High-dimensional immunotyping of tumors grown in obese and non-obese mice

Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine whether tumors evolving in obese environments adapt differential interactions with immune cells and whether this can be connected to disease outcome. Most of these studies have been limited to single-cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T-cell-suppressive cell types and a decrease in CD8 T cells.publishedVersio

C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.publishedVersio

Carbon Dot Therapeutic Platforms: Administration, Distribution, Metabolism, Excretion, Toxicity, and Therapeutic Potential

Ultrasmall nanoparticles are often grouped under the broad umbrella term of “nanoparticles” when reported in the literature. However, for biomedical applications, their small sizes give them intimate interactions with biological species and endow them with unique functional physiochemical properties. Carbon quantum dots (CQDs) are an emerging class of ultrasmall nanoparticles which have demonstrated considerable biocompatibility and have been employed as potent theragnostic platforms. These particles find application for increasing drug solubility and targeting, along with facilitating the passage of drugs across impermeable membranes (i.e., blood brain barrier). Further functionality can be triggered by various environmental conditions or external stimuli (i.e., pH, temperature, near Infrared (NIR) light, ultrasound), and their intrinsic fluorescence is valuable for diagnostic applications. The focus of this review is to shed light on the therapeutic potential of CQDs and identify how they travel through the body, reach their site of action, administer therapeutic effect, and are excreted. Investigation into their toxicity and compatibility with larger nanoparticle carriers is also examined. The future of CQDs for theragnostic applications is promising due to their multifunctional attributes and documented biocompatibility. As nanomaterial platforms become more commonplace in clinical treatments, the commercialization of CQD therapeutics is anticipated.publishedVersio

High-dimensional immunotyping of tumors grown in obese and non-obese mice

Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine whether tumors evolving in obese environments adapt differential interactions with immune cells and whether this can be connected to disease outcome. Most of these studies have been limited to single-cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T-cell-suppressive cell types and a decrease in CD8 T cells

C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network