Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic.

Our research aims to understand the adaptive, ergo potentially metastatic, responses of prostate cancer to changing microenvironments. Emerging evidence implicates a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state.

Bystanders or active players: the role of extra centrosomes as signaling hubs.

Centrosomes serve as microtubule-organizing organelles that function in spindle pole organization, cell cycle progression, and cilia formation. A non-canonical role of centrosomes that has gained traction in recent years is the ability to act as signal transduction centers. Centrosome amplification, which includes numerical and structural aberrations of centrosomes, is a candidate hallmark of cancer.

Single-Cell Proteomic and Transcriptomic Characterization of Drug-Resistant Prostate Cancer Cells Reveals Molecular Signatures Associated with Morphological Changes.

This study delves into the proteomic intricacies of drug-resistant cells (DRCs) within prostate cancer, which are known for their pivotal roles in therapeutic resistance, relapse, and metastasis. Utilizing single-cell proteomics (SCP) with an optimized high-throughput Data Independent Acquisition (DIA) approach with the throughput of 60 sample per day, we characterized the proteomic landscape of DRCs in comparison to parental PC3 cells. This optimized DIA method allowed for robust and reproducible protein quantification at the single-cell level, enabling the identification and quantification of over 1,300 proteins per cell on average.

Polyploid cancer cells reveal signatures of chemotherapy resistance.

Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of CTC-IGC was significantly associated with poorer progression-free survival.

Polyploid cancer cells reveal signatures of chemotherapy resistance.

Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival.

Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic.

There remains a large need for a greater understanding of the metastatic process within the prostate cancer field. Our research aims to understand the adaptive - ergo potentially metastatic - responses of cancer to changing microenvironments. Emerging evidence has implicated a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency.

Oncogenic signaling in the adult prostate-like accessory gland leads to activation of a conserved pro-tumorigenic program, in the absence of proliferation.

models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the proliferating tissues of the larval stages of development, when tissues are highly mitotically active, or stem cells are abundant. Fewer tumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic.

Urinary extracellular vesicle-derived miR-126-3p predicts lymph node invasion in patients with high-risk prostate cancer.

To investigate extracellular vesicles (EVs), biomarkers for predicting lymph node invasion (LNI) in patients with high-risk prostate cancer (HRPCa), plasma, and/or urine samples were prospectively collected from 45 patients with prostate cancer (PCa) and five with benign prostatic hyperplasia (BPH). Small RNA sequencing was performed to identify miRNAs in the EVs. All patients with PCa underwent radical prostatectomy and extended pelvic lymph node dissection.

Multiparameter flow cytometric detection and analysis of rare cells in models of cancer metastasis.

Rapid and reliable circulating tumor cell (CTC) and disseminated tumor cell (DTC) detection are critical for rigorous evaluation of metastasis models. Clinical data show that each step of the metastatic cascade presents increasing barriers to success, limiting the number of successful metastatic cells to fewer than 1 in 1,500,000,000. As such, it is critical for scientists to employ approaches that allow for the evaluation of metastatic competency at each step of the cascade.

Lung adenocarcinomas without driver genes converge to common adaptive strategies through diverse genetic, epigenetic, and niche construction evolutionary pathways.

Somatic evolution selects cancer cell phenotypes that maximize survival and proliferation in dynamic environments. Although cancer cells are molecularly heterogeneous, we hypothesized convergent adaptive strategies to common host selection forces can be inferred from patterns of epigenetic and genetic evolutionary selection in similar tumors. We systematically investigated gene mutations and expression changes in lung adenocarcinomas with no common driver genes (n = 313).

Punctuational evolution is pervasive in distal site metastatic colonization.

The evolution of metastasis represents a lethal stage of cancer progression. Yet, the evolutionary kinetics of metastatic disease remain unresolved. Here, using single cell CRISPR-Cas9 lineage tracing data, we show that in metastatic disease, gradual molecular evolution is punctuated by episodes of rapid evolutionary change associated with lineage divergence.

Urinary extracellular vesicle-derived miR-126-3p predicts lymph node invasion in patients with high-risk prostate cancer.

To investigate extracellular vesicles (EVs) biomarkers for predicting lymph node invasion (LNI) in patients with high-risk prostate cancer (HRPCa), plasma and/or urine samples were prospectively collected from 45 patients with prostate cancer (PCa) and five with benign prostatic hyperplasia (BPH). Small RNA sequencing was performed to identify miRNAs in the EVs. All patients with PCa underwent radical prostatectomy and extended pelvic lymph node dissection.

Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues.

Chemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX and medium.

Cancer cells employ lipid droplets to survive toxic stress.

Background: Lipid reprogramming is a known mechanism to increase the energetic demands of proliferating cancer cells to drive and support tumorigenesis and progression. Elevated lipid droplets (LDs) are a well-known alteration of lipid reprogramming in many cancers, including prostate cancer (PCa), and are associated with high tumor aggressiveness as well as therapy resistance. The mechanism of LD accumulation and specific LD functions are still not well understood; however, it has been shown that LDs can form as a protective mechanism against lipotoxicity and lipid peroxidation in the cell.

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.

Unlabelled: Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling.

The contribution of evolvability to the eco-evolutionary dynamics of competing species.

Evolvability is the capacity of a population to generate heritable variation that can be acted upon by natural selection. This ability influences the adaptations and fitness of individual organisms. By viewing this capacity as a trait, evolvability is subject to natural selection and thus plays a critical role in eco-evolutionary dynamics.

A mathematical investigation of polyaneuploid cancer cell memory and cross-resistance in state-structured cancer populations.

The polyaneuploid cancer cell (PACC) state promotes cancer lethality by contributing to survival in extreme conditions and metastasis. Recent experimental evidence suggests that post-therapy PACC-derived recurrent populations display cross-resistance to classes of therapies with independent mechanisms of action. We hypothesize that this can occur through PACC memory, whereby cancer cells that have undergone a polyaneuploid transition (PAT) reenter the PACC state more quickly or have higher levels of innate resistance.

Targeting MerTK decreases efferocytosis and increases anti-tumor immune infiltrate in prostate cancer.

The prostate cancer tumor microenvironment (TME) is comprised of many cell types that can contribute to and influence tumor progression. Some of the most abundant prostate cancer TME cells are macrophages, which can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages). A function of M2-like macrophages is efferocytosis, the phagocytosis of apoptotic cells.

survival in response to ciprofloxacin antibiotic stress correlates with increased nucleoid length and effective misfolded protein management.

The evolution of antibiotic resistance is a fundamental problem in disease management but is rarely quantified on a single-cell level owing to challenges associated with capturing the spatial and temporal variation across a population. To evaluate cell biological phenotypic responses, we tracked the single-cell dynamics of filamentous bacteria through time in response to ciprofloxacin antibiotic stress. We measured the degree of phenotypic variation in nucleoid length and the accumulation of protein damage under ciprofloxacin antibiotic and quantified the impact on bacterial survival.

Updating the Definition of Cancer.

Most definitions of cancer broadly conform to the current NCI definition: "Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body." These definitions tend to describe what cancer "looks like" or "does" but do not describe what cancer "is" or "has become." While reflecting past insights, current definitions have not kept pace with the understanding that the cancer cell is itself transformed and evolving.

Cells in the polyaneuploid cancer cell (PACC) state have increased metastatic potential.

Although metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells (~ 1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.

Nuclear morphology predicts cell survival to cisplatin chemotherapy.

The emergence of chemotherapy resistance drives cancer lethality in cancer patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying resistance phenotypes have been explored, less is known about the cell biological characteristics of cancer cells that survive to eventually seed the recurrence. To identify the unique phenotypic characteristics associated with survival upon chemotherapy exposure, we characterized nuclear morphology and function as prostate cancer cells recovered following cisplatin treatment.

Novel urinary tract obstruction marker discovery by multi-marker profiling of urinary extracellular vesicles derived from a rat UTO model.

Introduction: Congenital urinary obstruction is a common cause of end-stage renal disease in the pediatric population. However, non-invasive diagnostics to predict which patients will benefit from early intervention are lacking.

Methods: Using a rat model of upper and lower urinary tract partial obstruction and the Nanostring nCounter Fibrosis V2 Panel, we evaluated the mRNA cargo of urinary small extracellular vesicles (sEVs) and mRNA expression patterns of kidney and bladder tissues from rats with lower tract urinary obstruction and upper tract urinary obstruction.