Biology subjects

Karthaus, W. R.

Publications and source records attributed to Karthaus, W. R..

7 recordsLinked to original sources

bioRxiv2025

TRIM24 Degradation Counteracts Adaptation to Androgen Receptor Inhibition in Prostate Cancer

The androgen receptor (AR) is the primary therapeutic target in prostate cancer. While androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSi) are effective, the disease eventually progresses to fatal castration-resistant prostate cancer (CRPC). That said, little is known about the mechanisms in residual disease that initiates tumor relapse upon ADT/ARSi. Here, we discover a crucial role for TRIM24 in supporting the survival of residual cell clusters primed for tumor relapse in vivo. Consequently, reducing TRIM24 with bifunctional degraders (dTRIM24) significantly delays or even prevents the emergence of CRPC in the context of AR reactivation and lineage plasticity. dTRIM24 not only inhibits AR signaling but also counteracts adaptive pathways engaged by AR inhibition itself, such as STAT3 activation and EMT. Our findings underscore the potential of TRIM24 as an effective and druggable target for preventing prostate cancer progression under AR inhibition. SignificanceDespite advances in targeting AR signaling in prostate cancer, tumor relapse remains a major concern. Here, we provide evidence that more durable responses can be achieved by pharmacologically degrading TRIM24. At the molecular level, TRIM24 degradation inhibits both AR signaling and adaptive pathways that enable tumor relapse.

cancer biology↗

bioRxiv2025

Stochastically Emergent Tumors offer in vivo whole genome interrogation of cancer evolution from non-malignant precursors

Interrogating the stochastic events underlying tumor evolution from non-malignant precursors is crucial for understanding therapy resistance. Current methods are complicated by chromosomal instability, obscuring driver identification and yielding non-representative genetics. Inspired by patient tumors that evolve without chromosomal instability, we developed Stochastically Emergent Tumors (SETs) by inducing mismatch repair deficiency in non-malignant precursors, then engrafting in mice. Barcoded SETs exhibited increased tumoral and drug target heterogeneity over current models. SETs delineated the stochastic contributions, mutational landscapes, and selective pressures distinguishing tumorigenesis from non-malignant precursor in vitro growth. SETs are an unlimited source for diverse Stochastically Emergent cell Lines (SELs), bolstering under-represented cancers. Since SETs composition dynamically reflects therapy exposure, they are a whole-genome platform for precision oncology. We identified three novel genetic drivers (ZFHX3, CIC, KMT2D) of differential prostate cancer therapy responses. These alterations are enriched in patients of African and Chinese ancestry and correlate with significant differences in survival.

cancer biology↗

bioRxiv2024

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types. SIGNIFICANCE STATEMENTTreatment of prostate cancer is rapidly evolving with several promising new drugs targeting different cell surface antigens. Selection of patients most likely to benefit from these therapies requires an understanding of how expression of these cell surface antigens varies across patients and how they change during disease progression, particularly in tumors that undergo lineage plasticity. Using immunohistochemistry and single cell mRNA sequencing, we reveal heterogeneity of cell states across a cohort of advanced disease prostate cancer patients; this heterogeneity is not captured by conventional histology-based designations of adenocarcinoma and neuroendocrine prostate cancer. We show these cell states can be identified by gene regulatory networks that could provide additional diagnostic precision based on their correlation with clinically relevant cell surface antigen expression.

cancer biology↗

bioRxiv2024

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1

Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and interrogate the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e.g., Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+), but only those with Rb1 deletion progress to ASCL1+ neuroendocrine prostate cancer (NEPC), a highly aggressive, androgen receptor signaling inhibitor (ARSI)-resistant tumor. Importantly, we show this lineage transition requires a native in vivo microenvironment not replicated by conventional organoid culture. By integrating multiplexed immunofluorescence, spatial transcriptomics and PrismSpot to identify cell type-specific spatial gene modules, we reveal that ASCL1+ cells arise from KRT8+ luminal epithelial cells that progressively acquire transcriptional heterogeneity, producing large ASCL1+;KRT8- NEPC clusters. Ascl1 loss in established NEPC results in transient tumor regression followed by recurrence; however, Ascl1 deletion prior to transplantation completely abrogates lineage plasticity, yielding adenocarcinomas with elevated AR expression and marked sensitivity to castration. The dynamic feature of this model reveals the importance of timing of therapies focused on lineage plasticity and offers a platform for identification of additional lineage plasticity drivers.

cell biology↗

bioRxiv2021

Multilineage plasticity in prostate cancer through expansion of stem-like luminal epithelial cells with elevated inflammatory signaling

Lineage plasticity is a well-established mechanism of resistance to targeted therapies in lung and prostate cancer, where tumors transition from adenocarcinoma to small-cell or neuroendocrine carcinoma. Through single-cell analysis of a cohort of heavily-treated castration-resistant human prostate cancers (CRPC), we report a greater degree of plasticity than previously appreciated, with multiple distinct neuroendocrine (NEPC), mesenchymal (EMT-like), and other subpopulations detected within single biopsies. To explore the steps leading to this plasticity, we turned to two genetically engineered mouse models of prostate cancer that recapitulate progression from adenocarcinoma to neuroendocrine disease. Time course studies reveal expansion of stem-like luminal epithelial cells (Sca1+, Psca+, called L2) that, based on trajectories, gave rise to at least 4 distinct subpopulations, NEPC (Ascl1+), POU2F3 (Pou2f3+), TFF3 (Tff3+) and EMT-like (Vim+, Ncam1+)--these populations are also seen in human prostate and small cell lung cancers. Transformed L2-like cells express stem-like and gastrointestinal endoderm-like transcriptional programs, indicative of reemerging developmental plasticity programs, as well as elevated Jak/Stat and interferon pathway signaling. In sum, while the magnitude of multilineage heterogeneity, both within and across patients, raises considerable treatment challenges, the identification of highly plastic luminal cells as the likely source of this heterogeneity provides a target for more focused therapeutic intervention. One Sentence SummaryMultilineage plasticity results from expansion of stem-like luminal cells with JAK/STAT activation, serving as a therapeutic target.

cancer biology↗

bioRxiv2019

A rectal cancer model establishes a platform to study individual responses to chemoradiation

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation, and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to individual patients. We established a biorepository of 32 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic, or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlate well with responses noted in individual patients tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive rectal cancer followed by metastasis to lung and liver. Importantly, engrafted tumors closely reflected the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, in vitro platform coupled with endoluminal propagation in animals.

cancer biology↗

bioRxiv2019

Tumor mutational landscape is a record of the pre-malignant state

Chromatin structure has a major influence on the cell-specific density of somatic mutations along the cancer genome. Here, we present a pan-cancer study in which we searched for the putative cancer cell-of-origin of 2,550 whole genomes, representing 32 cancer types by matching their mutational landscape to the regional patterns of chromatin modifications ascertained in 104 normal tissue types. We found that, in almost all cancer types, the cell-of-origin can be predicted solely from their DNA sequences. Our analysis validated the hypothesis that high-grade serous ovarian cancer originates in the fallopian tube and identified distinct origins of breast cancer subtypes. We also demonstrated that the technique is equally capable of identifying the cell-of-origin for a series of 2,044 metastatic samples from 22 of the tumor types available as primaries. Moreover, cancer drivers, whether inherited or acquired, reside in active chromatin regions in the respective cell-of-origin. Taken together, our findings highlight that many somatic mutations accumulate while the chromatin structure of the cell-of-origin is maintained and that this historical record, captured in the DNA, can be used to identify the often elusive cancer cell-of-origin.

genomics↗