Lcn2) that regulates receptor trafficking, innate immune responses, inflammation, microbiome dynamics and iron homeostasis. Previous work from our group and others has shown that Lcn2 can promote stemness and tumorigenesis in models of solid tumor progression. However, uncertainty persists about the stage or stages at which LCN2 exerts tumorigenic effects and whether the mechanisms of LCN2 action vary based upon stage or tumor location. In this regard, we have recently performed unbiased single-cell spatial proteomic and transcriptomic screens of breast and pancreatic cancer patient samples leading us to define tumor cell autonomous and non-atonomous roles for Lcn2/LCN2 in promoting solid tumor progression. Based upon these findings, the central hypothesis of this proposal is that Lcn2 promotes FGFR2 signaling and adaptive anti-inflammatory immunity to support solid tumor progression. The overall objective of this proposal is to determine the spatiotemporal dynamics of Lcn2- governed tumor cell autonomous and non-autonomous mechanisms driving metastatic progression of solid tumors. Our rationale for pursing this work is that understanding these mechanisms will position Lcn2 as a biomarker for immune therapy resistance and target for improving immune therapy success in immunologically cold tumors. To test the central hypothesis, we propose to specific aims that will (I) identify the tumor cell autonomous signaling mechanisms governing Lcn2-dependent FGF2-induced tumor cell invasion and (II) define the intercellular communication mechanisms by which Lcn2 reduces inflammation and enriches regulatory T cells within the metastatic niche. The basis of this project is conceptually innovative and employs technically innovative transgenic, pharmacology, cell cycle reporter, protein reporter tagging, single-cell spatial omics, spinning disc time-lapse confocal and CRISPR methods in combination with preclinical allo- graft/xenograft models of solid tumors and hetero-multicellular cancer spheroid cultures. This work is expected to (1) provide exceptional research opportunities for undergraduates while enhancing the research environ- ment at Baylor University and (2) elucidate targetable mechanisms that govern solid tumor progres- sion/metastasis. As such, the proposed studies will have a positive impact on Baylor student success and identify novel treatment strategies to improve cancer outcomes.

Public health relevance public domain (NIH RePORTER)

PUBLIC HEALTH RELEVANCE STATEMENT – PROJECT NARRATIVE Cancer metastasis is a primary cause of mortality in patients with solid tumors. Our current understanding of the mechanisms that solid tumor employ to spread and survive within foreign premetastatic or metastatic niches is very limited, making it very challenging for patients and clinician to successfully treat metastatic cancers. By defining new signaling and regulatory pathways that control solid tumor progression, there is great potential to identify new therapeutic strategies for improving outcomes for patients with advanced stage malignancies.