ABSTRACT
The role of tumor-macrophage hybrid cells in prostate cancer metastasis
AR signaling inhibitors (ARSIs) are commonly used to treat recurrent prostate cancer whose growth depends on
AR activities. However, ARSIs can result in selective pressure, transitioning AR-dependent tumors to AR-
independent tumors. Extensive studies have revealed signal-switching mechanisms by which ARSIs exert the
phenotypic transition leading to metastatic castration-resistant prostate cancer (mCRPC). Apart from these
signaling circumventions, here we propose that tumor-macrophage hybrid (TMH) cells are a novel cellular
contributor to mCRPC. Our preliminary data suggest that TMH cells adopt macrophages' characteristics to evade
immune surveillance and withstand hemodynamic stress in the vasculature for distant colonization. In addition,
TMH cells intrinsically express very low AR/AR-targets, resembling an adenocarcinoma-immune subtype of
mCRPC that resists ARSIs. Three specific aims will use systems-level approaches to mechanistically define the
role of TMH cells in mCRPC. In Aim 1, we will demonstrate that TMH cells leverage abundant c-Myc from parental
cancer cells to upregulate M1/M2 polarization loci derived from parental macrophages. This unique transcription
machinery, not observed in either parental cells, is being exploited to confound the host immune system, thereby
enhancing the immunoevasive features of TMH cells. In this regard, c-Myc acts as an immunoevasive driver, not
primarily as an oncogenic driver per se, in TMH cells. In Aim 2, we will show that as a result of cellular fusions,
TMH cells undergo transcriptomic rewiring of the AR cistrome, leading to treatment resistance of ARSIs.
Consequently, these cells overtake AR-dependent cancer cell populations for malignant outgrowth. In Aim 3, we
will evaluate whether integrin-mediated mechanotransduction in TMH cells strengthens their resistance to fluid
shear stress in blood circulation. The signaling cascade enhances a mesenchymal feature of TMH cells, endowing
them with higher viability and motility than circulating tumor cells (CTCs). Therefore, our proposed study highlights
an overlooked cell-intrinsic factor contributing to mCRPC. Furthermore, enumeration and molecular profiling of
TMH cells represent a new type of liquid biopsy for prostate cancer patients.