Research
Cancer cells departing from primary tumors spread throughout the body using blood and lymphatic circulations. The selective arrest in capillary beds and seeding of distant organs both depend on a variety of molecules and mechanisms. Cancer cells adhere to the wall of blood vessels via recognition of specific adhesion molecules and exit the circulation in response of chemotactic factors generated by normal cells residing in the surrounding tissue stroma. Following extravasation, disseminated tumor cells must rapidly adapt to the new microenvironment, as failing to do so will lead to either death or dormancy. This cellular adaptation depends on the effective utilization of trophic factors that are either already present in the new microenvironment or produced by the stroma in response to signals spawned by the disseminated cancer cells.
Deciphering Cellular Heterogeneity, Phenotypic Plasticity and IL-1β Signaling in the Metastatic Niche.
Metastatic tumors are not composed of a single homogeneous population of cancer cells. Instead, they consist of diverse and dynamically evolving cellular states that cooperate with one another and with the surrounding stromal microenvironment to sustain metastatic growth. A major goal of our laboratory is to understand how this functional heterogeneity emerges, how it evolves during disease progression and therapy, and how it can be therapeutically targeted.
Our earlier studies demonstrated that metastatic prostate cancer lesions contain distinct cancer cell populations that establish reciprocal interactions with osteoblasts, osteoclasts, immune cells and cancer-associated fibroblasts to create a metastatic niche that promotes tumor survival and expansion. These findings established the concept that metastatic progression depends on cooperative interactions among genetically and phenotypically distinct tumor cells rather than on the autonomous behavior of individual clones.
We initially discovered that bone-tropic prostate cancer cells express high levels of the alpha-receptor for Platelet-Derived Growth Factor (PDGFRα) Oncogene, 2005 and that the exogenous expression of this receptor in low-expressing and non-metastatic cells confers metastatic behavior Oncogene, 2009.
We also reported that this receptor could initiate downstream signaling upon trans-activation by the soluble fraction of bone marrow. Cancer Research, 2007 and 2010.
Furthermore, we showed that targeting PDGFRα with a humanized monoclonal antibody reduced bone metastases by 70% in animal models Clinical Cancer Research 2010.
The studies above led us to examine human cancer cells expressing or over-expressing PDGFRα as well as cells with low levels or lacking this receptor. Using genome-wide comparative microarrays analyses we have identified three genes correlated with the metastatic behavior of prostate cancer cells. Cancer Research 2013. One of these genes, interleukin-1beta (IL-1β), is responsible for co-opting the bone stroma to support the survival and growth of cancer cells, including malignant phenotypes that lack this cytokine and are incapable of independently colonizing the skeleton Oncogene, 2017.
Our most recent work has further identified inflammatory signaling as a major driver of aggressive metastatic phenotypes. We discovered that suppression or loss of androgen receptor activity, a hallmark of advanced prostate cancer following androgen-deprivation therapy, induces expression of the pro-metastatic cytokine IL-1β. Cancer Research Communications 2022.
We are currently identifying a mechanistic connection between therapy-induced phenotypic plasticity, inflammatory reprogramming and metastatic progression.
Together, these studies support a unifying model in which metastatic progression is driven by the dynamic interplay among tumor-cell plasticity, inflammatory signaling and the tissue microenvironment.
Ultimately, our research seeks to identify the molecular mechanisms governing these interactions and translate these discoveries into therapeutic strategies capable of preventing metastatic recurrence and overcoming treatment resistance in prostate cancer.
Define the Role of CX3CR1 in Metastatic Progression, Tumor-Cell Plasticity and Therapy Resistance
Our laboratory investigates how the chemokine receptor CX3CR1 and its unique ligand, CX3CL1/Fractalkine, regulate the dissemination and progression of metastatic prostate and breast cancers. We initially demonstrated that CX3CR1 expressed by prostate cancer cells interacts with Fractalkine produced by the bone microenvironment, promoting adhesion to bone-marrow endothelial cells, migration and skeletal seeding. Cancer Research, 2004.
We extended these findings to breast cancer and showed that genetic or pharmacologic disruption of this axis impairs the establishment and progression of disseminated tumors Cancer Research, 2008 and Breast Cancer Research, 2011.
Our more recent studies have revealed that CX3CR1 also identifies a rare but functionally important population of metastasis-initiating cells. CX3CR1-high cells detected in primary and metastatic prostate and breast cancers co-express OCT4A and NANOG, display stem-like transcriptional programs, efficiently initiate metastatic tumors and resist docetaxel chemotherapy. Suppression of CX3CR1 expression or signaling disrupts these properties, establishing the receptor as an active regulator rather than simply a marker of the metastasis-initiating state. Oncogene, 2022
Importantly, this state is not fixed. Cancer cells lacking surface CX3CR1 can re-expose the receptor, reacquire metastatic competence and transition toward a partially mesenchymal phenotype. In prostate cancer models, early receptor re-exposure is mediated in part by intracellular trafficking rather than new transcription. Bone and visceral metastatic microenvironments markedly enrich and stabilize CX3CR1-positive cells, whereas removal from these environments restores the predominantly CX3CR1-negative equilibrium observed in culture. Tumor-associated stromal cells and activated fibroblasts contribute to this process by sustaining the continuous replenishment of CX3CR1-positive metastasis-initiating phenotypes.
Pharmacologic inhibition of CX3CR1 dramatically suppresses skeletal and visceral metastatic burden in preclinical prostate cancer models. Our findings indicate that this effect is associated with increased apoptotic vulnerability, particularly during early metastatic colonization, rather than simply with inhibition of tumor-cell proliferation.
Together, these studies identify CX3CR1 as a multifunctional regulator of metastatic seeding, phenotypic plasticity, metastasis initiation and therapy resistance. Our current research seeks to define the mechanisms controlling receptor trafficking and surface exposure and to develop CX3CR1-directed therapies for metastatic prostate and breast cancers.