Project Summary / Abstract
Neuroendocrine tumors (NETs) that are clinically and pathologically similar display significant differences in
disease progression, therapeutic response, and overall survival. The limited accuracy of current prognostic
biomarkers is a major unmet clinical need, particularly in a tumor type rapidly rising in prevalence and incidence.
While genetic drivers have been identified, these genetic alterations are limited to cancer cells and do not provide
a systematic assessment of information encoded within the intact tumor microenvironment (TME), including the
role of the tumor architecture and the spatially organized immunological processes. For example, while emerging
evidence proposes a key role for tumor-associated macrophages (TAMs) in orchestrating an
immunosuppressive TME, patient-specific factors that mediate cell-to-cell interactions and localized chemokine
and cytokine signaling in NETs are currently unknown. To address this knowledge gap, work from our group on
single-cell transcriptomic profiling of NETs has established that TAMs display an adverse continuum of cell states
(i.e. not separated into the historical M1 or M2 groupings), while expressing tumor-specific chemokines and
cytokines involved in regulating key immune pathways. Our findings highlight the significant heterogeneity within
the myeloid compartments of NETs, particularly TAMs, and may offer potential promising targets for prognosis
and therapy. However, unlocking this potential requires the systematic understanding of the spatial distributions
and interactions of these different macrophage cell populations with both the cancer cell and lymphoid cell
populations, which together - as a multi-cellular system - dictate immunosuppression or activation. These
intricate spatial insights are still majorly lacking and obtaining them is only recently possible with the advent of
new spatial technologies. To understand the underlying processes that drive NET progression, as well as reveal
potential therapeutic vulnerabilities, we will test our hypothesis across two mutually reinforcing aims. In Aim 1,
we will identify the exact spatial composition, architecture and cellular crosstalk of the tumor and TME of archival
NETs and connect the obtained information with macrophage-centric signaling and processes. In Aim 2, we will
determine if systematic spatial distributions and interactions of the macrophage cell populations and NET-
specific chemokine profiles are associated with disease outcomes in NETs. The successful implementation of
the proposed studies could provide innovative and data-driven insights into complex macrophage biology and
concurrently establish high-dimensional profiling of the TME as clinical biomarkers, thereby transforming
prognostic stratification and clinical management for patients with NETs and potentially identifying novel
druggable targets within the tumor as a whole.
